WO2003010327A2

WO2003010327A2 - Novel proteins and nucleic acids encoding same

Info

Publication number: WO2003010327A2
Application number: PCT/US2002/014199
Authority: WO
Inventors: Charles E. Miller; Ramesh Kekuda; Uriel M. Malyankar; Li Li; Carol E. A. Pena; Kimberly A. Spytek; Linda Gorman; Xiaojia Guo; Elma R. Fernandes; Glennda Smithson; David J. Stone; Bryan D. Zerhusen; Meera Patturajan; David W. Anderson; Peter S. Mezes; John A. Peyman; John R. Macdougall; Muralidhara Padigaru; Luca Rastelli; Suresh G. Shenoy
Original assignee: Curagen Corporation
Priority date: 2001-02-21
Filing date: 2002-05-02
Publication date: 2003-02-06
Also published as: WO2003010327A3

Abstract

The present invention provides novel isolated polynucleotides and small molecule target polypeptides encoded by the polynucleotides. Antibodies that immunospecifically bind to a novel small molecule target polypeptide or any derivative, variant, mutant or fragment of that polypeptide, polynucleotide or antibody are disclosed, as are methods in which the small molecule target polypeptide, polynucleotide and antibody are utilized in the detection and treatment ofa broad range of pathological states. More specifically, the present invention discloses methods of using recombinantly expressed and/or endogenously expressed proteins in various screening procedures for the purpose of identifying therapeutic antibodies and therapeutic small molecules associated with diseases.

Description

Novel Proteins and Nucleic Acids Encoding Same

FIELD OF THE INVENTION

The present invention relates to novel polypeptides that are targets of small molecule drugs and that have properties related to stimulation of biochemical or physiological responses in a cell, a tissue, an organ or an organism. More particularly, the novel polypeptides are gene products of novel genes, or are specified biologically active fragments or derivatives thereof. Methods of use encompass diagnostic and prognostic assay procedures as well as methods of treating diverse pathological conditions.

BACKGROUND

Eukaryotic cells are characterized by biochemical and physiological processes which under normal conditions are exquisitely balanced to achieve the preservation and propagation of the cells. When such cells are components of multicellular organisms such as vertebrates, or more particularly organisms such as mammals, the regulation of the biochemical and physiological processes involves intricate signaling pathways. Frequently, such signaling pathways are constituted of extracellular signaling proteins, cellular receptors that bind the signaling proteins and signal transducing components located within the cells. Signaling proteins may be classified as endocrine effectors, paracrine effectors or autocrine effectors. Endocrine effectors are signaling molecules secreted by a given organ into the circulatory system, which are then transported to a distant target organ or tissue. The target cells include the receptors for the endocrine effector, and when the endocrine effector binds, a signaling cascade is induced. Paracrine effectors involve secreting cells and receptor cells in close proximity to each other, for example two different classes of cells in the same tissue or organ. One class of cells secretes the paracrine effector, which then reaches the second class of cells, for example by diffusion through the extracellular fluid. The second class of cells contains the receptors for the paracrine effector; binding of the effector results in induction of the signaling cascade that elicits the corresponding biochemical or physiological effect. Autocrine effectors are highly analogous to paracrine effectors, except that the same cell type that secretes the autocrine effector also contains the receptor. Thus the autocrine effector binds to receptors on the same cell, or on identical neighboring cells. The binding process then elicits the characteristic biochemical or physiological effect. Signaling processes may elicit a variety of effects on cells and tissues including by way of nonlimiting example induction of cell or tissue proliferation, suppression of growth or proliferation, induction of differentiation or maturation ofa cell or tissue, and suppression of differentiation or maturation of a cell or tissue.

Many pathological conditions involve dysregulation of expression of important effector proteins. In certain classes of pathologies the dysregulation is manifested as diminished or suppressed level of synthesis and secretion protein effectors. In a clinical setting a subject may be suspected of suffering from a condition brought on by diminished or suppressed levels of a protein effector of interest. Therefore there is a need to be able to assay for the level of the protein effector of interest in a biological sample from such a subject, and to compare the level with that characteristic of a nonpathological condition. There further is a need to provide the protein effector as a product of manufacture. Administration of the effector to a subject in need thereof is useful in treatment of the pathological condition, or the protein effector deficiency or suppression may be favorably acted upon by the administration of another small molecule drug product. Accordingly, there is a need for a method of treatment of a pathological condition brought on by a diminished or suppressed levels of the protein effector of interest.

Small molecule targets have been implicated in various disease states or pathologies. These targets may be proteins, and particularly enzymatic proteins, which are acted upon by small molecule drugs for the purpose of altering target function and achieving a desired result. Cellular, animal and clinical studies can be performed to elucidate the genetic contribution to the etiology and pathogenesis of conditions in which small molecule targets are implicated in a variety of physiologic, pharmacologic or native states. These studies utilize the core technologies at CuraGen Corporation to look at differential gene expression, protein-protein interactions, large-scale sequencing of expressed genes and the association of genetic variations such as, but not limited to, single nucleotide polymorphisms (SNPs) or splice variants in and between biological samples from experimental and control groups. The goal of such studies is to identify potential avenues for therapeutic intervention in order to prevent, treat the consequences or cure the conditions.

In order to treat diseases, pathologies and other abnormal states or conditions in which a mammalian organism has been diagnosed as being, or as being at risk for becoming, other than in a normal state or condition, it is important to identify new therapeutic agents. Such a procedure includes at least the steps of identifying a target component within an affected tissue or organ, and identifying a candidate therapeutic agent that modulates the functional attributes of the target. The target component may be any biological macromolecule implicated in the disease or pathology. Commonly the target is a polypeptide or protein with specific functional attributes. Other classes of macromolecule may be a nucleic acid, a polysaccharide, a lipid such as a complex lipid or a glycolipid; in addition a target may be a sub-cellular structure or extra-cellular structure that is comprised of more than one of these classes of macromolecule. Once such a target has been identified, it may be employed in a screening assay in order to identify favorable candidate therapeutic agents from among a large population of substances or compounds. In many cases the objective of such screening assays is to identify small molecule candidates; this is commonly approached by the use of combinatorial methodologies to develop the population of substances to be tested. The implementation of high throughput screening methodologies is advantageous when working with large, combinatorial libraries of compounds.

SUMMARY OF THE INVENTION

The invention is based in part upon the discovery of nucleic acid sequences encoding novel polypeptides. These nucleic acids and polypeptides, as well as derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as "NOVX" nucleic acid, which represents the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or polypeptide sequences, which represents the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101.

In one aspect, the invention provides an isolated polypeptide comprising a mature form of a NONX amino acid. One example is a variant ofa mature form of a ΝOVX amino acid sequence, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed. The amino acid can be, for example, a ΝOVX amino acid sequence or a variant of a ΝONX amino acid sequence, wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed. The invention also includes fragments of any of these. In another aspect, the invention also includes an isolated nucleic acid that encodes a ΝOVX polypeptide, or a fragment, homolog, analog or derivative thereof.

Also included in the invention is a ΝOVX polypeptide that is a naturally occurring allelic variant of a ΝOVX sequence. In ohe embodiment, the allelic variant includes an amino acid sequence that is the translation ofa nucleic acid sequence differing by a single nucleotide from a NOVX nucleic acid sequence. In another embodiment, the NOVX polypeptide is a variant polypeptide described therein, wherein any amino acid specified in the chosen sequence is changed to provide a conservative substitution. In one embodiment, the invention discloses a method for determining the presence or amount of the NOVX polypeptide in a sample. The method involves the steps of: providing a sample; introducing the sample to an antibody that binds immunospecifically to the polypeptide; and determining the presence or amount of antibody bound to the NOVX polypeptide, thereby determining the presence or amount of the NOVX polypeptide in the sample. In another embodiment, the invention provides a method for determining the presence of or predisposition to a disease associated with altered levels of a NOVX polypeptide in a mammalian subject. This method involves the steps of: measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and comparing the amount of the polypeptide in the sample of the first step to the amount of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, the disease, wherein an alteration in the expression level of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

In a further embodiment, the invention includes a method of identifying an agent that binds to a NOVX polypeptide. This method involves the steps of: introducing the polypeptide to the agent; and determining whether the agent binds to the polypeptide. In various embodiments, the agent is a cellular receptor or a downstream effector.

In another aspect, the invention provides a method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of a NOVX polypeptide. The method involves the steps of: providing a cell expressing the NOVX polypeptide and having a property or function ascribable to the polypeptide; contacting the cell with a composition comprising a candidate substance; and determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition devoid of the substance, the substance is identified as a potential therapeutic agent. In another aspect, the invention describes a method for screening for a modulator of activity or of latency or predisposition to a pathology associated with the NOVX polypeptide. This method involves the following steps: administering a test compound to a test animal at increased risk for a pathology associated with the NOVX polypeptide, wherein the test animal recombinantly expresses the NOVX polypeptide. This method involves the steps of measuring the activity of the NOVX polypeptide in the test animal after administering the compound of step; and comparing the activity of the protein in the test animal with the activity of the NOVX polypeptide in a control animal not administered the polypeptide, wherein a change in the activity of the NOVX polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency of, or predisposition to, a pathology associated with the NOVX polypeptide. In one embodiment, the test animal is a recombinant test animal that expresses a test protein transgene or expresses the transgene under the control of a promoter at an increased level relative to a wild-type test animal, and wherein the promoter is not the native gene promoter of the transgene. In another aspect, the invention includes a method for modulating the activity of the NOVX polypeptide, the method comprising introducing a cell sample expressing the NOVX polypeptide with a compound that binds to the polypeptide in an amount sufficient to modulate the activity of the polypeptide.

The invention also includes an isolated nucleic acid that encodes a NOVX polypeptide, or a fragment, homolog, analog or derivative thereof. In a preferred embodiment, the nucleic acid molecule comprises the nucleotide sequence of a naturally occurring allelic nucleic acid variant. In another embodiment, the nucleic acid encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant. In another embodiment, the nucleic acid molecule differs by a single nucleotide from a NOVX nucleic acid sequence. In one embodiment, the NOVX nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or a complement of the nucleotide sequence. In another aspect, the invention provides a vector or a cell expressing a NOVX nucleotide sequence.

In one embodiment, the invention discloses a method for modulating the activity of a NOVX polypeptide. The method includes the steps of: introducing a cell sample expressing the NOVX polypeptide with a compound that binds to the polypeptide in an amount sufficient to modulate the activity of the polypeptide. In another embodiment, the invention includes an isolated NOVX nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising a NOVX amino acid sequence or a variant of a mature form of the NOVX amino acid sequence, wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed. In another embodiment, the invention includes an amino acid sequence that is a variant of the NOVX amino acid sequence, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed.

In one embodiment, the invention discloses a NOVX nucleic acid fragment encoding at least a portion of a NOVX polypeptide or any variant of the polypeptide, wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed. In another embodiment, the invention includes the complement of any of the NOVX nucleic acid molecules or a naturally occurring allelic nucleic acid variant. In another embodiment, the invention discloses a NOVX nucleic acid molecule that encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence ofa naturally occurring polypeptide variant. In another embodiment, the invention discloses a NOVX nucleic acid, wherein the nucleic acid molecule differs by a single nucleotide from a NOVX nucleic acid sequence. In another aspect, the invention includes a NOVX nucleic acid, wherein one or more nucleotides in the NOVX nucleotide sequence is changed to a different nucleotide provided that no more than 15% of the nucleotides are so changed. In one embodiment, the invention discloses a nucleic acid fragment of the NOVX nucleotide sequence and a nucleic acid fragment wherein one or more nucleotides in the NOVX nucleotide sequence is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed. In another embodiment, the invention includes a nucleic acid molecule wherein the nucleic acid molecule hybridizes under stringent conditions to a NOVX nucleotide sequence or a complement of the NOVX nucleotide sequence. In one embodiment, the invention includes a nucleic acid molecule, wherein the sequence is changed such that no more than 15% of the nucleotides in the coding sequence differ from the NOVX nucleotide sequence or a fragment thereof. In a further aspect, the invention includes a method for determining the presence or amount of the NOVX nucleic acid in a sample. The method involves the steps of: providing the sample; introducing the sample to a probe that binds to the nucleic acid molecule; and determining the presence or amount of the probe bound to the NOVX nucleic acid molecule, thereby determining the presence or amount of the NOVX nucleic acid molecule in the sample. In one embodiment, the presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type.

In another aspect, the invention discloses a method for determining the presence of or predisposition to a disease associated with altered levels of the NOVX nucleic acid molecule of in a first mammalian subject. The method involves the steps of: measuring the amount of NOVX nucleic acid in a sample from the first mammalian subject; and comparing the amount of the nucleic acid in the sample of step (a) to the amount of NOVX nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel nucleotides and polypeptides encoded thereby. Included in the invention are the novel nucleic acid sequences, their encoded polypeptides, antibodies, and other related compounds. The sequences are collectively referred to herein as "NOVX nucleic acids" or "NOVX polynucleotides" and the corresponding encoded polypeptides are referred to as "NOVX polypeptides" or "NOVX proteins." Unless indicated otherwise, "NOVX" is meant to refer to any of the novel sequences disclosed herein. Table 1 provides a summary of the NOVX nucleic acids and their encoded polypeptides.

TABLE 1. Sequences and Corresponding SEQ ID Numbers

Table 1 indicates homology of NOVX nucleic acids to known protein families. Thus, the nucleic acids and polypeptides, antibodies and related compounds according to the invention corresponding to a NOVX as identified in column 1 of Table 1 will be useful in therapeutic and diagnostic applications implicated in, for example, pathologies and disorders associated with the known protein families identified in column 5 of Table 1.

NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.

Consistent with other known members of the family of proteins, identified in column 5 of Table 1, the NOVX polypeptides of the present invention show homology to, and contain domains that are characteristic of, other members of such protein families. Details of the sequence relatedness and domain analysis for each NOVX are presented in Example A.

The NOVX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVX activity or function. Specifically, the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit diseases associated with the protein families listed in Table 1.

The NOVX nucleic acids and polypeptides are also useful for detecting specific cell types. Details of the expression analysis for each NOVX are presented in Example C. Accordingly, the NOVX nucleic acids, polypeptides, antibodies and related compounds according to the invention will have diagnostic and therapeutic applications in the detection ofa variety of diseases with differential expression in normal vs. diseased tissues, e.g. a variety of cancers.

Additional utilities for NOVX nucleic acids and polypeptides according to the invention are disclosed herein.

The present invention is based on the identification of biological macromolecules differentially modulated in a pathologic state, disease, or an abnormal condition or state. Among the pathologies or diseases of present interest include metabolic diseases including those related to endocrinologic disorders, cancers, various tumors and neoplasias, _ inflammatory disorders, central nervous system disorders, and similar abnormal conditions or states. In very significant embodiments of the present invention, the biological macromolecules implicated in the pathologies and conditions are proteins and polypeptides, and in such cases the present invention is related as well to the nucleic acids that encode them. Methods that may be employed to identify relevant biological macromolecules include any procedures that detect differential expression of nucleic acids encoding proteins and polypeptides associated with the disorder, as well as procedures that detect the respective proteins and polypeptides themselves. Significant methods that have been employed by the present inventors, include GeneCalling ® technology and SeqCalling TM technology, disclosed respectively, in U. S. Patent No. 5,871,697, and in U. S. Ser. No. 09/417,386, filed Oct. 13, 1999, each of which is incorporated herein by reference in its entirety. GeneCalling ® is also described in Shimkets, et al., "Gene expression analysis by transcript profiling coupled to a gene database query" Nature Biotechnology 17:198-803 (1999).

The invention provides polypeptides and nucleotides encoded thereby that have been identified as having novel associations with a disease or pathology, or an abnormal state or condition, in a mammal. The present invention further identifies a set of proteins and polypeptides, including naturally occurring polypeptides, precursor forms or proproteins, or mature forms of the polypeptides or proteins, which are implicated as targets for therapeutic agents in the treatment of various diseases, pathologies, abnormal states and conditions. A target may be employed in any ofa variety of screening methodologies in order to identify candidate therapeutic agents which interact with the target and in so doing exert a desired or favorable effect. The candidate therapeutic agent is identified by screening a large collection of substances or compounds in an important embodiment of the invention. Such a collection may comprise a combinatorial library of substances or compounds in which, in at least one subset of substances or compounds, the individual members are related to each other by simple structural variations based on a particular canonical or basic chemical structure. The variations may include, by way of nonlimiting example, changes in length or identity of a basic framework of bonded atoms; changes in number, composition and disposition of ringed structures, bridge structures, alicyclic rings, and aromatic rings; and changes in pendent or substituents atoms or groups that are bonded at particular positions to the basic framework of bonded atoms or to the ringed structures, the bridge structures, the alicyclic structures, or the aromatic structures. A polypeptide or protein described herein, and that serves as a target in the screening procedure, includes the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, e.g., the full-length gene product, encoded by the corresponding gene. The naturally occurring polypeptide also includes the polypeptide, precursor or proprotein encoded by an open reading frame described herein. A "mature" form of a polypeptide or protein arises as a result of one or more naturally occurring processing steps as they may occur within the cell, including a host cell. The processing steps occur as the gene product arises, e.g., via cleavage of the amino-terminal methionine residue encoded by the initiation codon of an open reading frame, or the proteolytic cleavage ofa signal peptide or leader sequence. Thus, a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N remaining. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an amino-terminal signal sequence from residue 1 to residue M is cleaved, includes the residues from residue M+l to residue N remaining. A "mature" form of a polypeptide or protein may also arise from non- proteolytic post-translational modification. Such non-proteolytic processes include, e.g., glycosylation, myristylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or the combination of any of them.

As used herein, "identical" residues correspond to those residues in a comparison between two sequences where the equivalent nucleotide base or amino acid residue in an alignment of two sequences is the same residue. Residues are alternatively described as "similar" or "positive" when the comparisons between two sequences in an alignment show that residues in an equivalent position in a comparison are either the same amino acid or a conserved amino acid as defined below. As used herein, a "chemical composition" relates to a composition including at least one compound that is either synthesized or extracted from a natural source. A chemical compound may be the product of a defined synthetic procedure. Such a synthesized compound is understood herein to have defined properties in terms of molecular formula, molecular structure relating the association of bonded atoms to each other, physical properties such as chromatographic or spectroscopic characterizations, and the like. A compound extracted from a natural source is advantageously analyzed by chemical and physical methods in order to provide a representation of its defined properties, including its molecular formula, molecular structure relating the association of bonded atoms to each other, physical properties such as chromatographic or spectroscopic characterizations, and the like.

As used herein, a "candidate therapeutic agent" is a chemical compound that includes at least one substance shown to bind to a target biopolymer. In important embodiments of the invention, the target biopolymer is a protein or polypeptide, a nucleic acid, a polysaccharide or proteoglycan, or a lipid such as a complex lipid. The method of identifying compounds that bind to the target effectively eliminates compounds with little or no binding affinity, thereby increasing the potential that the identified chemical compound may have beneficial therapeutic applications. In cases where the "candidate therapeutic agent" is a mixture of more than one chemical compound, subsequent screening procedures may be carried out to identify the particular substance in the mixture that is the binding compound, and that is to be identified as a candidate therapeutic agent. As used herein, a "pharmaceutical agent" is provided by screening a candidate therapeutic agent using models for a disease state or pathology in order to identify a candidate exerting a desired or beneficial therapeutic effect with relation to the disease or pathology. Such a candidate that successfully provides such an effect is termed a pharmaceutical agent herein. Nonlimiting examples of model systems that may be used in such screens include particular cell lines, cultured cells, tissue preparations, whole tissues, organ preparations, intact organs, and nonhuman mammals. Screens employing at least one system, and preferably more than one system, may be employed in order to identify a pharmaceutical agent. Any pharmaceutical agent so identified may be pursued in further investigation using human subjects.

NOVX Nucleic Acids and Polypeptides NOVX clones

The NOVX genes and their corresponding encoded proteins are useful for preventing, treating or ameliorating medical conditions, e.g., by protein or gene therapy. Pathological conditions can be diagnosed by determining the amount of the new protein in a sample or by determining the presence of mutations in the new genes. Specific uses are described for each of the NOVX genes, based on the tissues in which they are most highly expressed. Uses include developing products for the diagnosis or treatment of a variety of diseases and disorders.

The NOVX nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.

In one specific embodiment, the invention includes an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101 ; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 101 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; and (e) a fragment of any of (a) through (d).

In another specific embodiment, the invention includes an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence given SEQ ID NO: 2n, wherein n is an integer between 1 and 101; (b) a variant ofa mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101 wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101 or any variant of said polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and (f) the complement of any of said nucleic acid molecules.

In yet another specific embodiment, the invention includes an isolated nucleic acid molecule, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101; (b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; (c) a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101; and (d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed.

One aspect of the invention pertains to isolated nucleic acid molecules that encode NOVX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify NOVX-encoding nucleic acids (e.g., NOVX mRNAs) and fragments for use as PCR primers for the amplification and/or mutation of NOVX nucleic acid molecules. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNA generated using nucleotide analogs, and derivatives, fragments and homologs thereof. The nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double-stranded DNA. An NOVX nucleic acid can encode a mature NOVX polypeptide. As used herein, a "mature" form ofa polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product, encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. The product "mature" form arises, again by way of nonlimiting example, as a result of one or more naturally occurring processing steps as they may take place within the cell, or host cell, in which the gene product arises. Examples of such processing steps leading to a "mature" form of a polypeptide or protein include the cleavage of the N-terminal methionine residue encoded by the initiation codon of an ORF, or the proteolytic cleavage ofa signal peptide or leader sequence. Thus a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N remaining after removal of the N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N-terminal signal sequence from residue 1 to residue M is cleaved, would have the residues from residue M+l to residue N remaining. Further as used herein, a "mature" form of a polypeptide or protein may arise from a step of post-translational modification other than a proteolytic cleavage event. Such additional processes include, by way of non-limiting example, glycosylation, myristoylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or a combination of any of them.

The term "probes", as utilized herein, refers to nucleic acid sequences of variable length, preferably between at least about 10 nucleotides (nt), 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences. Longer length probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single- or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies.

The term "isolated" nucleic acid molecule, as utilized herein, is one, which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5'- and 3'-termini of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated NOVX nucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material or culture medium when produced by recombinant techniques, or of chemical precursors or other chemicals when chemically synthesized. A nucleic acid molecule of the invention, e.g. , a nucleic acid molecule having the nucleotide sequence SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or a complement of this aforementioned nucleotide sequence, can be isolated using standard molecular biology techniques and the sequence information provided herein. Using all or a portion of the nucleic acid sequence of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101 as a hybridization probe, NOVX molecules can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, et al., (eds.), MOLECULAR CLONING: A LABORATORY MANUAL 2^nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989; and Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993.) A nucleic acid of the invention can be amplified using cDNA, mRNA or alternatively, genomic DNA, as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to NOVX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer. As used herein, the term "oligonucleotide" refers to a series of linked nucleotide residues, which oligonucleotide has a sufficient number of nucleotide bases to be used in a PCR reaction. A short oligonucleotide sequence may be based on, or designed from, a genomic or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides comprise portions of a nucleic acid sequence having about 10 nt, 50 nt, or 100 nt in length, preferably about 15 nt to 30 nt in length. In one embodiment of the invention, an oligonucleotide comprising a nucleic acid molecule less than 100 nt in length would further comprise at least 6 contiguous nucleotides SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or a complement thereof. Oligonucleotides may be chemically synthesized and may also be used as probes. In another embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule that is a complement of the nucleotide from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer or a fragment encoding a biologically-active portion of an NOVX polypeptide). A nucleic acid molecule that is complementary to the nucleotide sequence from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101 is one that is sufficiently complementary to the nucleotide sequence from the group consisting of SEQ ID NO: 2n- 1, wherein n is an integer between 1 and 101 that it can hydrogen bond with little or no mismatches to the nucleotide sequence from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, thereby forming a stable duplex.

As used herein, the term "complementary" refers to Watson-Crick or Hoogsteen base pairing between nucleotides units ofa nucleic acid molecule, and the term "binding" means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction can be either direct or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates. Fragments provided herein are defined as sequences of at least 6 (contiguous) nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, respectively, and are at most some portion less than a full length sequence. Fragments may be derived from any contiguous portion of a nucleic acid or amino acid sequence of choice. Derivatives are nucleic acid sequences or amino acid sequences formed from the native compounds either directly or by modification or partial substitution. Analogs are nucleic acid sequences or amino acid sequences that have a structure similar to, but not identical to, the native compound but differs from it in respect to certain components or side chains. Analogs may be synthetic or from a different evolutionary origin and may have a similar or opposite metabolic activity compared to wild type. Homologs are nucleic acid sequences or amino acid sequences of a particular gene that are derived from different species.

A full-length NOVX clone is identified as containing an ATG translation start codon and an in-frame stop codon. Any disclosed NOVX nucleotide sequence lacking an ATG start codon therefore encodes a truncated C-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 5' direction of the disclosed sequence. Any disclosed NOVX nucleotide sequence lacking an in-frame stop codon similarly encodes a truncated N-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 3' direction of the disclosed sequence.

Derivatives and analogs may be full length or other than full length, if the derivative or analog contains a modified nucleic acid or amino acid, as described below. Derivatives or analogs of the nucleic acids or proteins of the invention include, but are not limited to, molecules comprising regions that are substantially homologous to the nucleic acids or proteins of the invention, in various embodiments, by at least about 70%, 80%, or 95% identity (with a preferred identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to the complement ofa sequence encoding the aforementioned proteins under stringent, moderately stringent, or low stringent conditions. See e.g. Ausubel, et al, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993, and below.

A "homologous nucleic acid sequence" or "homologous amino acid sequence," or variations thereof, refer to sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences encode those sequences coding for isoforms of NOVX polypeptides. Isoforms can be expressed in different tissues of the same organism as a result of, for example, alternative splicing of RNA. Alternatively, isoforms can be encoded by different genes. In the invention, homologous nucleotide sequences include nucleotide sequences encoding for an NOVX polypeptide of species other than humans, including, but not limited to: vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and other organisms. Homologous nucleotide sequences also include, but are not limited to, naturally occurring allelic variations and mutations of the nucleotide sequences set forth herein. A homologous nucleotide sequence does not, however, include the exact nucleotide sequence encoding human NOVX protein. Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, as well as a polypeptide possessing NOVX biological activity. Various biological activities of the NOVX proteins are described below.

An NOVX polypeptide is encoded by the open reading frame ('ORF") of an NOVX nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be translated into a polypeptide. A stretch of nucleic acids comprising an ORF is uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG "start" codon and terminates with one of the three "stop" codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For an ORF to be considered as a good candidate for coding for a bonafide cellular protein, a minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more.

The nucleotide sequences determined from the cloning of the human NOVX genes allows for the generation of probes and primers designed for use in identifying and/or cloning NOVX homologues in other cell types, e.g. from other tissues, as well as NOVX homologues from other vertebrates. The probe/primer typically comprises substantially purified oligonucleotide. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutive sense strand nucleotide sequence SEQ ID NO: 2n- 1, wherein n is an integer between 1 and 101; or an anti-sense strand nucleotide sequence of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101.

Probes based on the human NOVX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various embodiments, the probe further comprises a label group attached thereto, e.g. the label group can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis-express an NOVX protein, such as by measuring a level of an NOVX-encoding nucleic acid in a sample of cells from a subject e.g., detecting NOVX mRNA levels or determining whether a genomic NOVX gene has been mutated or deleted.

"A polypeptide having a biologically-active portion of an NOVX polypeptide" refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide of the invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a "biologically-active portion of NOVX" can be prepared by isolating a portion SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, that encodes a polypeptide having an NOVX biological activity (the biological activities of the NOVX proteins are described below), expressing the encoded portion of NOVX protein (e.g., by recombinant expression in vitro) and assessing the activity of the encoded portion of NOVX. NOVX Nucleic Acid and Polypeptide Variants

The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences shown in SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101 due to degeneracy of the genetic code and thus encode the same NOVX proteins as that encoded by the nucleotide sequences shown in SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a protein having an amino acid sequence shown in SEQ ID NO: 2n, wherein n is an integer between 1 and 101.

In addition to the human NOVX nucleotide sequences shown in SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of the NOVX polypeptides may exist within a population (e.g., the human population). Such genetic polymorphism in the NOVX genes may exist among individuals within a population due to natural allelic variation. As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame (ORF) encoding an NOVX protein, preferably a vertebrate NOVX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the NOVX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the NOVX polypeptides, which are the result of natural allelic variation and that do not alter the functional activity of the NOVX polypeptides, are intended to be within the scope of the invention.

Moreover, nucleic acid molecules encoding NOVX proteins from other species, and thus that have a nucleotide sequence that differs from the human SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101 are intended to be within the scope of the invention. Nucleic acid molecules corresponding to natural allelic variants and homologues of the NOVX cDNAs of the invention can be isolated based on their homology to the human NOVX nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.

Accordingly, in another embodiment, an isolated nucleic acid molecule of the invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101. In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule of the invention hybridizes to the coding region. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 60% homologous to each other typically remain hybridized to each other.

Homologs (i.e., nucleic acids encoding NOVX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or high stringency hybridization with all or a portion of the particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning.

As used herein, the phrase "stringent hybridization conditions" refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5 °C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% of the probes complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess, at Tm, 50% of the probes are occupied at equilibrium. Typically, stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30°C for short probes, primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about 60°C for longer probes, primers and oligonucleotides. Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide. Stringent conditions are known to those skilled in the art and can be found in

Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, N.Y. (1989). 6.3.1-6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6X SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65°C, followed by one or more washes in 0.2X SSC, 0.01% BSA at 50°C. An isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to the sequences SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, corresponds to a naturally-occurring nucleic acid molecule. As used herein, a

"naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).

In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or fragments, analogs or derivatives thereof, under conditions of moderate stringency is provided. A non-limiting example of moderate stringency hybridization conditions are hybridization in 6X SSC, 5X Denhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55°C, followed by one or more washes in IX SSC, 0.1% SDS at 37°C. Other conditions of moderate stringency that may be used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990; GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY.

In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide, 5X SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/ml denatured salmon sperm DNA, 10% (wt/vol) dextran sulfate at 40°C, followed by one or more washes in 2X SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDS at 50°C Other conditions of low stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN

MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg, 1981. Proc Natl Acad Sci USA 78: 6789-6792.

Conservative Mutations In addition to naturally-occurring allelic variants of NOVX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, thereby leading to changes in the amino acid sequences of the encoded NOVX proteins, without altering the functional ability of said NOVX proteins. For example, nucleotide substitutions leading to amino acid substitutions at

"non-essential" amino acid residues can be made in the sequence SEQ ID NO: 2n, wherein n is an integer between 1 and 101. A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequences of the NOVX proteins without altering their biological activity, whereas an "essential" amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the NOVX proteins of the invention are predicted to be particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well-known within the art.

Another aspect of the invention pertains to nucleic acid molecules encoding NOVX proteins that contain changes in amino acid residues that are not essential for activity. Such NOVX proteins differ in amino acid sequence from SEQ ID NO: 2n-l , wherein n is an integer between 1 and 101 yet retain biological activity. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least about 45% homologous to the amino acid sequences SEQ ID NO: 2n, wherein n is an integer between 1 and 101. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to SEQ ID NO: 2n, wherein n is an integer between 1 and 101; more preferably at least about 70% homologous SEQ ID NO: 2n, wherein n is an integer between 1 and 101; still more preferably at least about 80% homologous to SEQ ID NO: 2n, wherein n is an integer between 1 and 101; even more preferably at least about 90% homologous to SEQ ID NO: 2n, wherein n is an integer between 1 and 101; and most preferably at least about 95% homologous to SEQ ID NO: 2n, wherein n is an integer between 1 and 101.

An isolated nucleic acid molecule encoding an NOVX protein homologous to the protein of SEQ ID NO: 2n, wherein n is an integer between 1 and 101 can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein.

Mutations can be introduced into SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101 standard techniques, such as site-directed mutagenesis and

PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted, non-essential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the NOVX protein is replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of an NOVX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for NOVX biological activity to identify mutants that retain activity. Following mutagenesis SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, the encoded protein can be expressed by any recombinant technology known in the art and the activity of the protein can be determined.

The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved "strong" residues or fully conserved "weak" residues. The "strong" group of conserved amino acid residues may be any one of the following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the "weak" group of conserved residues may be any one of the following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, HFY, wherein the letters within each group represent the single letter amino acid code.

In one embodiment, a mutant NOVX protein can be assayed for ( ) the ability to form protei protein interactions with other NOVX proteins, other cell-surface proteins, or biologically-active portions thereof, (ii) complex formation between a mutant NOVX protein and an NOVX ligand; or (iii) the ability of a mutant NOVX protein to bind to an intracellular target protein or biologically-active portion thereof; (e.g. avidin proteins).

In yet another embodiment, a mutant NOVX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release).

Antisense Nucleic Acids

Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or fragments, analogs or derivatives thereof. An "antisense" nucleic acid comprises a nucleotide sequence that is complementary to a "sense" nucleic acid encoding a protein (e.g., complementary to the coding strand ofa double-stranded cDNA molecule or complementary to an mRNA sequence). In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire NOVX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of an NOVX protein of SEQ ID NO: 2n, wherein n is an integer between 1 and 101, or antisense nucleic acids complementary to an NOVX nucleic acid sequence of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, are additionally provided. In one embodiment, an antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence encoding an NOVX protein. The term "coding region" refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleotide sequence encoding the NOVX protein. The term "noncoding region" refers to 5' and 3' sequences which flank the coding region that are not translated into amino acids (i.e., also referred to as 5' and 3' untranslated regions).

Given the coding strand sequences encoding the NOVX protein disclosed herein, antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of NOVX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of NOVX mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of NOVX mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally-occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids (e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used). Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluraci 1 , 5 -methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding an NOVX protein to thereby inhibit expression of the protein (e.g., by inhibiting transcription and/or translation). The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface (e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens). The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient nucleic acid molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.

In yet another embodiment, the antisense nucleic acid molecule of the invention is an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl. Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (See, e.g., Inoue, et al. 1987. Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (See, e.g., Inoue, et al., 1987. FEBS Lett. 215: 327-330.

Ribozymes and PNA Moieties

Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.

In one embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of ^■ cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in Haselhoff and Gerlach 1988. Nature 334: 585-591) can be used to catalytically cleave NOVX mRNA transcripts to thereby inhibit translation of NOVX mRNA. A ribozyme having specificity for an NOVX-encoding nucleic acid can be designed based upon the nucleotide sequence of an NOVX cDNA disclosed herein (/. e. , SEQ ID NO: 2n-l , wherein n is an integer between 1 and 101). For example, a derivative ofa Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an NOVX-encoding mRNA. See, e.g., U.S. Patent 4,987,071 to Cech, et al. and U.S. Patent 5,116,742 to Cech, et al. NOVX mRNA can also be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., (1993) Science 261 :1411-1418. Alternatively, NOVX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the NOVX nucleic acid (e.g., the NOVX promoter and/or enhancers) to form triple helical structures that prevent transcription of the NOVX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene, et al. 1992. Ann. NY. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15.

In various embodiments, the NOVX nucleic acids can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids. See, e.g., Hyrup, et al., 1996. Bioorg Med Chem 4: 5-23. As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics (e.g., DNA mimics) in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al., 1996. supra; Perry-O'Keefe, et al., 1996. Proc. Natl. Acad. Sci. USA 93: 14670-14675.

PNAs of NOVX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of NOVX can also be used, for example, in the analysis of single base pair mutations in a gene (e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., Si nucleases (See, Hyrup, et al, 1996.supra); or as probes or primers for DNA sequence and hybridization (See, Hyrup, et al., 1996, supra; Perry-O'Keefe, et al, 1996. supra).

In another embodiment, PNAs of NOVX can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA-chimeras of NOVX can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes (e.g., RNase H and DNA polymerases) to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (see, Hyrup, et al., 1996. supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al, 1996. supra and Finn, et al., 1996. Nucl Acids Res 24: 3357-3363. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5' end of DNA. See, e.g., Mag, et al., 1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment. See, e.g., Finn, et al., 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment. See. e.g., Petersen, et al., 1975. Bioorg. Med. Chem. Lett. 5: 1119-11124. In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger, et al, 1989. Proc. Natl. Acad Sci. U.S.A. 86: 6553-6556; Lemaitre, et al., 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g., Krol, et al, 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988. Pharm. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, and the like. NOVX Polypeptides

A polypeptide according to the invention includes a polypeptide including the amino acid sequence of NOVX polypeptides whose sequences are provided in SEQ ID NO: 2n, wherein n is an integer between 1 and 101. The invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residues shown in SEQ ID NO: 2n, wherein n is an integer between 1 and 101 while still encoding a protein that maintains its NOVX activities and physiological functions, or a functional fragment thereof. In general, an NOVX variant that preserves NOVX-like function includes any variant in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues of the parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or deletion is encompassed by the invention. In favorable circumstances, the substitution is a conservative substitution as defined above.

One aspect of the invention pertains to isolated NOVX proteins, and biologically- active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise anti-NOVX antibodies. In one embodiment, native NOVX proteins can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, NOVX proteins are produced by recombinant DNA techniques. Alternative to recombinant expression, an NOVX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques.

An "isolated" or "purified" polypeptide or protein or biologically-active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the NOVX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of NOVX proteins in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly-produced. In one embodiment, the language "substantially free of cellular material" includes preparations of NOVX proteins having less than about 30% (by dry weight) of non-NOVX proteins (also referred to herein as a "contaminating protein"), more preferably less than about 20% of non-NOVX proteins, still more preferably less than about 10% of non-NOVX proteins, and most preferably less than about 5% of non-NOVX proteins. When the NOVX protein or biologically-active portion thereof is recombinantly-produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% of the volume of the NOVX protein preparation. The language "substantially free of chemical precursors or other chemicals" includes preparations of NOVX proteins in which the protein is separated from chemical precursors or other chemicals that are involved in the synthesis of the protein. In one embodiment, the language "substantially free of chemical precursors or other chemicals" includes preparations of NOVX proteins having less than about 30% (by dry weight) of chemical precursors or non-NOVX chemicals, more preferably less than about 20% chemical precursors or non-NOVX chemicals, still more preferably less than about 10% chemical precursors or non-NOVX chemicals, and most preferably less than about 5% chemical precursors or non-NOVX chemicals.

Biologically-active portions of NOVX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences of the NOVX proteins (e.g., the amino acid sequence shown in SEQ ID NO: 2n, wherein n is an integer between 1 and 101) that include fewer amino acids than the full-length NOVX proteins, and exhibit at least one activity of an NOVX protein. Typically, biologically- active portions comprise a domain or motif with at least one activity of the NOVX protein. A biologically-active portion of an NOVX protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acid residues in length.

Moreover, other biologically-active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities ofa native NOVX protein.

In an embodiment, the NOVX protein has an amino acid sequence shown SEQ ID NO: 2n, wherein n is an integer between 1 and 101. In other embodiments, the NOVX protein is substantially homologous to SEQ ID NO: 2n, wherein n is an integer between 1 and 101, and retains the functional activity of the protein of SEQ ID NO: 2n, wherein n is an integer between 1 and 101, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the NOVX protein is a protein that comprises an amino acid sequence at least about 45% homologous to the amino acid sequence SEQ ID NO: 2n, wherein n is an integer between 1 and 101, and retains the functional activity of the NOVX proteins of SEQ ID NO: 2n, wherein n is an integer between 1 and 101.

Determining Homology Between Two or More Sequences To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence ofa first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid "homology" is equivalent to amino acid or nucleic acid "identity"). The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs known in the art, such as GAP software provided in the GCG program package. See, Needleman and Wunsch, 1970. JMol Biol 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP extension penalty of 0.3, the coding region of the analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, with the CDS (encoding) part of the DNA from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101.

The term "sequence identity" refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the case of nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The term "substantial identity" as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison region.

Chimeric and Fusion Proteins The invention also provides NOVX chimeric or fusion proteins. As used herein, an NOVX "chimeric protein" or "fusion protein" comprises an NOVX polypeptide operatively-linked to a non-NOVX polypeptide. An "NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to an NOVX protein SEQ ID NO: 2n, wherein n is an integer between 1 and 101, whereas a "non-NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially homologous to the NOVX protein, e.g. , a protein that is different from the NOVX protein and that is derived from the same or a different organism. Within an NOVX fusion protein the NOVX polypeptide can correspond to all or a portion of an NOVX protein. In one embodiment, an NOVX fusion protein comprises at least one biologically-active portion of an NOVX protein. In another embodiment, an NOVX fusion protein comprises at least two biologically-active portions of an NOVX protein. In yet another embodiment, an NOVX fusion protein comprises at least three biologically- active portions of an NOVX protein. Within the fusion protein, the term "operatively- linked" is intended to indicate that the NOVX polypeptide and the non-NOVX polypeptide are fused in-frame with one another. The non-NOVX polypeptide can be fused to the N-terminus or C-terminus of the NOVX polypeptide. In one embodiment, the fusion protein is a GST-NOVX fusion protein in which the

NOVX sequences are fused to the C-terminus of the GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant NOVX polypeptides.

In another embodiment, the fusion protein is an NOVX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of NOVX can be increased through use ofa heterologous signal sequence.

In yet another embodiment, the fusion protein is an NOVX-immunoglobulin fusion protein in which the NOVX sequences are fused to sequences derived from a member of the immunoglobulin protein family. The NOVX-immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between an NOVX ligand and an NOVX protein on the surface ofa cell, to thereby suppress NOVX-mediated signal transduction in vivo. The NOVX-immunoglobulin fusion proteins can be used to affect the bioavailability of an NOVX cognate ligand. Inhibition of the NOVX ligand/NOVX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well as modulating (e.g. promoting or inhibiting) cell survival. Moreover, the NOVX-immunoglobulin fusion proteins of the invention can be used as immunogens to produce anti-NOVX antibodies in a subject, to purify NOVX ligands, and in screening assays to identify molecules that inhibit the interaction of NOVX with an NOVX ligand. An NOVX chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g., Ausubel, et al. (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). An NOVX-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the NOVX protein.

NOVX Agonists and Antagonists

The invention also pertains to variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists. Variants of the NOVX protein can be generated by mutagenesis (e.g., discrete point mutation or truncation of the NOVX protein). An agonist of the NOVX protein can retain substantially the same, or a subset of, the biological activities of the naturally occurring form of the NOVX protein. An antagonist of the NOVX protein can inhibit one or more of the activities of the naturally occurring form of the NOVX protein by, for example, competitively binding to a downstream or upstream member ofa cellular signaling cascade which includes the NOVX protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. In one embodiment, treatment ofa subject with a variant having a subset of the biological activities of the naturally occurring form of the protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the NOVX proteins.

Variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists can be identified by screening combinatorial libraries of mutants (e.g. , truncation mutants) of the NOVX proteins for NOVX protein agonist or antagonist activity. In one embodiment, a variegated library of NOVX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of NOVX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential NOVX sequences is expressible as i individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of NOVX sequences therein. There are a variety of methods which can be used to produce libraries of potential NOVX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential NOVX sequences. Methods for synthesizing degenerate oligonucleotides are well-known within the art. See, e.g., Narang, 1983. Tetrahedron 39: 3; Itakura, et al., 1984. Annu. Rev. Biochem. 53: 323; Itakura, et al, 1984. Science 198: 1056; Ike, et al, 1983. Nucl. Acids Res. 11: 477.

Polypeptide Libraries

In addition, libraries of fragments of the NOVX protein coding sequences can be used to generate a variegated population of NOVX fragments for screening and subsequent selection of variants of an NOVX protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of an NOVX coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double-stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with Si nuclease, and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-terminal and internal fragments of various sizes of the NOVX proteins.

Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of NOVX proteins. The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection ofa desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify NOVX variants. See, e.g., Arkin and Yourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 781 1-7815; Delgrave, et al, 1993. Protein Engineering 6:327-331.

NOVX Antibodies

The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, F_ab, F_at,' and F(_ab')2 fragments, and an F_ab expression library. In general, antibody molecules obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. -Certain classes have subclasses as well, such as IgGi, IgG₂, and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.

An isolated protein of the invention intended to serve as an antigen, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of the full length protein, such as an amino acid sequence shown in SEQ ID NO: 2n, wherein n is an integer between 1 and 101, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope. Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.

In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a region of NOVX that is located on the surface of the protein, e.g., a hydrophilic region. A hydrophobicity analysis of the human NOVX protein sequence will indicate which regions of a NOVX polypeptide are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 3824- 3828; Kyte and Doolittle 1982, J. Mol. Biol. 157: 105-142, each incorporated herein by reference in their entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.

A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.

Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, incorporated herein by reference). Some of these antibodies are discussed below. Polyclonal Antibodies

For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents. Additional examples of adjuvants which can be employed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate). The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immύnoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia PA, Vol. 14, No. 8 (April 17, 2000), pp. 25-28).

Monoclonal Antibodies The term "monoclonal antibody" (MAb) or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.

Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro.

The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell [Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103]. Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine ("HAT medium"), which substances prevent the growth of HGPRT-deficient cells.

Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell

Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies [Kozbor, L Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63].

The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980). It is an objective, especially important in therapeutic applications of monoclonal antibodies, to identify antibodies having a high degree of specificity and a high binding affinity for the target antigen.

After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods (Goding, 1986). Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal. The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Patent No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.

Humanized Antibodies

The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')₂ or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321 :522-525 (1986); Riechmann et al., Nature. 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S. Patent No. 5,225,539.) In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those ofa non-human immunoglobulin and all or substantially all of the framework regions are those ofa human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. Op. Struct. Biol.. 2:593-596 (1992)).

Human Antibodies Fully human antibodies essentially relate to antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed "human antibodies", or "fully human antibodies" herein. Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol

Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).

In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol.. 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al. (Bio/Technology 10, 779-783 (1992)); Lonberg et al. (Nature 368 856-859 (1994)); Morrison ( Nature 368, 812-13 (1994)); Fishwild et al.( Nature Biotechnology 14. 845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93 (1995)).

Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT publication WO94/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the Xenomouse™ as disclosed in PCT publications WO 96/33735 and WO 96/34096. This animal produces B cells which secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation ofa polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.

An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Patent No. 5,939,598. It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.

A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Patent No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain.

In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049. F_ab Fragments and Single Chain Antibodies

According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Patent No. 4,946,778). In addition, methods can be adapted for the construction of F_ab expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal F_ab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F(_ab')2 fragment produced by pepsin digestion of an antibody molecule; (ii) an F_a fragment generated by reducing the disulfide bridges of an F(_ab_')2 fragment; (iii) an F_ab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) F_v fragments.

Bispecific Antibodies

Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.

Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture often different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., EMBO J.. 10:3655-3659 (1991). Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CHI) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986).

According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.

Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab')₂ bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab')₂ fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes. Additionally, Fab' fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) describe the production ofa fully humanized bispecific antibody F(ab')₂ molecule. Each Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.

Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5): 1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The "diabody" technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (V_H) connected to a light-chain variable domain (V_L) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the V_H and V_L domains of one fragment are forced to pair with the complementary VL and V_H domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994). Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).

Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD 16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).

Heteroconjugate Antibodies

Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Patent No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Patent No. 4,676,980.

Effector Function Engineering

It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement- mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al.. J. Exp Med., 176: 1191-1195 (1992 nd Shopes. J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560- 2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989).

Immunoconjugates The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate). Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include Bi, I, In, Y, and Re.

Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)- ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as l,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14- labeled l-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026.

In another embodiment, the antibody can be conjugated to a "receptor" (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration ofa "ligand" (e.g., avidin) that is in turn conjugated to a cytotoxic agent.

Immunoliposomes The antibodies disclosed herein can also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556.

Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG- derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in

Martin et al ., J. Biol. Chem.. 257: 286-288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon et al., J. National Cancer Inst. 81_.(19): 1484 (1989).

Diagnostic Applications of Antibodies Directed Against the Proteins of the Invention Antibodies directed against a protein of the invention may be used in methods known within the art relating to the localization and/or quantitation of the protein (e.g., for use in measuring levels of the protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies against the proteins, or derivatives, fragments, analogs or homologs thereof, that contain the antigen binding domain, are utilized as pharmacologically-active compounds (see below).

An antibody specific for a protein of the invention can be used to isolate the protein by standard techniques, such as immunoaffinity chromatography or immunoprecipitation. Such an antibody can facilitate the purification of the natural protein antigen from cells and of recombinantly produced antigen expressed in host cells. Moreover, such an antibody can be used to detect the antigenic protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the antigenic protein. Antibodies directed against the protein can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ^12:T, 1, ³⁵S or H.

Antibody Therapeutics Antibodies of the invention, including polyclonal, monoclonal, humanized and fully human antibodies, may used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology in a subject. An antibody preparation, preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Such an effect may be one of two kinds, depending on the specific nature of the interaction between the given antibody molecule and the target antigen in question. In the first instance, administration of the antibody may abrogate or inhibit the binding of the target with an endogenous ligand to which it naturally binds. In this case, the antibody binds to the target and masks a binding site of the naturally occurring ligand, wherein the ligand serves as an effector molecule. Thus the receptor mediates a signal transduction pathway for which ligand is responsible.

Alternatively, the effect may be one in which the antibody elicits a physiological result by virtue of binding to an effector binding site on the target molecule. In this case the target, a receptor having an endogenous ligand which may be absent or defective in the disease or pathology, binds the antibody as a surrogate effector ligand, initiating a receptor-based signal transduction event by the receptor.

A therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target, and in other cases, promotes a physiological response. The amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered. Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week.

Pharmaceutical Compositions of Antibodies

Antibodies specifically binding a protein of the invention, as well as other, molecules identified by the screening assays disclosed herein, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington : The Science And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa. : 1995; Drug Absorption Enhancement : Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York.

If the antigenic protein is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions. The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

Sustained-release preparations can be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.3,773,919), copolymers of L-glutamic acid and γ ethyl-L-glutamate, non- degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT ™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.

ELISA Assay

An agent for detecting an analyte protein is an antibody capable of binding to an analyte protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., F_a or F _ab)2) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling ofa DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term "biological sample", therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting immunoassays are described, for example in "ELISA: Theory and Practice: Methods in Molecular Biology", Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, NJ, 1995; "Immunoassay", E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, CA, 1996; and "Practice and Thory of Enzyme Immunoassays", P.

Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-an analyte protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

NOVX Recombinant Expression Vectors and Host Cells

Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding an NOVX protein, or derivatives, fragments, analogs or homologs thereof. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as "expression vectors". In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g. , replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions. The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably-linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).

The term "regulatory sequence" is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZY OLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g. , tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., NOVX proteins, mutant forms of NOVX proteins, fusion proteins, etc.).

The recombinant expression vectors of the invention can be designed for expression of NOVX proteins in prokaryotic or eukaryotic cells. For example, NOVX proteins can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

Expression of proteins in prokaryotes is most often carried out in Escheήchia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non- fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: ( ) to increase expression of recombinant protein; ( ) to increase the solubility of the recombinant protein; and (Hi) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al, (1988) Gene 69:301-315) and pET 1 Id (Studier et al, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89).

One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (see, e.g., Wada, et al, 1992. Nucl. Acids Res. 20: 21 11-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques.

In another embodiment, the NOVX expression vector is a yeast expression vector. Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSecl (Baldari, et al., 1987. EMBOJ. 6: 229-234), pMFa (Kurjan and Herskowitz, 1982. Cell 30: 933-943), pJRY88 (Schultz et al, 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Calif), and picZ (InVitrogen Corp, San Diego, Calif). Alternatively, NOVX can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, et al, 1983. Mol. Cell. Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39).

In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nαtwre 329: 840) and pMT2PC (Kaufman, et al, 1987. EMBOJ. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.

In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al, 1987. Genes Dev. 1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Banerji, et al, 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al, 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264, 166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the α-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546).

The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to NOVX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub, et al, "Antisense RNA as a molecular tool for genetic analysis," Reviews- Trends in Genetics, Vol. 1(1) 1986.

Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms "host cell" and "recombinant host cell" are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. A host cell can be any prokaryotic or eukaryotic cell. For example, NOVX protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.

Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms

"transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.

For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding NOVX or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).

A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) NOVX protein. Accordingly, the invention further provides methods for producing NOVX protein using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding NOVX protein has been introduced) in a suitable medium such that NOVX protein is produced. In another embodiment, the method further comprises isolating NOVX protein from the medium or the host cell.

Transgenic NOVX Animals

The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which NOVX protein-coding sequences have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous NOVX sequences have been introduced into their genome or homologous recombinant animals in which endogenous NOVX sequences have been altered. Such animals are useful for studying the function and/or activity of NOVX protein and for identifying and/or evaluating modulators of NOVX protein activity. As used herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous NOVX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.

A transgenic animal of the invention can be created by introducing NOVX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g. , by microinjection, retroviral infection) and allowing the oocyte to develop in a pseudopregnant female foster animal. The human NOVX cDNA sequences SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101 can be introduced as a transgene into the genome ofa non-human animal. Alternatively, a non-human homologue of the human NOVX gene, such as a mouse NOVX gene, can be isolated based on hybridization to the human NOVX cDNA (described further supra) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably-linked to the NOVX transgene to direct expression of NOVX protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866; 4,870,009; and 4,873,191; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the NOVX transgene in its genome and/or expression of NOVX mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene-encoding NOVX protein can further be bred to other transgenic animals carrying other transgenes.

To create a homologous recombinant animal, a vector is prepared which contains at least a portion of an NOVX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the NOVX gene. The NOVX gene can be a human gene (e.g. , the cDNA of SEQ ID NO: 2n-l , wherein n is an integer between 1 and 101), but more preferably, is a non-human homologue of a human NOVX gene. For example, a mouse homologue of human NOVX gene of SEQ ID NO: 2n- 1 , wherein n is an integer between 1 and 101 can be used to construct a homologous recombination vector suitable for altering an endogenous NOVX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous recombination, the endogenous NOVX gene is functionally disrupted (i. e. , no longer encodes a functional protein; also referred to as a "knock out" vector). Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous NOVX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous NOVX protein). In the homologous recombination vector, the altered portion of the NOVX gene is flanked at its 5'- and 3 '-termini by additional nucleic acid of the NOVX gene to allow for homologous recombination to occur between the exogenous NOVX gene carried by the vector and an endogenous NOVX gene in an embryonic stem cell. The additional flanking NOVX nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5'- and 3'-termini) are included in the vector. See, e.g., Thomas, et al, 1987. Cell 51: 503 for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced NOVX gene has homologously- recombined with the endogenous NOVX gene are selected. See, e.g., Li, et al, 1992. Cell 69: 915. The selected cells are then injected into a blastocyst of an animal (e.g. , a mouse) to form aggregation chimeras. See, e.g., Bradley, 1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously- recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously-recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, 1991. Curr. Opin. Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354; WO 91/01140; WO 92/0968; and WO 93/04169.

In another embodiment, transgenic non-humans animals can be produced that contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage PL For a description of the cre/loxP recombinase system, See, e.g., Lakso, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See, O'Gorman, et al., 1991. Science 251 :1351-1355. If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al, 1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G₀ phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone of the animal from which the cell (e.g., the somatic cell) is isolated. Pharmaceutical Compositions

The NOVX nucleic acid molecules, NOVX proteins, and anti-NOVX antibodies (also referred to herein as "active compounds") of the invention, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, NJ.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use ofa coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound (e.g., an NOVX protein or anti-NOVX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds ofa similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g. , with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery. In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Patent No. 5,328,470) or by stereotactic injection (see, e.g., Chen, et al, 1994. Proc. Natl. Acad. Sci. USA 91: 3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g. , retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. Screening and Detection Methods

The isolated nucleic acid molecules of the invention can be used to express NOVX protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect NOVX mRNA (e.g., in a biological sample) or a genetic lesion in an NOVX gene, and to modulate NOVX activity, as described further, below. In addition, the NOVX proteins can be used to screen drugs or compounds that modulate the NOVX protein activity or expression as well as to treat disorders characterized by insufficient or excessive production of NOVX protein or production of NOVX protein forms that have decreased or aberrant activity compared to NOVX wild-type protein (e.g. ; diabetes (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting disorders associated with chronic diseases and various cancers, and infectious disease(possesses anti-microbial activity) and the various dyslipidemias. In addition, the anti-NOVX antibodies of the invention can be used to detect and isolate NOVX proteins and modulate NOVX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absorption of nutrients and the disposition of metabolic substrates in both a positive and negative fashion. The invention further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra.

Screening Assays

The invention provides a method (also referred to herein as a "screening assay") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to NOVX proteins or have a stimulatory or inhibitory effect on, e.g., NOVX protein expression or NOVX protein activity. The invention also includes compounds identified in the screening assays described herein. In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity of the membrane-bound form of an

NOVX protein or polypeptide or biologically-active portion thereof. The test compounds of the invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the "one-bead one-compound" library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 1997. Anticancer Drug Design 12: 145. A "small molecule" as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention.

Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al, 1993. Proc. Natl. Acad. Sci. U.S.A. 90: 6909; Erb, et al, 1994. Proc. Natl. Acad. Sci. U.S.A. 91: 11422; Zuckermann, et al, 1994. J. Med. Chem. 37: 2678; Cho, etal., 1993. Science 261: 1303; Carrell, et al, 1994. Angew. Chem. Int. Ed. Eng . 33: 2059; Carell, et al, 1994. Angew. Chem. Int. Ed. Engl 33: 2061; and Gallop, et al, 1994. J. Med. Chem. 37: 1233. Libraries of compounds may be presented in solution (e.g., Houghten, 1992.

Biotechniques 13: 412-421), or on beads (Lam, 1991. Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Patent No. 5,223,409), spores (Ladner, U.S. Patent 5,233,409), plasmids (Cull, et al, 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al, 1990. Proc. Natl. Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J Mol. Biol. 222: 301-310; Ladner, U.S. Patent No. 5,233,409.).

In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of NOVX protein, or a biologically- active portion thereof, on the cell surface is contacted with a test compound and the ability of the test compound to bind to an NOVX protein determined. The cell, for example, can of mammalian origin or a yeast cell. Determining the ability of the test compound to bind to the NOVX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the NOVX protein or biologically-active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with ^I251, ³⁵S, ¹⁴C, or ³H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with an NOVX protein, wherein determining the ability of the test compound to interact with an NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX protein or a biologically-active portion thereof as compared to the known compound. In another embodiment, an assay is a cell-based assay comprising contacting a cell expressing a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX or a biologically-active portion thereof can be accomplished, for example, by determining the ability of the NOVX protein to bind to or interact with an NOVX target molecule. As used herein, a "target molecule" is a molecule with which an NOVX protein binds or interacts in nature, for example, a molecule on the surface ofa cell which expresses an NOVX interacting protein, a molecule on the surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal surface of a cell membrane or a cytoplasmic molecule. An NOVX target molecule can be a non-NOVX molecule or an NOVX protein or polypeptide of the invention. In one embodiment, an NOVX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of a compound to a membrane-bound NOVX molecule) through the cell membrane and into the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with NOVX. Determining the ability of the NOVX protein to bind to or interact with an NOVX target molecule can be accomplished by one of the methods described above for determining direct binding. In one embodiment, determining the ability of the NOVX protein to bind to or interact with an NOVX target molecule can be accomplished by determining the activity of the target molecule. For example, the activity of the target molecule can be determined by detecting induction of a cellular second messenger of the target (i.e. intracellular Ca²⁺, diacylglycerol, IP₃, etc.), detecting catalytic/enzymatic activity of the target an appropriate substrate, detecting the induction of a reporter gene (comprising an NOVX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g. , luciferase), or detecting a cellular response, for example, cell survival, cellular differentiation, or cell proliferation.

In yet another embodiment, an assay of the invention is a cell-free assay comprising contacting an NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to bind to the NOVX protein or biologically-active portion thereof. Binding of the test compound to the NOVX protein can be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with an NOVX protein, wherein determining the ability of the test compound to interact with an NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX or biologically-active portion thereof as compared to the known compound.

In still another embodiment, an assay is a cell-free assay comprising contacting NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to modulate (e.g. stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX can be accomplished, for example, by determining the ability of the NOVX protein to bind to an NOVX target molecule by one of the methods described above for determining direct binding. In an alternative embodiment, determining the ability of the test compound to modulate the activity of NOVX protein can be accomplished by determining the ability of the NOVX protein further modulate an NOVX target molecule. For example, the catalytic/enzymatic activity of the target molecule on an appropriate substrate can be determined as described, supra.

In yet another embodiment, the cell-free assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with an NOVX protein, wherein determining the ability of the test compound to interact with an NOVX protein comprises determining the ability of the NOVX protein to preferentially bind to or modulate the activity of an NOVX target molecule. The cell-free assays of the invention are amenable to use of both the soluble form or the membrane-bound form of NOVX protein. In the case of cell-free assays comprising the membrane-bound form of NOVX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of NOVX protein is maintained in solution. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton^® X-100, Triton^® X-l 14, Thesit^®, Isotridecypoly(ethylene glycol ether)_n, N-dodecyl— N,N-dimethy 1-3 -ammonio-1 -propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1 -propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-l -propane sulfonate (CHAPSO).

In more than one embodiment of the above assay methods of the invention, it may be desirable to immobilize either NOVX protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Binding of a test compound to NOVX protein, or interaction of NOVX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix. For example, GST-NO VX fusion proteins or GST-target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or NOVX protein, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra. Alternatively, the complexes can be dissociated from the matrix, and the level of NOVX protein binding or activity determined using standard techniques.

Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either the NOVX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated NOVX protein or target molecules can be prepared from biotin-NHS

(N-hydroxy-succinimide) using techniques well-known within the art (e.g. , biotinylation kit, Pierce Chemicals, Rockford, 111.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with NOVX protein or target molecules, but which do not interfere with binding of the NOVX protein to its target molecule, can be derivatized to the wells of the plate, and unbound target or NOVX protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the NOVX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the NOVX protein or target molecule.

In another embodiment, modulators of NOVX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of NOVX mRNA or protein in the cell is determined. The level of expression of NOVX mRNA or protein in the presence of the candidate compound is compared to the level of expression of NOVX mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of NOVX mRNA or protein expression based upon this comparison. For example, when expression of NOVX mRNA or protein is greater (i.e., statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of NOVX mRNA or protein expression. Alternatively, when expression of NOVX mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of NOVX mRNA or protein expression. The level of NOVX mRNA or protein expression in the cells can be determined by methods described herein for detecting NOVX mRNA or protein.

In yet another aspect of the invention, the NOVX proteins can be used as "bait proteins" in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Patent No. 5,283,317; Zervos, et al, 1993. Cell 72: 223-232; Madura, et al., 1993. J. Biol. Chem. 268:

12046-12054; Bartel, et al, 1993. Biotechniques 14: 920-924; Iwabuchi, et al, 1993. Oncogene 8: 1693-1696; and Brent WO 94/10300), to identify other proteins that bind to or interact with NOVX ("NOVX-binding proteins" or "NOVX-bp") and modulate NOVX activity. Such NOVX-binding proteins are also likely to be involved in the propagation of signals by the NOVX proteins as, for example, upstream or downstream elements of the NOVX pathway. The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for NOVX is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation domain of the known transcription factor. If the "bait" and the "prey" proteins are able to interact, in vivo, forming an NOVX-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g. , LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein which interacts with NOVX. The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein.

Detection Assays

Portions or fragments of the cDNA sequences identified herein (and the corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: (i) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (ii) identify an individual from a minute biological sample (tissue typing); and (Hi) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below.

Chromosome Mapping

Once the sequence (or a portion of the sequence) ofa gene has been isolated, this sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments of the NOVX sequences, SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or fragments or derivatives thereof, can be used to map the location of the NOVX genes, respectively, on a chromosome. The mapping of the NOVX sequences to chromosomes is an important first step in correlating these sequences with genes associated with disease.

Briefly, NOVX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the NOVX sequences. Computer analysis of the NOVX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the NOVX sequences will yield an amplified fragment. Somatic cell hybrids are prepared by fusing somatic cells from different mammals

(e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, et «/., 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions.

PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using a single thermal cycler. Using the NOVX sequences to design oligonucleotide primers, sub-localization can be achieved with panels of fragments from specific chromosomes.

Fluorescence in situ hybridization (FISH) ofa DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a DNA sequence as short as 500 or 600 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al, HUMAN CHROMOSOMES: A MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988).

Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.

Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, e.g., in McKusick, MENDELIAN INHERITANCE IN MAN, available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland, et al, 1987. Nature, 325: 783-787.

Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the NOVX gene, can be determined. If a mutation is observed in some or all of the affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are visible from chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence ofa mutation and to distinguish mutations from polymorphisms. Tissue Typing

The NOVX sequences of the invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences of the invention are useful as additional DNA markers for RFLP ("restriction fragment length polymorphisms," described in U.S. Patent No. 5,272,057). Furthermore, the sequences of the invention can be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the NOVX sequences described herein can be used to prepare two PCR primers from the 5'- and 3'-termini of the sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it. Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences of the invention can be used to obtain such identification sequences from individuals and from tissue. The NOVX sequences of the invention uniquely represent portions of the human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Much of the allelic variation is due to single nucleotide polymorphisms (SNPs), which include restriction fragment length polymorphisms (RFLPs). Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If predicted coding sequences, such as those in SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101 are used, a more appropriate number of primers for positive individual identification would be 500-2,000.

Predictive Medicine The invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the invention relates to diagnostic assays for determining NOVX protein and/or nucleic acid expression as well as NOVX activity, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, associated with aberrant NOVX expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. For example, mutations in an NOVX gene can be assayed in a biological sample. Such assays can be used for prognostic or predictive purpose to thereby prophylactically treat an individual prior to the onset ofa disorder characterized by or associated with NOVX protein, nucleic acid expression, or biological activity.

Another aspect of the invention provides methods for determining NOVX protein, nucleic acid expression or activity in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (referred to herein as "pharmacogenomics"). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual examined to determine the ability of the individual to respond to a particular agent.) Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX in clinical trials.

These and other agents are described in further detail in the following sections.

Diagnostic Assays

An exemplary method for detecting the presence or absence of NOVX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes NOVX protein such that the presence of NOVX is detected in the biological sample. An agent for detecting NOVX mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to NOVX mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length NOVX nucleic acid, such as the nucleic acid of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to NOVX mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein.

An agent for detecting NOVX protein is an antibody capable of binding to NOVX protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or

F(ab')₂) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect NOVX mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of NOVX mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of NOVX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of NOVX genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of NOVX protein include introducing into a subject a labeled anti-NOVX antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting NOVX protein, mRNA, or genomic DNA, such that the presence of NOVX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of NOVX protein, mRNA or genomic DNA in the control sample with the presence of NOVX protein, mRNA or genomic DNA in the test sample.

The invention also encompasses kits for detecting the presence of NOVX in a biological sample. For example, the kit can comprise: a labeled compound or agent capable of detecting NOVX protein or mRNA in a biological sample; means for determining the amount of NOVX in the sample; and means for comparing the amount of NOVX in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect NOVX protein or nucleic acid.

Prognostic Assays

The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant NOVX expression or activity in which a test sample is obtained from a subject and NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. As used herein, a "test sample" refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., serum), cell sample, or tissue.

Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant NOVX expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder. Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with aberrant NOVX expression or activity in which a test sample is obtained and NOVX protein or nucleic acid is detected (e.g., wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant NOVX expression or activity).

The methods of the invention can also be used to detect genetic lesions in an NOVX gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding an NOVX-protein, or the misexpression of the NOVX gene. For example, such genetic lesions can be detected by ascertaining the existence of at least one of: ( ) a deletion of one or more nucleotides from an NOVX gene; (ii) an addition of one or more nucleotides to an NOVX gene; (Hi) a substitution of one or more nucleotides of an NOVX gene, (iv) a chromosomal rearrangement of an NOVX gene; (v) an alteration in the level of a messenger RNA transcript of an NOVX gene, ( 0 aberrant modification of an NOVX gene, such as of the methylation pattern of the genomic DNA, (vii) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of an NOVX gene, (viii) a non- wild-type level of an NOVX protein, (ix) allelic loss of an NOVX gene, and (x) inappropriate post-translational modification of an NOVX protein. As described herein, there are a large number of assay techniques known in the art which can be used for detecting lesions in an NOVX gene. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

In certain embodiments, detection of the lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Patent Nos. 4,683,195 and

4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran, et αl., 1988. Science 241: 1077-1080; and Nakazawa, et al., 1994. Proc. Natl. Acad. Sci. USA 91 : 360-364), the latter of which can be particularly useful for detecting point mutations in the NOVX-gene (see, Abravaya, et al., 1995. Nucl. Acids Res. 23: 675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to an NOVX gene under conditions such that hybridization and amplification of the NOVX gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.

Alternative amplification methods include: self sustained sequence replication (see, Guatelli, et al, 1990. Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (see, Kwoh, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 1173-1177); Qβ Replicase (see, Lizardi, et al, 1988. BioTechnology 6: 1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. In an alternative embodiment, mutations in an NOVX gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Patent No. 5,493,531) can be used to score for the presence of specific mutations by development or loss ofa ribozyme cleavage site.

In other embodiments, genetic mutations in NOVX can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high-density arrays containing hundreds or thousands of oligonucleotides probes. See, e.g., Cronin, et al, 1996. Human Mutation 7: 244-255; Kozal, et al, 1996. Nat. Med. 2: 753-759. For example, genetic mutations in NONX can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, et al., supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene. In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the NOVX gene and detect mutations by comparing the sequence of the sample NOVX with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl. Acad. Sci. USA 74: 560 or Sanger, 1977. Proc. Natl. Acad. Sci. USA 74: 5463. It is also contemplated that any ofa variety of automated sequencing procedures can be utilized when performing the diagnostic assays (see, e.g., Naeve, et al, 1995. Biotechniques 19: 448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101 ; Cohen, et al, 1996. Adv. Chromatography 36: 127-162; and Griffin, et al, 1993. Appl. Biochem. Biotechnol. 38: 147-159). Other methods for detecting mutations in the NOVX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers, et al, 1985. Science 230: 1242. In general, the art technique of "mismatch cleavage" starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type NOVX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with Sj nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., Cotton, et al, 1988. Proc. Natl. Acad. Sci. USA 85: 4397; Saleeba, et al, 1992. Methods Enzymol. 217: 286-295. In an embodiment, the control DNA or RNA can be labeled for detection. In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in NOVX cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches. See, e.g., Hsu, et al., 1994. Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, a probe based on an NOVX sequence, e.g., a wild-type NOVX sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Patent No. 5,459,039.

In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in NOVX genes. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids. See, e.g., Orita, et al., 1989. Proc. Natl. Acad. Sci. USA: 86: 2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Appl. 9: 73-79. Single-stranded DNA fragments of sample and control NOVX nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility. See, e.g., Keen, et al., 1991. Trends Genet. 7: 5. In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE). See, e.g., Myers, et al, 1985. Nature 313: 495. When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place ofa denaturing gradient to identify differences in the mobility of control and sample DNA. See, e.g., Rosenbaum and Reissner, 1987. Biophys. Chem. 265: 12753. Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al, 1986. Nature 324: 163; Saiki, et al, 1989. Proc. Natl. Acad. Sci. USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA. Alternatively, allele specific amplification technology that depends on selective

PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, et al., 1989. Nucl. Acids Res. 17: 2437-2448) or at the extreme 3'-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 11: 238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection. See, e.g., Gasparini, et al, 1992. Mol. Cell Probes 6: 1. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification. See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3'-terminus of the 5' sequence, making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification. The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g. , in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving an NONX gene.

Furthermore, any cell type or tissue, preferably peripheral blood leukocytes, in which ΝOVX is expressed may be utilized in the prognostic assays described herein. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

Pharmacogenomics

Agents, or modulators that have a stimulatory or inhibitory effect on ΝOVX activity (e.g., ΝOVX gene expression), as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) disorders (The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.) In conjunction with such treatment, the pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) of the individual may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics of the individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of ΝOVX protein, expression of ΝOVX nucleic acid, or mutation content of ΝOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual.

Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol, 23: 983-985; Linder, 1997. Clin. Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g. , N-acetyltransferase 2 (NAT 2) and cytochrome PREGNANCY ZONE PROTEIN PRECURSOR enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.

Thus, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with an NOVX modulator, such as a modulator identified by one of the exemplary screening assays described herein.

Monitoring of Effects During Clinical Trials

Monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials.

For example, the effectiveness of an agent determined by a screening assay as described herein to increase NOVX gene expression, protein levels, or upregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting decreased NOVX gene expression, protein levels, or downregulated NOVX activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease NOVX gene expression, protein levels, or downregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting increased NOVX gene expression, protein levels, or upregulated NOVX activity. In such clinical trials, the expression or activity of NOVX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a "read out" or markers of the immune responsiveness of a particular cell. By way of example, and not of limitation, genes, including NOVX, that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) that modulates NOVX activity (e.g., identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of NOVX and other genes implicated in the disorder. The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of NOVX or other genes. In this manner, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent. In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of an NOVX protein, mRNA, or genomic DNA in the preadministration sample; (Hi) obtaining one or more post-administration samples from the subject; (tv) detecting the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the pre-administration sample with the NOVX protein, mRNA, or genomic DNA in the post administration sample or samples; and (v altering the administration of the agent to the subject accordingly. For example, increased administration of the agent may be desirable to increase the expression or activity of NOVX to higher levels than detected, i.e., to increase the effectiveness of the agent. Alternatively, decreased administration of the agent may be desirable to decrease expression or activity of NOVX to lower levels than detected, i.e., to decrease the effectiveness of the agent.

Methods of Treatment

The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant NOVX expression or activity. The disorders include cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease, AIDS, bronchial asthma, Crohn's disease; multiple sclerosis, treatment of Albright Hereditary Ostoeodystrophy, and other diseases, disorders and conditions of the like.

These methods of treatment will be discussed more fully, below. Disease and Disorders

Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to: (0 an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (ii) antibodies to an aforementioned peptide; (Hi) nucleic acids encoding an aforementioned peptide; (iv) administration of antisense nucleic acid and nucleic acids that are "dysfunctional" (i.e., due to a heterologous insertion within the coding sequences of coding sequences to an aforementioned peptide) that are utilized to "knockout" endogenous function of an aforementioned peptide by homologous recombination (see, e.g., Capecchi, 1989. Science 244: 1288-1292); or (v) modulators ( i.e., inhibitors, agonists and antagonists, including additional peptide mimetic of the invention or antibodies specific to a peptide of the invention) that alter the interaction between an aforementioned peptide and its binding partner.

Diseases and disorders that are characterized by decreased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability.

Increased or decreased levels can be readily detected by quantifying peptide and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or peptide levels, structure and/or activity of the expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot blots, in situ hybridization, and the like).

Prophylactic Methods In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant NOVX expression or activity, by administering to the subject an agent that modulates NOVX expression or at least one NOVX activity. Subjects at risk for a disease that is caused or contributed to by aberrant NOVX expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the NOVX aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending upon the type of NOVX aberrancy, for example, an NOVX agonist or NOVX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections. Therapeutic Methods

Another aspect of the invention pertains to methods of modulating NOVX expression or activity for therapeutic purposes. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of NOVX protein activity associated with the cell. An agent that modulates NOVX protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of an NOVX protein, a peptide, an NOVX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more NOVX protein activity. Examples of such stimulatory agents include active NOVX protein and a nucleic acid molecule encoding NOVX that has been introduced into the cell. In another embodiment, the agent inhibits one or more NOVX protein activity. Examples of such inhibitory agents include antisense NOVX nucleic acid molecules and anti-NOVX antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). As such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of an NOVX protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) NOVX expression or activity. In another embodiment, the method involves administering an NOVX protein or nucleic acid molecule as therapy to compensate for reduced or aberrant NOVX expression or activity.

Stimulation of NOVX activity is desirable in situations in which NOVX is abnormally downregulated and/or in which increased NOVX activity is likely to have a beneficial effect. One example of such a situation is where a subject has a disorder characterized by aberrant cell proliferation and/or differentiation (e.g., cancer or immune associated disorders). Another example of such a situation is where the subject has a gestational disease (e.g., preclampsia).

Determination of the Biological Effect of the Therapeutic

In various embodiments of the invention, suitable in vitro or in vivo assays are performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue. In various specific embodiments, in vitro assays may be performed with representative cells of the type(s) involved in the patient's disorder, to determine if a given Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects. Similarly, for in vivo testing, any of the animal model system known in the art may be used prior to administration to human subjects.

Prophylactic and Therapeutic Uses of the Compositions of the Invention

The NOVX nucleic acids and proteins of the invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders including, but not limited to: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.

As an example, a cDNA encoding the NOVX protein of the invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof. By way of non-limiting example, the compositions of the invention will have efficacy for treatment of patients suffering from: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias. Both the novel nucleic acid encoding the NOVX protein, and the NOVX protein of the invention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. A further use could be as an anti-bacterial molecule (i.e., some peptides have been found to possess antibacterial properties). These materials are further useful in the generation of antibodies, which immunospecifically-bind to the novel substances of the invention for use in therapeutic or diagnostic methods.

Sequence Analyses

The sequence of NOVX was derived by laboratory cloning of cDNA fragments, by in silico prediction of the sequence. cDNA fragments covering either the full length of the DNA sequence, or part of the sequence, or both, were cloned. In silico prediction was based on sequences available in CuraGen's proprietary sequence databases or in the public human sequence databases, and provided either the full length DNA sequence, or some portion thereof.

The laboratory cloning was performed using one or more of the methods summarized below:

SeqCalIing™Technology: cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then sequenced using CuraGen Corporation's SeqCalling technology which is disclosed in full in U. S. Ser. Nos. 09/417,386 filed Oct. 13, 1999, and 09/614,505 filed July 11, 2000. Sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatics programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations.

Variant sequences are also included in this application. A variant sequence can include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA. A SNP can arise in several ways. For example, a SNP may be due to a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a transversion. A SNP can also arise from a deletion of a nucleotide or an insertion of a nucleotide. relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration of the amino acid encoded by the gene at the position of the SNP. Intragenic SNPs may also be silent, when a codon including a SNP encodes the same amino acid as a result of the redundancy of the genetic code. SNPs occurring outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation of the expression pattern. Examples include alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message.

Presented information includes that associated with genomic clones, public genes and ESTs sharing sequence identity with the disclosed sequence and CuraGen Corporation's Electronic Northern bioinformatic tool.

EXAMPLES Example A: Polynucleotide and Polypeptide Sequences, and Homology Data

The NOV1 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 1 A.

Further analysis of the NOV la protein yielded the following properties shown in Table IB.

Table IB. Protein Sequence Properties NOVla

Psort analysis: j 0.6500 probability located in cytoplasm; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen); 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOVla protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 1C.

In a BLAST search of public sequence datbases, the NOVla protein was found to have homology to the proteins shown in the BLASTP data in Table ID.

PFam analysis predicts that the NOVla protein contains the domains shown in the Table IE.

Example 2.

The NOV2 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 2 A. Table 2A. NOV2 Sequence Analysis

SEQ ID NO: 3 3005 bp

NOV2a, CCAAACACACTAAAATAAATATGAGGTCATCAATCTTTTGTTGGTCTCCTTGGCATGC -01 DNA Sequence ACCTATTCAGACTGTTAGTATTATGTATTTACTTCAAATTTTAGCAGTTATATTTTAA CTTGATTGATTTTTCCTCAGATATAAGTATGAGAAATGACAGAAAGAAACAACAACTG GAAAAGAAGCATTGCATAAGACCAGGATGTCTCTGAAATGGACGTCAGTCTTTCTGCT

GATACAGCTCAGTTTTTACTTTAGCTCTGGGAGTTGTGGAAAGGTGCTGGTATGGCCC ACAGAATACAGCCTTTGGATGAATATGAAGACAATCCTGAAAGAACTTGTTCAGAGAG GTCATGAGGTGACTGTACTGGCATCTTCAGCTTCCATTCTTTTTGATCCCAACGACTC ATCCACTCTTAAACTTGAAGTTTATCCTACATCTTTAACTAAAAATGAATTTGAGAAT ATCATCATGCAATTGGTTAAGAGATGGATATATGGTGTTTCAAAAAGATGCATTTTGG TTACCTTTCACAAGAACAAGAAATCCTGTGGGCAATATTATGACATAATTAGAAACTT CTGTAAAGATGTAGTTTCAAATAAGAAACTTATGAAAAAACTACAAGAGTCAAGATTT GACATCGTTTTTGCAGATGCTTATTTACCCTGTGGTGAGCTGCTGGCTGAGCTATTTA ACATACCCTTTGTGTACAGTCTCCGCTTCTCTGTTGGCTACACAGTTGAGAAGAATGG TGGAGGATTTCTGTTCCCTCCTTCCTATGTACCTGTTGTTATGTCAGAATTAAGTGAT CAAATGACTTTCATGGAGAGGGTAAAAAATATGATCTATGTGCTTTACTTTGACTTTT GGTTCGAAATATTTGACATGAAGAAGTGGGATCAGTTTTATAGTGAAGTTCTAGGAAG ACCCACTACATTATCTGAGACAATGGGGAAAGCTGACGTATGGCTTATTCGAAACTAC TGGGATTTTCAATTTCCTCACCCACTCTTACCAAATGTTGAGTTCGTTGGAGGACTCC ACTGCAAACCTGCCAAACCCCTACCGAAGGAAATGGAAGAGTTTGTCCAGAGCTCTGG AGAAAATGGTGTTGTGGTGTTTTCTCTGGGGTCGATGGTCAGTAACATGTCAGAAGAA AGTGCCAACATGATTGCATCAGCCCTTGCCCAGATCCCACAAAAGGTTCTATGGAGAT TTGATGGCAAGAAGCCAAATACTTTAGGTTCCAATACTCGACTGTACAAGTGGATACC CCAGAATGACCTTCTAGGTCATCCAAAGACCAAAGCTTTTATAACTCATGGTGGAACC AATGGCATCTATGAGGCAATCTACCATGGGATCCCTATGGTGGGCATTCCCTTGTTTG CGGATCAACATGATAACATTGCTCACATGAAAGCCAAGGGAGCAGCCCTCAGTGTGGA CATCAGGACCATGTCAAGTAGAGATTTGCTCAATGCATTGAAGTCAGTCATTAATGAC CCTATCTATAAAGAGAATATCATGAAATTATCAAGAATTCATCATGATCAACCAATGA AGCCCCTGGATCGAGCAGTCTTCTGGATTGAGTTTGTCATGCGCCACAAAGGAGCCAA GCACCTTCGAGTCGCAGCCCACAACCTCACCTGGTTCCAGTACCACTCTTTGGATGTG ATAGCATTCCTGCTGGCCTGCGTGGCAACTATGATATTTATGATCACAAAATGTTGCC TGTTTTGTTTCCGAAAGTTTGCTAGAAAAGCAAAGAAGGGAAAAAATGATTAGTTATA

TCTGAGATTTGAAGCTGGGGAATTCCGTTTATTGAAGATTCAGGTTAACCTGAATCAA GTTAACCCAGTCTCAAATGCTCACTTATCCTTTCTTCTTGTGACAAATCTCTCCTCTC CTGGATTGCCAAAGAAAATTCAAATTATTCTTCAATTAGTCAGGATGATTTGACTATC AGCAGTTCATAGTACCCATCTTCATAACTAAGCCACCTAGGGATCCAGCAGAAAAAAA AGGGATGAGGGGAGTCATCATACAGGAGGTGGATCATTTACCAGGATCCACACTTCCT ACAAAGCGGTTGTAATGTTAAATAACAAAACTGTTTTTTATTCCAATCTTCACATAAA ACAGGAATAATTGTATACTTTCTTACTAATGTGTTCCATGGAGTTTTTCCTCCAAGAA GTGGCTTAGGGGAAAATGAGCCCCAGTAATGCTTTGTGGCATCCAATCCTTCTACCCC GACCCTTTGACTTTCTGCCCCAGCCCCTCTTAGTTCTCCTAGAATTAGGACTAAGGTT AAGTGCCCTCTTGGGATATGACTTCCTTCCCTTCCTCTTGATACAAAAAGAGCCTATT ACCAACCCTCATACACACAAGAGTTCCCTTCCTAGTTGCAGACTCTTCTGCTCCAGCT GGACTCCCCTAGCTCTGGACTCCCACTAGATCACACAGGGGTCCCTGCATGTCAGTAA ACTTTGGATGACCTTGGGAGACCAAAAAATGGAATATCATTTTTTGATCTAAACAAAA TAGTTTCCTGATTTAACACTGGCCAGGAAGGTGGGCTGCACCCTCAGTCTCTCTCTCC CATCATGGTTTTCACATGATATCAAAGGACTCTCATAACAGTCTGATTCTTATGAGTT GGGCATCCTGTGTTTCCCTTTAGGGGCCTGCTTCCTTCAAATAGAGGAGATGGGTGCT ATGAAACCTATTCACTCTGGACTTGGGATGGCTCTTCTCCATCTTCCCAAGTCTGAGC TGGAGCCTCCATGCCCAACTCTGCTCTGCTCTTCTATTTCCTGACAGCAGCTAAGGCA TGTTCCTGTTCTGCCCCCAAATTGACCTTACTAACAGTGAGAACTTGGAGGAGTCTTC GGGTCTTGGGAAATCCAAGTTTTCCCGGAAACGTTTTGTTGTAAACAGTGTCCACACT CTTTGCTCCAATAAAGCTCGGTTCCTTAAGCCAAAAAAAAAAAAAAA

ORF Start: ATG at 201 ORF Stop: TAG at 1791

SEQ ID NO: 4 530 aa M W at 60923.7kD

NOV2a, MSLKWTSVF LIQLSI^FSSGSCGKVLV PTEYS M MKTILKE VQRGHEVTVLiAS 01 Protein Sequence SASILFDP DSSTLK EVYPTSLTKNEFENIIMQLVKR IYGVSKRCI VTFHKNKKS CGQYYDIIRNFCKDWSNKKL KK QESRFDIVFADAY PCGELLAE FNIPFVYS R FSVGYTVEKNGGGFLFPPSYVPWMSELSDQMTFMERVKN IYV YFDFWFEIFDMKK DQFYSEVLGRPTTLSET GKADVWLIRNYWDFQFPHP LPNVEFVGG HCKPAKPLP KEMEEFVQSSGENGWVFSLGSMVSNMSEESANMIASALAQIPQKVLWRFDGKKPNT GSNTRLYK IPQNDLLGHPKTKAFITHGGTNGIYEAIYHGIPMVGIP FADQHDNIAH KAKGAALSVDIRTMSSRDLLNALKSVINDPIYKENI KLSRIHHDQPMKPLDRAVFW IEFVMRHKGAKHLRVAAHNLTWFQYHS DVIAF LACVATMIFMITKCCIJFCFRKFAR KAKKGKND Further analysis of the NOV2a protein yielded the following properties shown in Table 2B.

Table 2B. Protein Sequence Properties NOV2a

PSort analysis: 0.8200 probability located in endoplasmic reticulum (membrane); 0.4600 probability located in plasma membrane; 0.2000 probability located in lysosome (membrane);

0.1790 probability located in microbody (peroxisome)

SignalP analysis: Cleavage site between residues 25 and 26

A search of the NOV2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 2C.

In a BLAST search of public sequence datbases, the NOV2a protein was found to have homology to the proteins shown in the BLASTP data in Table 2D.

PFam analysis predicts that the NOV2a protein contains the domains shown in the Table 2E.

Example 3.

The NOV3 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 3 A. Table 3A. NOV3 Sequence Analysis

SEQ ID NO: 5 2310 bp

NOV3a, TGGCCGGCGATAAGGGTTTCACCTTCAGGACTGGAGCTCCACAAGATTCAACCGTTAT CG I 00179-01 DNA Sequence ATCAACCTCCCCGGCCCAGGTCTTACCATCACAGCGTCACAAACTCCAGGTCGCCTAG GCGCTGCGCAGGAAGCGCTTGCCAGCCCCGGACTTCTGCGCGCGCTGCATGCCCATTG GATGTGCTCATTGCCACCCCAGCCAATCCCGAAACTCGCTCGGACGCTGACAGAAGAC TGCGCCGCTGCTTTGGGATTGGTAGCTGAGTTTTGTGTCGCGCCTTTTCTGACGATGC GAACAACATGGCGGCGGAAAGTGGTAGCGATTTTCAGCAGAGACGTAGAAGGCGCCGG

GACCCGGAGGAACCGGAAAAAACAGAACTCAGCGAAAGAGAGCTGGCAGTAGCAGTGG CGGTGTCCCAGGAGAACGATGAGGAGAACGAAGAGCGCTGGGTTGGACCTTTACCTGT GGAGGCAACACTGGCCAAGAAGAGGAAAGTCTTAGAGTTTGAAAGAGTCTATCTTGAT AATCTCCCCAGTGCATCCATGTATGAGCGCAGTTACATGCATAGAGATGTTATCACCC ATGTGGTATGCACCAAGACAGATTTTATTATTACTGCCAGTCATGATGGACATGTCAA GTTCTGGAAAAAAATAGAAGAGGGAATTGAATTTGTTAAACATTTTCGTAGTCACCTG GGTGTTATTGAGAGTATTGCAGTTAGCTCTGAGGGAGCATTGTTCTGTTCTGTGGGTG ATGATAAAGCAATGAAGGTGTTTGATGTAGTGAACTTTGACATGATCAACATGCTGAA ACTTGGGTATTTTCCTGGACAGTGTGAGTGGATCTATTGCCCAGGGGATGCAATTTCT TCAGTTGCTGCTTCCGAAAAGAGTACAGGAAAAATTTTCATTTATGATGGCCGAGGAG ATAACCAGCCACTTCATATTTTTGACAAACTCCATACATCACCTCTTACTCAGATACG GCTAAACCCAGTTTACAAAGCAGTAGTGTCTTCTGACAAATCTGGGATGATTGAATAC TGGACTGGGCCTCCTCATGAATATAAATTCCCCAAAAATGTGAACTGGGAATATAAAA CTGACACTGATTTATATGAATTTGCCAAGTGTAAGGCTTATCCAACCAGCGTATGTTT TTCACCAGATGGGAAGAAAATAGCTACTATTGGTTCTGATAGAAAAGTTAGAATTTTC AGATTTGTAACTGGAAAACTCATGAGAGTCTTTGATGAATCACTAAGCATGTTTACTG AACTGCAACAGATGAGGCAACAGTTACCAGACATGGAATTTGGCCGACGAATGGCTGT AGAACGTGAGTTGGAGAAGGTTGATGCTGTAAGATTAATTAATATAGTTTTTGATGAA ACTGGACACTTCGTGCTGTATGGAACAATGCTGGGCATTAAAGTTATAAATGTAGAGA CAAACAGGTGTGTGCGGATTTTAGGCAAACAAGAAAATATTAGAGTGATGCAATTGGC TTTGTTCCAGGGGATAGCCAAAAAGCATCGTGCTGCAACTACTATAGAAATGAAAGCT TCTGAAAATCCTGTTCTTCAGAATATTCAAGCTGACCCAACAATAGTCTGTACATCAT TCAAAAAGAATAGATTTTATATGTTTACCAAACGAGAACCAGAAGATACGAAAAGTGC AGATTCTGATCGAGATGTTTTTAATGAGAAACCTTCTAAAGAAGAAGTCATGGCAGCT ACTCAAGCTGAAGGACCTAAACGAGTTTCGGACAGTGCCATTATCCACACCAGCATGG GAGACATTCACACCAAACTTTTTCCTGTTGAGTGCCCTAAGACAGTGGAAAACTTCTG TGTTCACAGCAGAAATGGTTATTATAATGGGCATACATTTCACCGTATAATTAAGGGC TTTATGATTCAGACTGGAGATCCAACAGGTACTGGTATGGGAGGAGAAAGCATATGGG GAGGAGAATTTGAAGATGAATTTCATTCAACATTACGACATGACAGGCCGTACACACT CAGCATGGCTAACGCGGGATCAAATACTAATGGATCCCAGTTTTTCATAACGGTAGTA CCAACGCCTTGGCTTGATAATAAGCATACAGTATTTGGACGAGTGACTAAAGGAATGG AAGTTGTACAGAGGATCTCCAACGTCAAAGTCAATCCCAAAACAGATAAGCCCTATGA GGATGTCAGCATCATAAATATTACTGTCAAGTAAAATAAGATTTGTTTTAATGTACTT GCAAATAAAAATACAATATTAAACAGATTATTTTACATTAGGAAGCTT

ORF Start: ATG at 298 ORF Stop: TAA at 2236

SEQ ID NO: 6 646 aa MW at 73574.2kD

NOV3a, MAAESGSDFQQRRRRRRDPEEPEKTE SERELAVAVAVSQENDEENEER VGP PVEA CGI00179-01 Protein Sequence TLAKKR VLEFERVYLDNLPSASMYERSYMHRDVITHWCTKTDFIITASHDGHVKFW KKIEEGIEFVKHFRSHLGVIESIAVSSEGALFCSVGDDKAMKVFDWNFDMIN LKLG YFPGQCEWIYCPGDAISSVAASEKSTGKIFIYDGRGDNQPLHIFDKLHTSPLTQIRLN PVYKAWSSDKSGMIEY TGPPHEYKFPK VN EYKTDTDLYEFAKCKAYPTSVCFΞP DGKKIATIGSDRKVRIFRFVTGKLMRVFDESLSMFTELQQMRQQLPDMEFGRRMAVER E EKΛTOAVRLINIVFDETGHFV YGTM GIKVINVETNRCVRILGKQENIRVMQLALF QGIAKKHRAATTIE KASENPVLQNIQADPTIVCTSF KNRFY FTKREPEDTKSADS DRDVFNEKPSKEEVMAATQAEGPKRVSDSAIIHTS GDIHTKLFPVECPKTVENFCVH SRNGYYNGHTFHRIIKGF IQTGDPTGTGMGGESIWGGEFEDEFHSTLRHDRPYTLSM ANAGSIΠWGSQFFITVVPTPWLDNKH VFGRVTKGMEVVQRISNVKVNPKTDKPYEDV SIINITVK

Further analysis ofthe NOV3a protein yielded the following properties shown in Table 3B.

A search of the NOV3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3C.

In a BLAST search of public sequence datbases, the NOV3a protein was found to have homology to the proteins shown in the BLASTP data in Table 3D.

PFam analysis predicts that the NOV3a protein contains the domains shown in the Table 3E.

Example 4.

The NOV4 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 4A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 4B.

Further analysis of the NOV4a protein yielded the following properties shown in Table 4C.

Table 4C. Protein Sequence Properties NOV4a

PSort analysis: 0.6500 probability located in cytoplasm; 0.1572 probability located in lysosome

(lumen); 0.1000 probability located in mitochondrial matrix space; 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 4D.

In a BLAST search of public sequence datbases, the NOV4a protein was found to have homology to the proteins shown in the BLASTP data in Table 4E.

PFam analysis predicts that the NOV4a protein contains the domains shown in the Table 4F.

Example 5.

The NOV5 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 5A.

Further analysis of the NOV5a protein yielded the following properties shown in Table 5B.

Table 5B. Protein Sequence Properties NOV5a

PSort analysis: j 0.4500 probability located in cytoplasm; 0.1644 probability located in microbody (peroxisome); 0.1620 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space

Signal P analysis: No Known Signal Sequence Predicted

A search of the NOV5a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 5C.

In a BLAST search of public sequence datbases, the NOV5a protein was found to have homology to the proteins shown in the BLASTP data in Table 5D.

I l l

PFam analysis predicts that the NOV5a protein contains the domains shown in the Table 5E.

Example 6.

The NOV6 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 6A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 6B.

Further analysis of the NOVόa protein yielded the following properties shown in Table 6C. Table 6C. Protein Sequence Properties NOVόa

PSort analysis: 0.6400 probability located in microbody (peroxisome); 0.4500 probability located in cytoplasm; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

' SignalP analysis: No Known Signal Sequence Predicted

A search of the NOVόa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 6D.

In a BLAST search of public sequence datbases, the NOVόa protein was found to have homology to the proteins shown in the BLASTP data in Table 6E.

PFam analysis predicts that the NOVόa protein contains the domains shown in the Table 6F.

Example 7.

The NOV7 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 7A.

Further analysis of the NOV7a protein yielded the following properties shown in Table 7B.

Table 7B. Protein Sequence Properties NOV7a

PSort analysis: 0.6500 probability located in plasma membrane; 0.6400 probability located in microbody (peroxisome); 0.4500 probability located in cytoplasm; 0.1000 probability located in mitochondrial matrix space j SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 7C.

In a BLAST search of public sequence datbases, the NOV7a protein was found to have homology to the proteins shown in the BLASTP data in Table 7D.

PFam analysis predicts that the NOV7a protein contains the domains shown in the Table 7E.

Example 8.

The NOV8 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 8A. Table 8A. NOV8 Sequence Analysis

SEQ ID NO: 19 2646 bp

NOV8a, ATGTGGCTGCAGCAGCGGCTCAAGGGGCTGCCGGGACTGCTGTCGAGCAGCTGGGCCC CG I 00456-01 DNA Sequence GCCGCCTCCTCTGCCTGCTTGGCCTCCTGCTGCTGCTTCTGTGGTTTGGGGGGTCCGG CGCGCGGCGGGCGGCGGGCGGCCTGCACCTGCTGCCCTGGTCCCGCGGTGAGCCGGGC GCCGCCGAGCCGTCTGCCTGCCTGGAGGCGGCCACCCGCGCCTGGCGCGGCCTGCGGG AGCGCGGTGAGGTGGTACCGCTGGGTCCTGGAGTGCCGGCCCTGGTGGCCAACGGCTT CCTGGCCCTGGACGTGGCTGCCAATCGGCTGTGGGTGACTCCCGGGGAGCGGGAGCCC GCCGTGGCGCCGGACTTTGTGCCCTTCGTGCAGCTGCGCCCGCTGAGCGCGCTGGCTG AAGCTGGAGAGGCGGTGCTGCTGCTGCGGGAGGGGCTTCTGCGCCGCGTGCGTTGCCT GCAGCTGGGGTCCCCAGGTCCTGGCCCCGTGGCCGCCGGCCCCGGGCCCGCCTCCGTC TCTGGCCTTGCCGCGGGGTCCGGCCGCGACTGCGTGCTGCTGCAAGAGGACTTTCTGG CGCACAGGGGCCGACCCCACGTCTACCTGCAGCGCATCCAGCTCAACAACCCCACGGA GCGCGTGGCCGCGCTGCAGACTGTGGGGCCCACTGCCGGCCCAGCCCCCAATGCCTTC ACCAGTACCCTGGAGAAGGTCGGAGACCATCAGTTCCTCCTCTACTCAGGCCGGTCCC CGCCTACGCCCACTGGGTTGGTGCACCTGGTGGTGGTGGCCGCCAAGAAGCTGGTGAA CCGCCTCCAAGTGGCTCCCAAGACGCAGCTGGATGAGACGGTGCTGTGGGTGGTGCAC GTCTCTGGCCCCATTAACCCCCAGGTGCTCAAAAGCAAAGCAGCCAAGGAGCTCAAGG CGCTGCAGGACTTGGCACGGAAGGAAATGCTGGAGCTCTTGGACATGCCAGCGGCGGA GCTGCTTCAAGACCACCAGCTCCTCTGGGCTCAGCTCTTCAGCCCAGGTGTGGAAATG AAGAAGATCACTGACACCCACACGCCGTCTGGCCTCACCGTGAACCTGACGCTCTATT ACATGCTCTCCTGCTCGCCAGCCCCACTGCTCAGCCCCTCCCTGAGCCACAGGGAGCG AGACCAGATGGAGTCGACGCTCAACTATGAAGATCACTGCTTCAGCGGGCACGCCACC ATGCACGCCGAGAACCTGTGGCCGGGGCGGCTGTCCTCCGTCCAGCAGATCCTGCAGC TCTCTGACCTGTGGAGGCTGACCCTCCAGAAGCGTGGCTGCAAGGGGCTGGTGAAGGT GGGTGCCCCAGGCATCCTGCAGGGGATGGTGCTCAGCTTTGGGGGGCTGCAGTTCACA GAGAACCACCTCCAGTTCCAGGCCGACCCCGACGTGCTGCACAACAGCTATGCATTGC ATGGCATCCGCTACAAGAACGACCATATCAACCTGGCCGTGCTGGCGGATGCCGAGGG CAAGCCCTACCTACACGTGTCCGTGGAGTCCCGTGGCCAGCCTGTCAAGATCTATGCC TGCAAGGCAGGCTGCCTGGACGAGCCAGTGGAGCTGACCTCGGCGCCCACGGGCCACA CCTTCTCGGTCATGGTGACACAGCCCATCACGCCACTGCTCTACATCTCCACCGACCT CACACACCTGCAGGACCTGCGGCACACGCTGCACCTCAAGGCCATCCTGGCCCATGAT GAGCACATGGCCCAGCAGGACCCCGGGCTGCCCTTCCTCTTCTGGTTCAGCGTGGCCT CCCTAATCACCCTCTTCCACCTCTTCCTCTTCAAGCTCATCTACAACGAGTACTGTGG GCCTGGAGCCAAGCCCCTCTTCAGGAGTAAGGAAGATCCCAGTGTCTGAGTGAACTAA

CAGTCCTGCTTTCAGCCACCATTTGCACAAGACACCCAGCACTGAAAGTCCCGCTGCC AGGAGCAAGGGATCCTTTGGAAGCACCCGCCCTTTGTGCCTTGTTGGGGGAAACCGGT GACGCAGAAGTGAGTGTGGATACACCAGAGTTTGCATTGGAAGGAATGAGTGTCACGT GGGGAGGGAAGGGGCCAGTGGACCTTTTGTAAGCTTTCCACTCAATAAAATGAACCTG TATGGCAAATACTTGAAATGGAACTCACTCCTTCCACTTTCCCCCTTTCTTCTGTCCC AGGAAATAGATCATCTTTTGAAAAGACTCTTGTCTAGGAAAAGTTGTGTCCTTTTCCT AATTTAACGTGTTCTTTCTTAATGAAGTTTTAATTTATTTTTGTTGAGATTTTGCTAG ATGGCTTTTGCATCCCCTGTAGATGGTGAGTGTTGGCGGTGATGTCCGTCTCGGCGTT CGGAGGCCCCACGGTCCCGAGGCTGGGCCGGGGCCCCCCAGGGTGGCTGTGCTGCTGC CTGTAGGAGGGTGCGGGTTGTGCTGTCATCCTCGGGTTTGCACGCCCTTTTTTAGGAG CCTGTGGACATCTGTGGTTTTGTACTTTGGGGCTTCAGGGGAGGTGTTTAACTTTCTA GTGATTGATGATTGTCAGGTTTTGAAATACCAAAGCTTTTTTGTTCTGTTTTTAAATA AATATCTTTCAAACTTTCAAAAAAAAAAAAAAAAAA

ORF Start: ATG at 1 ORF Stop: TGA at 1903

SEQ ID NO: 20 634 aa MW at 69142.3kD

NOV8a, MWLQQRLKGLPG LSSS ARRLLCL G LLLLWFGGSGARRAAGGLHL P SRGEPG CGI 00456-01 Protein Sequence AAEPSACLEAATRARGLRERGEWP GPGVPALVANGFLALDVAA RL VTPGEREP AVAPDFVPFVQLRPLSALAEAGEAVLLLREGLLRRVRCLQLGSPGPGPVAAGPGPASV SGIiAAGSGRDC\π_LQEDFlAHRGRPHVYLQRIQL NPTERVAAQTVGPTAGPAPNAF TST EKVGDHQF LYSGRSPPTPTG VH VWAAKKLVNRLQVAPKTQLDETV WWH VSGPINPQVLKSKAAKELKALQDLARKEM EL DMPAAELLQDHQL WAQLFSPGVEM K ITDTHTPSGLTVNLTLYYMLSCSPAPLLSPSLSHRERDQMEST NYEDHCFSGHAT MHAEN PGRLSSVQQILQ SDLWR T QKRGCKG VKVGAPGILQGMV SFGGLQFT ENHLQFQADPDVLHNSYALHGIRYKNDHINLAVLADAEGKPY HVSVESRGQPVKIYA CKAGCLDEPVELTSAPTGHTFSVMVTQPITPLLYISTD TH QD RHTLHLKAILAHD EHMAQQDPG PFLF FSVAS ITLFHLFLFKLIYNEYCGPGAKPLFRSKEDPSV

Further analysis of the NOV8a protein yielded the following properties shown in Table 8B. Table 8B. Protein Sequence Properties NOV8a

PSort analysis: 0.4600 probability located in plasma membrane; 0.3000 probability located in lysosome (membrane); 0.2800 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP analysis: Cleavage site between residues 41 and 42

A search of the NOV8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 8C.

In a BLAST search of public sequence datbases, the NOV8a protein was found to have homology to the proteins shown in the BLASTP data in Table 8D.

PFam analysis predicts that the NOV8a protein contains the domains shown in the Table 8E.

Table 8E. Domain Analysis of NOV8a

Identities/

Pfam Domain NOV8a Match Region Similarities Expect Value for the Matched Region

Example 9.

The NOV9 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 9 A. Table 9A. NOV9 Sequence Analysis

SEQ ID NO: 21 905 bp

NOV9a, CCTGCCTCCTCTTTCCTTTCAACATGACAGATGCCGCTGTGTCCTTCGCCAAGGACTT CGI 00466-01 DNA Sequence CCTGGCAGGTGGAGTGGCCGAAGCCATCTCCAAGACAGCGGTAGCGCCCATCGAGCAG GTCAAGCTGCTGCTGCAGGTGCAGCATGCCAGCAAGCAGATCACCTCAGCTAAGCAAT ACAAGGGCATTATAGACTGCGTGGTCCGTATTCCCAAGAAGCAGGGAGTCCTGTCCTG GCGCGGTAACCTGGCCAATGCCATCAGATACTTCCCCACCCAGGCTTTTAACTTCGCC TTCAAAGATAAATACAAGCAGATCTTCCTGGGTGGTGTGGACAAAAGAACTCAGTTTG GGCGCTACTTTGCAGGGAATCTGGCATCAGGAGGTGCCGCTGGGGCCACATACTTGTG TTTTGTGTACCCTCTTGATTTTGCCCGTACCTGTCTAGCAGCTAATGTGGGTAAAGCT GAAGCTGAAAGGGAATTCCGAGGCCTCTGTGACTGCCTGGTTAAGATCTACAAATCTG ATGGGATTAAGGGCCTGTACCAAGGCTTTAACGTGTCTATGCAGGGTATTATCCGAGC TGCCTACTTCGGTATCTATGACACCGCAAAGGGAATGCTTCCGGATCCCAAGGACACT CACATCGTCATCAGCTGGATGACCACACAGACTGTCACTGCCTTTTCTGGGTTGACTT CCTATTCATTTGACATCGTTCGCGTGATGATTCAGTCAGGGCGCAAAGTAACTGACAT CATGTACACAGGCACACTTGACTGCTGGAGGAAGATTGCTGGTGATGAAGGAGGCAAA GCTTTTTTCAAGGGTTCATGGTCCAGTGTTCTCAGAGGCATGGGTGGTGCTTTTGTGC TTGTCTTGTTTGATGAAATCAAGAAGTACAGGTAA

ORF Start: ATG at 24 ORF Stop: TAA at 903

SEQ ID NO: 22 293 aa MW at 32215.1kD j NOV9a, MTDAAVSFAKDFLAGGVAEAISKTAVAPIEQVKLLLQVQHASKQITSAKQYKGIIDCV j CG I 00466-01 Protein Sequence VRIPKKQGVLS RGNLA AIRYFPTQAFNFAFKDKY QIF GGVDKRTQFGRYFAGN ASGGAAGATYLCFVYPLDFARTCIiAANVGKAEAEREFRGLCDCLVKIYKSDGIKGLYQ GFNVS QGIIRAAYFGIYDTAKGMLPDPKDTHIVISWMTTQTVTAFSGLTSYSFDIVR VMIQSGR VTDIMYTGT DC RKIAGDEGGKAFFKGS SSVLRGMGGAFV VLFDEIK KYR

Further analysis of the NOV9a protein yielded the following properties shown in Table 9B.

Table 9B. Protein Sequence Properties NOV9a

PSort analysis: 0.6400 probability located in microbody (peroxisome); 0.4500 probability located in cytoplasm; 0.2400 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV9a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 9C.

In a BLAST search of public sequence datbases, the NOV9a protein was found to have homology to the proteins shown in the BLASTP data in Table 9D.

PFam analysis predicts that the NOV9a protein contains the domains shown in the Table 9E.

Example 10.

The NOV 10 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 10A. Table 10A. NOV10 Sequence Analysis

SEQ ID NO: 23 858 bp

NOV 10a, ACATAGGCCCAGGTCTGTGGCTGGCCAGCTGCAGCTGTGGGGCCTGGCATGTGTCTCA CGI 00609-01 DNA Sequence ACATGGCCCTGGAGCTCTACATGGACCTGCTGTCAGCACCCTGCCGTGCCGTCTACAT CTTCTCGAAGAAGCATGACATCCAGTTCAACTTTCAGTTTGTGGATCTGCTGAAAGGT CACCACCACAGCAAAGAATACATTGACATCAACCCCCTCAGGAAGCTTCCCAGCCTCA AAGATGGGAAATTTATCTTAAGTGAAAGCGCGGCCATCCTTTACTACCTGTGCCGCAA GTACAGCGCACCATCGCACTGGTGCCCGCCAGACCTGCACGCACGTGCCCGTGTGGAT GAGTTCGTGGCTTGGCAACACACGGCCTTTCAGCTGCCCATGAAGAAGATAGTCTGGC TCAAGTTGCTGATCCCAAAGATAACAGGGGAGGAAGTTTCAGCTGAGAAGATGGAGCA TGCAGTGGAAGAGGTGAAGAACAGCCTGCAGCTCTTTGAGGAGTATTTTCTGCAGGAT AAGATGTTCATCACCGGGAACCAAATCTCACTGGCTGACCTGGTGGCCGTGGTGGAGA TGATGCAGCCCATGGCAGCCAACTATAATGTCTTCCTCAACAGCTCCAAGCTAGCTGA GTGGCGTATGCAGGTGGAGCTGAATATTGGCTCTGGCCTCTTTAGGGAGGCCCATGAT CGACTAATGCAGTTGGCCGACTGGGACTTTTCAACATTGGATTCAATGGTCAAGGAGA ATATTTCTGAGTTGCTGAAGAAGAGCAGGTGACCCTAAGCGCAGCCTGTCCCGCAGGG CCTGGCTGGCTTAGCAATCTGAGCCACCTTCCTTAAAGGAAATGTT

ORF Start: ATG at 49 ORF Stop: TGA at 784

SEQ ID NO: 24 245 aa MW at 28490.9kD

NOV 10a, MCLNMALE YMDLLSAPCRAVYIFSKHDIQFNFQFVD KGHHHSKEYIDINPLRKL CG100609-01 Protein Sequence PSLKDGKFI SESAAILYYLCRKYSAPSHWCPPDLHARARVDEFVAWQHTAFQLPMKK IVWLKLIiIPKITGEEVSAEKMEHAVEEVKNSLQLFEEYF QDK FITGNQISLADLVA VVEMMQPRAA1-TWF NSSKAE R QVELNIGSGLFREAHDRLMQADWDFSTLDSM VKENISE KKSR

Further analysis of the NOV 10a protein yielded the following properties shown in Table 10B.

Table 10B. Protein Sequence Properties NOVlOa

PSort analysis: j 0.4826 probability located in microbody (peroxisome); 0.4708 probability located in mitochondrial matrix space; 0.1732 probability located in mitochondrial inner membrane; 0.1732 probability located in mitochondrial intermembrane space

I SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV 10a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 1 OC.

O 03/010327

In a BLAST search of public sequence datbases, the NOVlOa protein was found to have homology to the proteins shown in the BLASTP data in Table 10D.

0

PFam analysis predicts that the NOVlOa protein contains the domains shown in the Table 10E.

Example 11.

The NOVl 1 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 11 A. MISSING AT THE TIME OF PUBLICATION

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 1 IB.

Further analysis of the NOVl la protein yielded the following properties shown in Table l lC.

Table 11C. Protein Sequence Properties NOVlla

PSort analysis: 0.4500 probability located in cytoplasm; 0.3000 probability located in microbody

(peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP analysis: No Known Signal Sequence Predicted A search of the NOVl la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 1 ID.

In a BLAST search of public sequence datbases, the NOVl la protein was found to have homology to the proteins shown in the BLASTP data in Table 1 IE.

PFam analysis predicts that the NOVl la protein contains the domains shown in the Table 1 IF.

Table 11F. Domain Analysis of NOVlla

Identities/

Pfam Domain NOVl la Match Region Similarities Expect Value for the Matched Region

Clathrin_lg_ch 3..235 154/257 (60%) 5.2e-142 226/257 (88%)

Example 12.

The NOV 12 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 12 A.

Further analysis of the NOVl 2a protein yielded the following properties shown in Table 12B.

Table 12B. Protein Sequence Properties NOV12a

PSort analysis: j 0.4500 probability located in cytoplasm; 0.3000 probability located in microbody (peroxisome); 0.1524 probability located in lysosome (lumen); 0.1000 probability located in mitochondria] matrix space

SignalP analysis: No Known Signal Sequence Predicted A search of the NOV 12a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 12C.

In a BLAST search of public sequence datbases, the NOVl 2a protein was found to have homology to the proteins shown in the BLASTP data in Table 12D.

PFam analysis predicts that the NOV 12a protein contains the domains shown in the Table 12E.

Table 12E. Domain Analysis of NOV12a

Identities/

Pfam Domain NOV 12a Match Region Similarities Expect Value for the Matched Region

AAA 346..542 60/221 (27%) 2.6e-32 140/221 (63%)

Example 13.

The NOV 13 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 13 A.

Further analysis of the NOV13a protein yielded the following properties shown in Table 13B.

Table 13B. Protein Sequence Properties NOV13a

PSort analysis: ] 0.6500 probability located in cytoplasm; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen); 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP analysis: No Known Signal Sequence Predicted A search of the NOVl 3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 13C.

In a BLAST search of public sequence datbases, the NOV13a protein was found to have homology to the proteins shown in the BLASTP data in Table 13D.

PFam analysis predicts that the NOV 13a protein contains the domains shown in the Table 13E.

Example 14.

The NOVl 4 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 14A. Table 14A. NOV14 Sequence Analysis

SEQ ID NO: 35 2626 bp

NOV 14a, CCTGCGTTGACCGCGTGCCGGGTGTCATGGCGGCCTGCAGGTACTGCTGCTCGTGCCT CGI 00819-01 DNA Sequence CCGGCTCCGGCCCCTGAGCGATGGTCCTTTCCTTCTGCCACGGCGGGATCGGGCACTC ACCCAGTTGCAAGTGCGAGCACTATGGAGTAGCGCAGGGTCTCGAGCTGTGGCCGTGG ACTTAGGCAACAGGAAATTAGAAATATCTTCTGGAAAGCTGGCCAGATTTGCAGATGG CTCTGCTGTAGTACAGTCAGGTGACACTGCAGTAATGGTCACAGCGGTCAGTAAAACA AAACCTTCCCCTTCCCAGTTTATGCCTTTGGTGGTAGACTACAGACAAAAAGCTGCTG CAGCAGGTAGAATTCCCACAAACTATCTGAGAAGAGAGATTGGTACTTCTGATAAAGA AATTCTAACAAGTCGAATAATAGATCGTTCAATTAGACCGCTCTTTCCAGCTGGCTAC TTCTATGATACACAGGTACTGTGTAATCTGTTAGCAGTAGATGGTGTAAATGAGCCTG ATGTCCTAGCAATTAATGGCGCTTCCGTAGCCCTCTCATTATCAGATATTCCTTGGAA TGGACCTGTTGGTGCAGTACGAATAGGAATAATTGATGGAGAATATGTTGTTAACCCA ACAAGAAAAGAAATGTCTTCTAGTACTTTAAATTTAGTGGTTGCTGGAGCACCTAAAA GTCAGATTGTCATGTTGGAAGCCTCTGCAGAGAACATTTTACAGCAGGACTTTTGCCA TGCTATCAAAGTGGGAGTGAAATATACCCAACAAATAATTCAGGGCATTCAGCAGTTG GTAAAAGAAACTGGTGTTACCAAGAGGACACCTCAGAAGTTATTTACCCCTTCGCCAG AGATTGTGAAATATACTCATAAACTTGCTATGGAGAGACTCTATGCAGTTTTTACAGA TTACGAGCATGACAAAGTTTCCAGAGATGAAGCTGTTAACAAAATAAGATTAGATACG GAGGAACAACTAAAAGAAAAATTTCCAGAAGCCGATCCATATGAAATAATAGAATCCT TCAATGTTGTTGCAAAGGAAGTTTTTAGAAGTATTGTTTTGAATGAATACAAAAGGTG CGATGGTCGGGATTTGACTTCACTTAGGAATGTAAGTTGTGAGGTAGATATGTTTAAA ACCCTTCATGGATCAGCATTATTTCAAAGAGGACAAACACAGGTGCTTTGTACCGTTA CATTTGATTCATTAGAATCTGGTATTAAGTCAGATCAAGTTATAACAGCTATAAATGG GATAAAAGATAAAAATTTCATGCTGCACTACGAGTTTCCTCCTTATGCAACTAATGAA ATTGGCAAAGTCACTGGTTTAAATAGAAGAGAACTTGGGCATGGTGCTCTTGCTGAGA AAGCTTTGTATCCTGTTATTCCCAGAGATTTTCCTTTCACCATAAGAGTTACATCTGA AGTCCTAGAGTCAAATGGGTCATCTTCTATGGCATCTGCATGTGGCGGAAGTTTAGCA TTAATGGATTCAGGGGTTCCAATTTCATCTGCTGTTGCAGGCGTAGCAATAGGATTGG TCACCAAAACCGATCCTGAGAAGGGTGAAATAGAAGATTATCGTTTGCTGACAGATAT TTTGGGAATTGAAGATTACAATGGTGACATGGACTTCAAAATAGCTGGCACTAATAAA GGAATAACTGCATTACAGGCTGATATTAAATTACCTGGAATACCAATAAAAATTGTGA TGGAGGCTATTCAACAAGCTTCAGTGGCAAAAAAGGAGATATTACAGATCATGAACAA AACTATTTCAAAACCTCGAGCATCTAGAAAAGAAAATGGACCTGTTGTAGAAACTGTT CAGGTTCCATTATCAAAACGAGCAAAATTTGTTGGACCTGGTGGCTATAACTTAAAAA AACTTCAGGCTGAAACAGGTGTAACTATTAGTCAGGTGGATGAAGAAACGTTTTCTGT ATTTGCACCAACACCCAGTGTTATGCATGAGGCAAGAGACTTCATTACTGAAATCTGC AAGGATGATCAGGAGCAGCAATTAGAATTTGGAGCAGTATATACCGCCACAATAACTG AAATCAGAGATACTGGTGTAATGGTAAAATTATATCCAAATATGACTGCGGTACTGCT TCATAACACACAACTTGATAACGAAAGATTAAACATCCTACTGCCCTAGGATTAGAAG TTGGCCAAGAAATTCAGGTGAAATACTTTGGACGTGACCCAGCCGATGGAAGAATGAG GCTTTCTCGAAAAGTGCTTCAGTCGCCAGCTACAACCGTGGTCAGAACTTTGAATGAC AGAAGTAGTATTGTAATGGGAGAACCTATTTCACAGTCATCATCTAATTCTCAGTGAT TTTTTTTTTTTAAAGAGAATTCTAGAATTCTATTTTGTCTAGGGTGATGTGCTGTAGA GCAACATTTTAGTAGATCTTCCATTGTGTAGATTTCTATATAATATAAATACATTTTA ATTATTTGTACTAAAATGCTCATTTACATGTGCCATTTTTTTAATTCGAGTAACCCAT ATTTGTTTAATTGTATTTACATTATAAATCAAGAAATATTTATTATTAAAAGTAAGTC ATTTATACATCTTAGA

ORF Start: ATG at 27 ORF Stop: TAG at 2193

SEQ ID NO: 36 722 aa MW at 79307.2kD

NOV 14a, MAACRYCCSC RLRPLSDGPFLLPRRDRA TQ QVRALWSSAGSRAVAVDLGNRK EI CGI 00819-01 Protein Sequence SSGKI.ARFADGSAWQSGDTAVMWAVSKTKPSPSQFMPLVVDYRQKAAAAGRIPTNY RREIGTSDKEILTSRIIDRSIRPLFPAGYFYDTQVLCNLIiAVDGVNEPDV AINGAS VALSLSDIPWNGPVGAVRIGIIDGEYWNPTRKEMSSSTLN WAGAPKSQIVMLEAS AENILQQDFCHAIKVGVTCYTQQIIQGIQQLVKETGVTKRTPQKLFTPSPEIVKYTHK AMERLYAVFTDYEHDKVSRDEAV KIR DTEEQ KEKFPEADPYEIIESFNWAKEVF RSIVLNEY RCDGRDLTSLRNVSCEVDMFKTLHGSALFQRGQTQV CTVTFDS ESGI KSDQVITAINGIKDKNF LHYEFPPYATNEIGKVTG RRELGHGALAEICAYPVIPR DFPFTIRVTSEVLESNGSSSMASACGGSLALMDSGVPISSAVAGVAIGLVTKTDPEKG EIEDYRLLTDILGIEDYNGDMDFKIAGTNKGITA QADIKLPGIPIKIVMEAIQQASV AKKEILQIMNKTISKPRASRKENGPWETVQVPLSKRAKFVGPGGY KK QAETGVT ISQVDEETFSVFAPTPSVMHEARDFITEICKDDQEQQLEFGAVYTATITEIRDTGVMV KLYPN TAVL HNTQLDNERLNILLP Further analysis of the NOV 14a protein yielded the following properties shown in Table 14B.

Table 14B. Protein Sequence Properties NOV14a

PSort analysis: 0.5016 probability located in mitochondrial matrix space; 0.4500 probability located in cytoplasm; 0.2212 probability located in mitochondrial inner membrane;

0.2212 probability located in mitochondrial intermembrane space

: SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV 14a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 14C.

In a BLAST search of public sequence datbases, the NOV 14a protein was found to have homology to the proteins shown in the BLASTP data in Table 14D.

PFam analysis predicts that the NOV 14a protein contains the domains shown in the Table 14E.

Example 15.

The NOV 15 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 15 A. Table 15A. NOV15 Sequence Analysis

SEQ ID NO: 37 2030 bp

NOV 15a, CCATGTCCTTCCAGAGTATCATCCACCTGTCCCTGGACAGCCCTGTCCATGCCGTTTG CGI 00872-01 DNA Sequence TGTGTTGGGCACAGAAATCTGCTTGGATCTCACCAGGTGTGCCCCCCAGAAGTGCCAG TGCTTCACCATCCATGGCTCTGGGAGGGTCTTGATCGATGTGGCCAACACGGTGATTT CTGAGAAGGAGGACGCCACCATCTGGTGGCCCCTGTCTGATCCCACGTACGCCACAGT GAAGATGACATCGCCCAGCCCTTCCGTGGATGCGGATAAGGTAAGCCTCACATACTAT GGGCCCAACGAGGATGCCCCCGTGGGCACAGCTGTGCTGTACCTCACTGGCATTGGTG AGTGTTGCTCCAACTGGGAGCCTCCCAACCGCTGGGACCCCAGATCCATTTTTTCTCA GAAAAAATGGATCTGGGGTCCCAGCGGTTGGGGTGCCATCCTGCTTGTGAATTGCAAC CCTGCTGATGTGGGCCAGCAACTTGAGGACAAGAAAACCAAGAAAGTGATCTTTTCAG AGGAAATAACGAATCTGTCCCAGATGACTCTGAATGTCCAAGGCCCCAGCTGTATCTT AAAGAAATATCGGCTAGTCCTCCATACCTCCAAGGAAGAGTCGAAGAAGGCGAGAGTC TACTGGCCCCAAAGTGAAGACAACTCCAGTACCTTTGAGTTGGTGCTGGGGCCCGACC AGCACGCCTATACCTTGGCCCTCCTCGGGAACCACTTGAAGGAGACTTTCTACGTTGA AGCTATAGCATTCCCATCTGCCGAATTCTCAGGCCTCATCTCCTACTCTGTGTCCCTG GTGGAGGAGTCTTTGCAGTCAATTCCAGAGACTGTGCTGTACAAAGACACGGTGGTGT TCCGGGTGGCTCCCTGTGTCTTCATTCCCTGTACCCAGGTGCCTCTGGAGGTTTACCT GTGCTATCTGAGCTGGGTGTTGAGGGTTGAGCAGGAGTTGGCAGGAAGGAAGGGGGTT CTTACCGTACCTTTTCCGGCAAACAATCTGTCTTCCTCTCCATTCCAGGATGAGATGG CCTTCTGCTACACCCAGGCTCCCCACAAGACAACGTCCTTGATCCTCGACACACCTCA GGCCGCCGATCTCGATGAGTTCCCCATGAAGTACTCACTGGTGCCTGGTATTGGCTAC ATGATCCAGGACACTGAGGACCATAAAGTGGCCAGCATGGATTCCATTGGGAACCTGA TGGTGTCCCCACCTGTCAAGGTCCAAGGGAAAGAGTACCCGCTGGGCAGAGTCCTCAT TGGCAGCAGCTTTTACCCCTCTAGCGCAGAGGGCCGGGCCATGAGTAAGACCCTCCGA GACTTCCTCTATGCCCAGCAGGTCCAAGCGCCGGTGGAGCTCTACTCAGATTGGCTAA TGACTGGCCACGTGGATGAGTTCATGTGCTTCATCCCCACAGATGACAAGCAGGGCTT CCTGCTGCTCCTGGCCAGCCCCAGTGCCTGCTATAAACTGTTCCGAGAGAAACAGAAG GAAGGCTATGGCGACGCTCTTCTGTTTGATGAGCTTAGAGCAGATCAGCTCCTGTCTA ATGGTAAGGGAACTCCCTTTCGCCCCCCCCCCCACCCACCCACCCACCCACAGAAGTG CATTCACCTGAACCGTGACATCCTGAAGACGGAGCTGGGCCTGGTGGAACAGGACATC ATCGAGATTCCCCAGCTGTTCTGCTTGGAGAAGCTGACTAACATCCCCTCTGACCAGC AGCCCAAGTTGCGGATGATTGTGATGGGCAAGAACCTGGGGATCCCCAAGCCTTTTGG GCCCCAAATCAAGGGGACCTGCTGCCTGGAAGAAAAGATTTGCTGCTTGCTGGAGCCC CTGGGCTTCAAGTGCACCTTCATCAATGACTTTGACTGTTACCTGACAGAGGTCGGAG ACATCTGTGCCTGTGCCAACATCCGCCGGGTGCCCTTTGCCTTCAAATGGTGGAAGAT GGTACCTTAGACCCAGGCCCTGGAGCTGCCAGCTCTGCCCCAGCGTGGATGGCCCACT

ORF Start: ATG at 3 ORF Stop: TAG at 1980

SEQ ID NO: 38 659 aa MW at 73697.2kD

NOV 15a, MSFQSIIHLSLDSPVHAVCV GTEICLDLTRCAPQKCQCFTIHGSGRVLIDVANTVIS CGI 00872-01 Protein Sequence EKEDATI PLSDPTYATVKMTSPSPSVDADKVSLTYYGPNEDAPVGTAVLYLTGIGE CCSNWEPP.mWDPRSIFSQKK WGPSGWGAILLraCNPADVGQQLEDKKTKK IFSE EITN SQMTLNVQGPSCILKKYRLVLHTSKEESK ARVYWPQSEDNSSTFELV GPDQ HAYT1A LGNH KETFYVEAIAFPSAEFSGLISYSVΞLVEESLQSIPETVLYKDTVVF RVAPCVFIPCTQVPLEVYCYLSWVLRVEQELAGRKGVLTVPFPANNLSSSPFQDEMA FCYTQAPHKTTSLILDTPQAAD DEFPMKYS VPGIGYMIQDTEDHKVASMDSIGN M VSPPVKVQGKEYP GRVLIGSSFYPSSAEGRA SKT RDFLYAQQVQAPVELYΞDWLM TGHVDEF CFIPTDDKQGFL ASPSACYK FREKQKEGYGDALLFDELRADQ SN GKGTPFRPPPHPPTHPQ CIHLNRDILKTELGLVEQDIIEIPQLFC EKLTNIPSDQQ PKLRMIVMGKN GIPKPFGPQIKGTCCLEEKICC LEPLGFKCTFINDFDCYLTEVGD ICACA IRRVPFAFKWKVP

Further analysis of the NOV 15a protein yielded the following properties shown in Table 15B. Table 15B. Protein Sequence Properties NOV15a

PSort analysis: j 0.4500 probability located in cytoplasm; 0.3600 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen); 0.0598 probability located in microbody (peroxisome)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV 15a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 15C.

In a BLAST search of public sequence datbases, the NOVl 5a protein was found to have homology to the proteins shown in the BLASTP data in Table 15D.

PFam analysis predicts that the NOVl 5a protein contains the domains shown in the Table 15E.

Example 16.

The NOV 16 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 16 A. Table 16A. NOV16 Sequence Analysis

SEQ ID NO: 39 2018 bp

NOV 16a, GATGGCCCCAAAGAGAGTTGTGCAGCTGTCCCTGAAGATGCCTACCCATGCCGTGTGT CG 100980-01 DNA Sequence GTGGTGGGAGTCGAGGCACATGTGGACATTCACAGTGATGTGCCCAAGGGTGCCAACA GCTTCAGGGTCTCTGGAAGCTCCGGGGTGGAGGTCTTCATGGTCTACAACCGCACACG TGTGAAAGAGCCCATAGGCAAGGCCCGTTGGCCGCTAGACACTGATGCAGACATGGTC GTATCTGTGGGCACAGCCAGTAAGGAATTAAAGGACTTCAAGGTAAGAGTCTCCTACT TTGGGGAGCAGGAAGACCAAGCTCTGGGCCGCAGCGTGCTTTACCTCACTGGCGTCCT AGAACCCCTTCCTGGAGCCTCCTGGGTCCCACTGATCCCAAGGCATCTTATTTTGCCA CAGAAAACCTGGCGCTGGGGCCCTGAGGGCTATGGGGCTATCTTGCTGGTGAACTGTG ACCGGGACAATCACAGGTCCGCAGAGCCTGACCTCACCCACAGCTGGCTGATGTCGCT GGCTGACCTGCAGGACATGTCCCCAATGCTGCTGAGCTGCAATGGCCCCGACAAGCTC TTCGACAGCCACAAGCTTGTCTTGAACGTGCCCTTTTCTGATTCCAAAAGAGTGAGGG TCTTCTGTGCCAGGGGTCCTGAGGATGTGTGTGAGGCCTATAGGCATGTGCTGGGCCA AAATAAGGTGTCCTATGAGGTACCCCGCTTGCATGGGGATGAGGAGCGCTTCTTCGTG GAAGGCCTGTCCTTCCCTGATGCCGGCTTCACAGGACTCATCTCCTTCCATGTCACTC TGCTGGACGACTCCAACGAGGATTTCTCGGCATCCCCTATCTTCACTGACACTGTGGT GTTCCGAGTGGCACCCTGGATCATGACGCCCAGCACTCTGCCACCCCTAGAGGTGTAT GTGTGCCGGGTGAGGAACAACACGTGTTTTGTGGATGCGGTGGCAGAGCTGGCCAGGA AGGCCGGCTGCAAGCTGACCATCTGCCCACAGGCCGAGAACCGCAACGACCGCTGGAT CCAGGATGAGATGGAGCTGGGCTACGTTCAGGCGCCGCACAAGACCCTCCCGGTGGTC TTTGACTCCCCAAGGAATGGGGAACTGCAGGATTTCCCTTACAAAAGAATCCTGGGTC CAGATTTTGGTTACGTGACTCGGGAACCACGCGACAGGTCTGTGAGTGGCCTGGACTC CTTTGGGAACCTGGAGGTCAGCCCTCCAGTGGTGGCCAATGGGAAAGAGTACCCCCTG GGGAGGATCCTCATTGGGGGCAACCTGCCTGGGTCAAGTGGCCGCAGGGTCACCCAGG TGGTGCGGGACTTCCTCCATGCCCAGAAGGTGCAGCCCCCCGTGGAGCTCTTTGTGGA CTGGTTGGCCGTGGGCCATGTGGATGAGTTTCTGAGCTTTGTCCCTGCCCCCGATGGG AAGGGCTTCCGGATGCTCCTGGCCAGCCCTGGGGCCTGCTTCAAGCTCTTCCAGGAAA AGCAGAAGTGTGGCCACGGGAGGGCCCTCCTGTTCCAGGGGGTTGTTGGTGATGAGCA GGTCAAGACCATCTCCATCAACCAGGTGCTCTCCAATAAAGACCTCATCAACTACAAT AAGTTTGTGCAGAGCTGCATTGACTGGAACCGTGAGGTGCTGAAGCGGGAGCTGGGCC TGGCAGAGTGTGACATCATTGACATCCCACAGCTCTTCAAGACCGAGAGGAAAAAAGC AACGGCCTTCTTCCCTGACTTGGTGAACATGCTGGTGCTGGGGAAGCACCTGGGCATC CCCAAGCCCTTTGGGCCCATCATCAATGGCTGCTGCTGCCTGGAGGAGAAGGTGCGGT CCCTGCTGGAGCCGCTGGGCCTCCACTGCACCTTCATTGATGACTTCACTCCATACCA CATGCTGCATGGGGAGGTGCACTGTGGCACCAATGTGTGCAGAAAGCCCTTCTCTTTC AAGTGGTGGAACATGGTGCCCTGAGACAGCTCCCACCCACCATCCT

ORF Start: ATG at 2 ORF Stop: TGA at 1994

SEQ ID NO: 40 664 aa MW at 74356.9kD

NOV 16a, MAPKRVVQLSLIMPTHAVCVVGVEAHVDIHSDVPKGANSFRVSGSSGVEVF VYNRTR CGI 00980-01 Protein Sequence VKEPIGKAR PLDTDADMWSVGTASKE KDFKVRVSYFGEQEDQA GRSVLYLTGVL EP PGASWVP IPRHLILPQKTWRWGPEGYGAILLVNCDRDNHRSAEPDLTHSWLMSL ADLQDMSPMLLSCNGPDK FDSHKLVLNVPFSDSKRVRVFCARGPEDVCEAYRHVLGQ NKVSYEVPRLHGDEERFFVEG ΞFPDAGFTGLISFHVT LDDSNEDFSASPIFTDTW FRVAP IMTPSTLPP EVYVCRVRNNTCFVDAVAELARKAGCK TICPQAENRNDRWI QDEMELGYVQAPHKT PWFDSPR GELQDFPYKRILGPDFGYVTREPRDRSVSG DS FGNLEVSPPWANGKEYPLGRI IGGN PGSSGRRVTQWRDF HAQKVQPPVELFVD WI-AVGHVDEF SFVPAPDGKGFRMLLASPGACFK FQEKQKCGHGRALLFQGWGDEQ VKTISINQVLSNKDLINYNKFVQSCIDWNREV KRELGLAECDIIDIPQ FKTERKKA TAFFPD VNMLV GKHLGIPKPFGPIINGCCC EEKVRS EPLGLHCTFIDDFTPYH LHGEVHCGTNVCRKPFSFKWWNMVP

Further analysis of the NOV 16a protein yielded the following properties shown in Table 16B. Table 16B. Protein Sequence Properties NOVlόa

Psort analysis: 0.5500 probability located in endoplasmic reticulum (membrane); 0.2424 probability located in lysosome (lumen); 0.1410 probability located in microbody

(peroxisome); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV 16a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 16C.

In a BLAST search of public sequence datbases, the NOVl 6a protein was found to have homology to the proteins shown in the BLASTP data in Table 16D.

PFam analysis predicts that the NOVlόa protein contains the domains shown in the Table 16E.

Table 16E. Domain Analysis of NOVlόa

Identities/

Pfam Domain NOVlόa Match Region Similarities Expect Value for the Matched Region

PAD 1..664 465/691 (67%) 623/691 (90%)

Example 17.

The NOV 17 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 17A.

Further analysis of the NOV 17a protein yielded the following properties shown in Table 17B.

Table 17B. Protein Sequence Properties NOVl 7a

PSort analysis: | 0.9200 probability located in mitochondrial matrix space; 0.8000 probability located in microbody (peroxisome); 0.6000 probability located in mitochondrial inner membrane; 0.6000 probability located in mitochondrial intermembrane space

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV 17a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 17C.

In a BLAST search of public sequence datbases, the NOV 17a protein was found to have homology to the proteins shown in the BLASTP data in Table 17D.

PFam analysis predicts that the NOV 17a protein contains the domains shown in the Table 17E.

Example 18.

The NOVl 8 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 18A.

Further analysis of the NOVl 8a protein yielded the following properties shown in Table 18B.

Table 18B. Protein Sequence Properties NOV18a

PSort analysis: j 0.6400 probability located in plasma membrane; 0.4600 probability located in Golgi body; 0.3700 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP analysis: Cleavage site between residues 64 and 65

A search of the NOVl 8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 18C.

In a BLAST search of public sequence datbases, the NOV 18a protein was found to have homology to the proteins shown in the BLASTP data in Table 18D.

PFam analysis predicts that the NOV 18a protein contains the domains shown in the Table 18E.

Example 19.

The NOV 19 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 19A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 19B.

Further analysis of the NOV 19a protein yielded the following properties shown in Table 19C.

Table 19C. Protein Sequence Properties NOV19a

PSort analysis: 0.4500 probability located in cytoplasm; 0.4275 probability located in microbody

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV 19a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 19D.

In a BLAST search of public sequence datbases, the NOV 19a protein was found to have homology to the proteins shown in the BLASTP data in Table 19E.

PFam analysis predicts that the NOV 19a protein contains the domains shown in the Table 19F.

Table 19F. Domain Analysis of NOV19a

Identities/

Pfam Domain NOV 19a Match Region Similarities Expect Value for the Matched Region aldo ket red I3..306 164/368 (45%) 1.5e-144 261/368 (71%)

Example 20.

The NOV20 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 20A.

Further analysis of the NOV20a protein yielded the following properties shown in Table 20B.

Table 20B. Protein Sequence Properties NOV20a

PSort analysis: j 0.3700 probability located in outside; 0.2339 probability located in microbody (peroxisome); 0.1080 probability located in nucleus; 0.1000 probability located in endoplasmic reticulum (membrane)

SignalP analysis: Cleavage site between residues 24 and 25

A search of the NOV20a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 20C.

In a BLAST search of public sequence datbases, the NOV20a protein was found to have homology to the proteins shown in the BLASTP data in Table 20D.

PFam analysis predicts that the NOV20a protein contains the domains shown in the Table 20E.

Table 20E. Domain Analysis of NOV20a

Identities/

Pfam Domain NOV20a Match Region Similarities Expect Value for the Matched Region

RnaseH 136..257 50/147 (34%) l . l e-27 93/147 (63%)

Example 21.

The NOV21 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 21 A.

Table 21A. NOV21 Sequence Analysis

SEQ ID NO: 51 2536 bp

NOV21a, GGGACACTGACATGGACTGAAGGAGTAGAAAAGAAGCCTTGGGCTCTCCCAGATGGAA CG57109-01 DNA Sequence GAATGACCGTGTGAGGAAACTGTTTAACCTCAAGGGCAGGGAAATCAGGAGCGTCTCT GATTTCTTCAGGGAAGGGGATGCTTTCATAGCTATGGGCAAAGAACCACTGACACTGA AGAGCATTCAGGTGGCTGTAGAAGAACTGTACCCCAACAAAGCCCGGGCCCTGACACT GGCCCAGCACAGCCGTGCCCCTTCTCCAAGGCTGAGGAGCAGGCTGTTTAGCAAGGCT CTGAAAGGAGACCACCGCTGTGGGGAGACCGAGACCCCCAAGAGCTGCAGCGAAGTTG CAGGATGCAAGGCAGCCATGAGGCACCAGGGGAAGATCCCCGAGGAGCTTTCACTAGA TGACAGAGCGAGGACCCAGAAGAAGTGGGGGAGGGGGAAATGGGAGCCAGAACCCAGT AGCAAGCCCCCCAGGGAAGCCACTCTGGAAGAGAGGCACGCAAGGGGAGAGAAGCATC TTGGGGTGGAGATTGAAAAGACCTCGGGTGAAATTATCAGATGCGAGAAGTGCAAGAG AGAGAGGGAGCTTCAGCAGAGCCTGGAGCGTGAGAGGCTTTCTCTGGGGACCAGTGAG CTGGATATGGGGAAGGGCCCAATGTATGATGTGGAGAAGCTGGTGAGGACCAGAAGCT GCAGGAGGTCTCCCGAGGCAAATCCTGCAAGTGGGGAGGAAGGGTGGAAGGGTGACAG CCACAGGAGCAGCCCCAGGAATCCCACTCAAGAGCTGAGGAGACCCAGCAAGAGCATG GACAAGAAAGAGGACAGAGGCCCAGAGGATCAAGAAAGCCATGCTCAGGGAGCAGCCA AGGCCAAGAAGGACCTTGTGGAAGTTCTTCCTGTCACAGAGGAGGGGCTGAGGGAGGT GAAGAAGGACACCAGGCCCATGAGCAGGAGCAAACATGGTGGCTGGCTCCTGAGAGAG CACCAGGCGGGCTTTGAGAAGCTCCGCAGGACCCGAGGAGAAGAGAAGGAGGCAGAGA AGGAGAAAAAGCCATGTATGTCTGGAGGCAGAAGGATGACTCTCAGAGATGACCAACC TGCAAAGCTAGAAAAGGAGCCCAAGACGAGGCCAGAAGAGAACAAGCCAGAGCGGCCC AGCGGTCGGAAGCCACGGCCCATGGGCATCATTGCCGCCAATGTGGAAAAGCATTATG AGACTGGCCGGGTCATTGGGGATGGGAACTTTGCTGTCGTGAAGGAGTGCAGACACCG CGAGACCAGGCAGGCCTATGCGATGAAGATCATTGACAAGTCCAGACTCAAGGGCAAG GAGGACATGGTGGACAGTGAGATCTTGATCATCCAGAGCCTCTCTCACCCCAACATCG TGAAATTGCATGAAGTCTACGAAACAGACATGGAAATCTACCTGATCCTGGAGTACGT GCAGGGAGGAGACCTTTTTGACGCCATCATAGAAAGTGTGAAGTTCCCGGAGCCCGAT GCTGCCCTCATGATCATGGACTTATGCAAAGCCCTCGTCCACATGCACGACAAGAGCA TTGTCCACCGGGACCTCAAGCCGGAAAACCTTTTGGTTCAGCGAAATGAGGACAAATC TACTACCTTGAAATTGGCTGATTTTGGACTTGCAAAGCATGTGGTGAGACCTATATTT ACTGTGTGTGGGACCCCAACTTACGTAGCTCCCGAAATTCTTTCTGAGAAAGGTTATG GACTGGAGGTGGACATGTGGGCGGCTGGCGTGATCCTCTATATCCTGCTGTGTGGCTT TCCCCCATTCCGCAGCCCTGAGAGGGACCAGGACGAGCTCTTTAACATCATCCAGCTG GGCCACTTTGAGTTCCTCCCCCCTTACTGGGACAATATCTCTGATGCTGCTAAAGATC TGGTGAGCCGGTTGCTGGTGGTAGACCCCAAAAAGCGCTACACAGCTCATCAGGTTCT TCAGCACCCCTGGATCGAAACAGCTGGCAAGACCAATACAGTGAAACGACAGAAGCAG GTGTCCCCCAGCAGCGAGGGTCACTTCCGGAGCCAGCACAAGAGGGTTGTGGAGCAGG TATCATAGTCACCACCTTGGGAATCTGTCCAGCCCCCAGTTCTGCTCAAGGACAGAGA AAAGGATAGAAGTTTGAGAGAAAAACAATGAAAGAGGCTTCTTCACATAATTGGTGAA TCAGAGGGAGAGACACTGAGTATATTTTAAAGCATATTAAAAAAATTAAGTCAATGTT AAATGTCACAACATATTTTTAGATTTGTATATTTAAAGCCTTTAATACATTTTTGGGG GGTAAGCATTGTCATCAGTGAGGAATTTTGGTAATAATGATGTGTTTTGCTTCCCCTT TGTAACCAAGTTTATTCTGTACTACAGGAGTGGTGCTTACCAGGGTCTAAACTCCCCC TGTGAGATTAATAAGGTGCATTGTGGTCTTTCTGTGTTAATAAAATGTGCTCTGAATA ACAGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGG

ORF Start: ATG at 150 ORF Stop: TAG at 2094

SEQ ID NO: 52 648 aa MW at 73813.6kD

NOV21a, MGKEPLTLKSIQVAVEELYPNKARA TLAQHSRAPSPR RSRLFSKALKGDHRCGETE CG57109-01 Protein Sequence TPKSCSEVAGC AAMRHQGKIPEELS DDRARTQKKWGRGKWEPEPSSKPPREATLEE RHARGEKHLGVEIEKTSGEIIRCEKCKRERELQQSLERERLSLGTSE DMGKGPMYDV EK VRTRSCRRSPEANPASGEEGWKGDSHRSSPRNPTQELRRPSKS DKKEDRGPEDQ ESHAC2GAAKAKKDLVEVX,PVTEEG REVKKDTRPMSRSKHGG LREHQAGFEK RRT RGEEKEAEKEKKPCMSGGRRMTLRDDQPAKLEKEPKTRPEENKPERPSGRKPRPMGII AANVEKHYETGRVIGDGNFAWKECRHRETRQAYAMKIIDKSRLKGKEDMVDSEILII QS SHPNIVKLHEVYETDMEIYLI EYVQGGDLFDAIIESVKFPEPDAALMIMDLCKA LVIIMHDKSIλmRD KPENLLVQRNEDKSTT KLADFGI-AKHVVRPIFTVCGTPTYVAP EILSEKGYG EVDMWAAGVILYILLCGFPPFRSPERDQDE FNIIQLGHFEFLPPY D NISDAAKDLVSRLLVλ/DPKKRYTAHQVLQHPWIETAGKTNTVKRQKQVSPSSEGHFRS QHKRWEQVS

SEQ ID NO: 53 2808 bp

NOV21b, TTTACAGAGTCAGGCCTCACCGTGAGAGGGCTCCTGTATTAGTCCCTTTTCATGCTGC CG57109-02 DNA Sequence TTATAGAGACATACCTGAGACTGGGCAATTTGCAGAGAAAGGTTTTCTTGGACTTACA GTTAGTTCCACGTGGCTGGGGAAGCCTCACAATCATGGCGGAAGGCAAGGAAGGGCAA GTCCCATCTTACATGGATGGCAGCAGGCAAAGAGAGAATGAGGAAGATGCAAAAGCGG AAACCCCTGATGTAACCATCAGATCTTATGAGATTTATTCΛCTACCATGGAACAGACA GCAAGGCGTATGTGACCATTCTCTAGAATATTTAAGCTCGAGAATCTCAGAGCGGAAG CTGCAAGGCTCCTGGCTGCCTGCCAGCCGAGGGAATCTGGAGAAACCATTCCTGGGGC CGCGTGGCCCCGTCGTGCCCTTGTTCTGCCCTCGGAATGGCCTTCACTCAGCACATCC TGAGAACAGCCCTCTGAAGCCCAGGGTCGTGACCGTAGTGAAGCTGGGTGGGCAGCGC CCCCGAAAGATCACTCTGCTCCTCAACAGGCGATCAGTGCAGACGTTCGAGCAGCTCT TAGCTGACATCTCAGAAGCCTTGGGCTCTCCCAGATGGAAGAATGACCGTGTGAGGAA ACTGTTTAACCTCAAGGGCAGGGAAATCAGGAGCGTCTCTGATTTCTTCAGGGAAGGG GATGCTTTCATAGCTATGGGCAAAGAACCACTGACACTGAAGAGCATTCAGGTGGCTG TAGAAGAACTGTACCCCAACAAAGCCCGGGCCCTGACACTGGCCCAGCACAGCCGTGC CCCTTCTCCAAGGCTGAGGAGCAGGCTGTTTAGCAAGGCTCTGAAAGGAGACCACCGC TGTGGGGAGACCGAGACCCCCAAGAGCTGCAGCGAAGTTGCAGGATGCAAGGCAGCCA TGAGGCACCAGGGGAAGATCCCCGAGGAGCTTTCACTAGATGACAGAGCGAGGACCCA GAAGAAGTGGGGGAGGGGGAAATGGGAGCCAGAACCCAGTAGCAAGCCCCCCAGGGAA GCCACTCTGGAAGAGAGGCACGCAAGGGGAGAGAAGCATCTTGGGGTGGAGATTGAAA AGACCTCGGGTGAAATTATCAGATGCGAGAAGTGCAAGAGAGAGAGGGAGCTCCAGCA GAGCCTGGAGCGTGAGAGGCTTTCTCTGGGGACCAGTGAGCTGGATATGGGGAAGGGC CCAATGTATGATGTGGAGAAGCTGGTGAGGACCAGAAGCTGCAGGAGGTCTCCCGAGG CAAATCCTGCAAGTGGGGAGGAAGGGTGGAAGGGTGACAGCCACAGGAGCAGCCCCAG GAATCCCACTCAAGAGCTGAGGAGACCCAGCAAGAGCATGGACAAGAAAGAGGACAGA GGCCCAGAGGATCAAGAAAGCCATGCTCAGGGAGCAGCCAAGGCCAAGAAGGACCTTG TGGAAGTTCTTCCTGTCACAGAGGAGGGGCTGAGGGAGGTGAAGAAGGACACCAGGCC CATGAGCAGGAGCAAACATGGTGGCTGGCTCCTGAGAGAGCACCAGGCGGGCTTTGAG AAGCTCCGCAGGACCCGAGGAGAAGAGAAGGAGGCAGAGAAGGAGAAAAAGCCATGTA TGTCTGGAGGCAGAAGGATGACTCTCAGAGATGACCAACCTGCAAAGCTAGAAAAGGA GCCCAAGACGAGGCCAGAAGAGAACAAGCCAGAGCGGCCCAGCGGTCGGAAGCCACGG CCCATGGGCATCATTGCCGCCAATGTGGAAAAGCATTATGAGACTGGCCGGGTCATTG GGGATGGGAACTTTGCTGTCGTGAAGGAGTGCAGACACCGCGAGACCAGGCAGGCCTA TGCGATGAAGATCATTGACAAGTCCAGACTCAAGGGCAAGGAGGACATGGTGGACAGT GAGATCTTGATCATCCAGAGCCTCTCTCACCCCAACATCGTGAAATTGCATGAAGTCT ACGAAACAGACATGGAAATCTACCTGATCCTGGAGTACGTGCAGGGAGGAGACCTTTT TGACGCCATCATAGAAAGTGTGAAGTTCCCGGAGCCCGATGCTGCCCTCATGATCATG GACTTATGCAAAGCCCTCGTCCACATGCACGACAAGAGCATTGTCCACCGGGACCTCA AGCCGGAAAACCTTTTGGTTCAGCGAAATGAGGACAAATCTACTACCTTGAAATTGGC TGATTTTGGACTTGCAAAGCATGTGGTGAGACCTATATTTACTGTGTGTGGGACCCCA ACTTACGTAGCTCCCGAAATTCTTTCTGAGAAAGGTTATGGACTGGAGGTGGACATGT GGGCTGCTGGCGTGATCCTCTATATCCTGCTGTGTGGCTTTCCCCCATTCCGCAGCCC TGAGAGGGACCAGGACGAGCTCTTTAACATCATCCAGCTGGGCCACTTTGAGTTCCTC CCCCCTTACTGGGACAATATCTCTGATACAGCTGCTAAAGATCTGGTGAGCCGGTTGC TGGTGGTAGACCCCAAAAAGCGCTACACAGCTCATCAGGTTCTTCAGCACCCCTGGAT CGAAACAGCTGGCAAGACCAATACAGTGAAACGACAGAAGCAGGTGTCCCCCAGCAGC GAGGGTCACTTCCGGAGCCAGCACAAGAGGGTTGTGGAGCAGGTATCATAGTCACCAC

CTTGGGAATCTGTCCAGCCCCCAGTTCTGCTCAAGGACAGAGAAAAGGATAGAAGTTT GAGAGAAAAACAATGAAAGAGGCTTCTTCACATAATTGGTGAATCAGAGGGAGAGACA CTGAGTATATTTTAAAGCATATTA

ORF Start: ATG at 151 ORF Stop: TAG at 2659

SEQ ID NO: 54 836 aa MW at 95152.6kD

NOV21b, MAEGKEGQVPSYMDGSRQRENEEDAKAETPDVTIRSYEIYSLPWNRQQGVCDHSLEYL 02 Protein Sequence SSRISERKLQGS PASRGN EKPFLGPRGPWPLFCPRNGLHΞAHPENSPLKPRWT VVKLGGQRPRKITL L RRSVQTFEQLLADISEALGSPRWKNDRVRKLFNLKGREIRS VSDFFREGDAFIAMGKEPLTLKSIQVAVEELYPNKARA TLAQHSRAPSPRLRSR FS KAIiKGDHRCGETETPKSCSEVAGCKAAMRHQGKIPEELSLDDRARTQKK GRGKWEPE PSSKPPREATLEERHARGEKHLGVEIEKTSGEIIRCEKCKRERELQQS ERERLSLGT SELDMGKGPMYDVEKLVRTRSCRRSPEANPASGEEGWKGDSHRSSPRNPTQE RRPSK SMDKKEDRGPEDQESHAQGAAKAKKDLVEVLPVTEEG REVKKDTRPMSRSKHGGW L REHQAGFEKLRRTRGEEKEAEKEKKPCMSGGRRMTLRDDQPAK EKEPKTRPEENKPE RPSGRKPRPMGIIAANVEKHYETGRVIGDGNFAWKECRHRETRQAYAMKIIDKSRIiK GKEDMVDSEILIIQS SHPNIVKXHEVYETDMEIY I EYVCDGGD FDAIIESVKFPE PDAALMIMD CKA VΗMHDKSIVHRDLKPENLLVQRNEDKSTTLKLADFGLAKHVVRP IFTVCGTPTYVAPEI SEKGYGI.EVDMWAAGVI YIL CGFPPFRSPERDQDE FNII QLGHFEF PPY DNISDTAAKDLVSRLLWDPKKRYTAHQVLQHPWIETAGKTNTVKR QKQVSPSSEGHFRSQHKRWEQVS SEQ ID NO: 55 3016 bp

NOV21c, TTTACΛGAGTCACrøC.Tα-CCGTCaGAGGGCrCC^GTATTAGTCCCTTTTCATGCTGC CG57109-03 DNA Sequence TTATAGAGACATACCTGAGAC GGGαΛTTrGCAGAGAAAGGTTTTCTTGGACTTACA GTTAGTTCCΛCGTGGCTGGGGAAGCCTCIACAATC-ATGGCGGAAGGC-AAGGAAGGGCAA GTCCCATCT'TA_ATGGATGGC-AGC-AGGCAAAGAGAGAATGAGGAAGATGCAAAAGCGG AAACCCCTGATGTAACCATCAGATCTTATGAGATTTATTCACTACCATGGAACAGACA GCAAGGCGTATGTGACCATTCTCTAGAATATTTAAGCTCGAGAATCTCAGAGCGGAAG CTGCAAGGCTCCTGGCTGCCTGCCAGCCGAGGGAATCTGGAGAAACCATTCCTGGGGC CGCGTGGCCCCGTCGTGCCCTTGTTCTGCCCTCGGAATGGCCTTCACTCAGCACATCC TGAGAACAGCCCTCTGAAGCCCAGGGTCGTGACCGTAGTGAAGCTGGGTGGGCAGCGC CCCCGAAAGATCACTCTGCTCCTCAACAGGCGATCAGTGCAGACGTTCGAGCAGCTCT TAGCTGACATCTCAGAAGCCTTGGGCTCTCCCAGATGGAAGAATGACCGTGTGAGGAA ACTGTTTAACCTCAAGGGCAGGGAAATCAGGAGCGTCTCTGATTTCTTCAGGGAAGGG GATGCTTTCATAGCTATGGGCAAAGAACCACTGACACTGAAGAGCATTCAGGTGGCTG TAGAAGAACTGTACCCCAACAAAGCCCGGGCCCTGACACTGGCCCAGCACAGCCGTGC CCCTTCTCCAAGGCTGAGGAGCAGGCTGTTTAGCAAGGCTCTGAAAGGAGACCACCGC TGTGGGGAGACCGAGACCCCCAAGAGCTGCAGCGAAGTTGCAGGATGCAAGGCAGCTA TGAGGCACCAGGGGAAGATCCCCGAGGAGCTTTCACTAGATGACAGAGCGAGGACCCA GAAGAAGTGGGGGAGGGGGAAATGGGAGCCAGAACCCAGTAGCAAGCCCCCCAGGGAA GCCACTCTGGAAGAGAGGCACGCAAGGGGAGAGAAGCATCTTGGGGTGGAGATTGAAA AGACCTCGGGTGAAATTATCAGATGCGAGAAGTGCAAGAGAGAGAGGGAGCTTCAGCA GAGCCTGGAGCGTGAGAGGCTTTCTCTGGGGACCAGTGAGCTGGATATGGGGAAGGGC CCAATGTATGATGTGGAGAAGCTGGTGAGGACCAGAAGCTGCAGGAGGTCTCCCGAGG CAAATCCTGCAAGTGGGGAGGAAGGGTGGAAGGGTGACAGCCACAGGAGCAGCCCCAG GAATCCCACTCAAGAGCTGAGGAGACCCAGCAAGAGCATGGACAAGAAAGAGGACAGA GGCCCAGAGGATCAAGAAAGCCATGCTCAGGGAGCAGCCAAGGCCAAGAAGGACCTTG TGGAAGTTCTTCCTGTCACAGAGGAGGGGCTGAGGGAGGTGAAGAAGGACACCAGGCC CATGAGCAGGAGCAAACATGGTGGCTGGCTCCTGAGAGAGCACCAGGCGGGCTTTGAG AAGCTCCGCAGGACCCGAGGAGAAGAGAAGGAGGCAGAGAAGGAGAAAAAGCCATGTA TGTCTGGAGGCAGAAGGATGACTCTCAGAGATGACCAACCTGCAAAGCTAGAAAAGGA GCCCAAGACGAGGCCAGAAGAGAACAAGCCAGAGCGGCCCAGCGGTCGGAAGCCACGG CCCATGGGCATCATTGCCGCCAATGTGGAAAAGCATTATGAGACTGGCCGGGTCATTG GGGATGGGAACTTTGCTGTCGTGAAGGAGTGCAGACACCGCGAGACCAGGCAGGCCTA TGCGATGAAGATCATTGACAAGTCCAGACTCAAGGGCAAGGAGGACATGGTGGACAGT GAGATCTTGCATGAAGTCTACGAAACAGACATGGAAATCTACCTGATCCTGGAGTACG TGCAGGGAGGAGACCTTTTTGACGCCATCATAGAAAGTGTGAAGTTCCCGGAGCCCGA TGCTGCCCTCATGATCATGGACTTATGCAAAGCCCTCGTCCACATGCACGACAAGAGC ATTGTCCACCGGGACCTCAAGCCGGAAAACCTTTTGGTTCAGCGAAATGAGGACAAAT CTACTACCTTGAAATTGGCTGATTTTGGACTTGCAAAGCATGTGGTGAGACCTATATT TACTGTGTGTGGGACCCCAACTTACGTAGCTCCCGAAATTCTTTCTGAGAAAGGTTAT GGACTGGAGGTGGACATGTGGGCTGCTGGCGTGATCCTCTATATCCTGCTGTGTGGCT TTCCCCCATTCCGCAGCCCTGAGAGGGACCAGGACGAGCTCTTTAACATCATCCAGCT GGGCCACTTTGAGTTCCTCCCCCCTTACTGGGACAATATCTCTGATGCTGCTAAAGAT CTGGTGAGCCGGTTGCTGGTGGTAGACCCCAAAAAGCGCTACACAGCTCATCAGGTTC TCAGCACCCCTGGATCGAAACAGCTGGCAAGACCAATACAGTGAAACGACAGAAGCA GGTGTCCCCCAGCAGCGAGGGTCACTTCCGGAGCCAGCACAAGAGGGTTGTGGAGCAG GTATCATAGTCACCACCTTGGGAATCTGTCCAGCCCCCAGTTCTGCTCAAGGACAGAG AAAAGGATAGAAGTTTGAGAGAAAAACAATGAAAGAGGCTTCTTCACATAATTGGTGA ATCAGAGGGAGAGACACTGAGTATATTTTAAAGCATATTAAAAAAATTAAGTCAATGT TAAATGTCACAACATATTTTTAGATTTGTATATTTAAAGCCrrTAATACATTTTTGGG GGGTAAGCATTGTCATCAGTGAGGAATTTTGGTAATAATGATGTGTTTTGCTTCCCCT TTGTAACCAAGTTTATTCTGTACTACAGGAGTGGTGCTTACCAGGGTCTAAACTCCCC CTGTGAGATTAATAAGGTGCACTGTGGTCTTTCTGTGTTAATAAAATGTGCTCTGAAT

ORF Start: ATG at 52 ORF Stop: TAG at 2617

SEQ ID NO: 56 855 aa MW at 97447.3kD

NOV21c, MIΛIETYI-RLG LQRKVF DLQLVPRGWGSLTIMAEGKEGQVPSYMDGSRQRENEEDA CG57109-03 Protein Sequence KAETPDVTIRSYEIYSLPWNRQQGVCDHSI-EYLSSRISERKLQGSWLPASRG LEKPF LGPRGPVΛ LFCPRNGLHSAHPENSPLKPRWTVVKLGGQRPRKITLLLNRRSVQTFE QLLADISEALGSPRWKNDRVRKLF LKGREIRSVSDFFREGDAFIAMGKEPLTLKSIQ VAVEELYPNKARALTLAQHSRAPSPRLRSRLFSKALKGDHRCGETETPKSCSEVAGCK AAMRHQGKIPEELSLDDRARTQKKWGRGKWEPEPSSKPPREATLEERHARGEKHLGVE IEKTSGEIIRCEKCKRERELQQSLERERLSLGTSELDMGKGPMYDVEKLVRTRSCRRS PEANPASGEEGWKGDSHRSSPRNPTQELRRPSKSMDKKEDRGPEDQESHAQGAAKAKK DLVEVLPVTEEGLREVKKDTRPMSRSKHGGWLLREHQAGFEKLRRTRGEEKEAEKEKK PCMSGGRRMTLRDDQPAKLEKEPKTRPEENKPERPSGRKPRPMGIIAANVEKHYETGR VIGDGNFAWKECRHRETRQAYAMKIIDKSRLKGKEDMVDSEILHEVYETDMEIYLIL EYVQGGDLFDAIIESVKFPEPDARLMIMDLCKALVHMHDKSIλmRDLKPENLLVQRNE DKSTTLKI-ADFGLAiαiVVRPIFTVCGTPTYVAPEILSEKGYGLEVDMWAAGVILYILL CGFPPFRSPERDQDELFNIIQLGHFEFLPPYWDNISDAAKDLVSRLLWDPKKRYTAH QVLQHPWIETAGKTNTVKRQKQVSPSSEGHFRSQHKRVVEQVS

SEQ ID NO: 57 2433 bp

NOV21d, TTTACAGAGTCAGGCCTCACCGTGAGAGGGCTCCTGTATTAGTCCCTTTTCATGCTGC CG57109-04 DNA Sequence TTATAGAGACATACCTGAGACTGGGCAATTTGCAGAGAAAGGTTTTCTTGGACTTACA GTTAGTTCCACGTGGCTGGGGAAGCCTCACAATCATGGCGGAAGGCAAGGAAGGGCAA GTCCCATCTTACATGGATGGCAGCAGGCAAAGAGAGAATGAGGAAGATGCAAAAGCGG AAACCCCTGATGTAACCATCAGATCTTATGAGATTTATTCACTACCATGGAACAGACA GCAAGGCGTATGTGACCATTCTCTAGAATATTTAAGCTCGAGAATCTCAGAGCGGAAG CTGCAAGGCTCCTGGCTGCCTGCCAGCCGAGGGAATCTGGAGAAACCATTCCTGGGGC CGCGTGGCCCCGTCGTGCCCTTGTTCTGCCCTCGGAATGGCCTTCACTCAGCACATCC TGAGAACAGCCCTCTGAAGCCCAGGGTCGTGACCGTAGTGAAGCTGGGTGGGCAGCGC CCCCGAAAGATCACTCTGCTCCTCAACAGGCGATCAGTGCAGACGTTCGAGCAGCTCT TAGCTGACATCTCAGAAGCCTTGGGCTCTCCCAGATGGAAGAATGACCGTGTGAGGAA ACTGTTTAACCTCAAGGGCAGGGAAATCAGGAGCGTCTCTGATTTCTTCAGGGAAGGG GATGCTTTCATAGCTATGGGCAAAGAACCACTGACACTGAAGAGCATTCAGGTGGCTG TAGAAGAACTGTACCCCAACAAAGCCCGGGCCCTGACACTGGCCCAGCACAGCCGTGC CCCTTCTCCAAGGCTGAGGAGCAGGCTGTTTAGCAAGGCTCTGAAAGGAGACCACCGC TGTGGGGAGACCGAGACCCCCAAGAGCTGCAGCGAAGTTGCAGGATGCAAGGCAGCCA TGAGGCACCAGGGGAAGATCCCCGAGGAGCTTTCACTAGATGACAGAGCGAGGACCCA GAAGAAGTGGGGGAGGGGGAAATGGGAGCCAGAACCCAGTAGCAAGCCCCCCAGGGAA GCCACTCTGGAAGAGAGGCACGCAAGGGGAGAGAAGCATCTTGGGGTGGAGATTGAAA AGACCTCGGGTGAAATTATCAGATGCGAGAAGTGCAAGAGAGAGAGGGAGCTCCAGCA GAGCCTGGAGCGTGAGAGGCTTTCTCTGGGGACCAGTGAGCTGGATATGGGGAAGGGC CCAATGTATGATGTGGAGAAAAAGCCATGTATGTCTGGAGGCAGAAGGATGACTCTCA GAGATGACCAACCTGCAAAGCTAGAAAAGGAGCCCAAGACGAGGCCAGAAGAGAACAA GCCAGAGCGGCCCAGCGGTCGGAAGCCACGGCCCATGGGCATCATTGCCGCCAATGTG GAAAAGCATTATGAGACTGGCCGGGTCATTGGGGATGGGAACTTTGCTGTCGTGAAGG AGTGCAGACACCGCGAGACCAGGCAGGCCTATGCGATGAAGATCATTGACAAGTCCAG ACTCAAGGGCAAGGAGGACATGGTGGACAGTGAGATCTTGATCATCCAGAGCCTCTCT CACCCCAACATCGTGAAATTGCATGAAGTTTACGAAACAGACATGGAAATCTACCTGA TCCTGGAGTACGTGCAGGGAGGAGACCTTTTTGACGCCATCATAGAAAGTGTGAAGTT CCCGGAGCCCGATGCTGCCCTCATGATCATGGACTTATGCAAAGCCCTCGTCCACATG CACGACAAGAGCATTGTCCACCGGGACCTCAAGCCGGAAAACCTTTTGGTTCAGCGAA ATGAGGACAAATCTACTACCTTGAAATTGGCTGATTTTGGACTTGCAAAGCATGTGGT GAGACCTATATTTACTGTGTGTGGGACCCCAACTTACGTAGCTCCCGAAATTCTTTCT GAGAAAGGTTATGGACTGGAGGTGGACATGTGGGCTGCTGGCGTGATCCTCTATATCC TGCTGTGTGGCTTTCCCCCATTCCGCAGCCCTGAGAGGGACCAGGACGAGCTCTTTAA CATCATCCAGCTGGGCCACTTTGAGTTCCTCCCCCCTTACTGGGACAATATCTCTGAT ACAGCTGCTAAAGATCTGGTGAGCCGGTTGCTGGTGGTAGACCCCAAAAAGCGCTACA CAGCTCATCAGGTTCTTCAGCACCCCTGGATCGAAACAGCTGGCAAGACCAATACAGT GAAACGACAGAAGCAGGTGTCCCCCAGCAGCGAGGGTCACTTCCGGAGCCAGCACAAG AGGGTTGTGGAGCAGGTATCATAGTCACCACCTTGGGAATCTGTCCAGCCCCCAGTTC TGCTCAAGGACAGAGAAAAGGATAGAAGTTTGAGAGAAAAACAATGAAAGAGGCTTCT TCACATAATTGGTGAATCAGAGGGAGAGACACTGAGTATATTTTAAAGCATATTA

ORF Start: ATG at 52 ORF Stop: TAG at 2284

SEQ ID NO: 58 744 aa MW at 84729.4kD

NOV21d, MLLIETYLRLGNLQRKVFLDLQLVPRGWGSLTI AEGKEGQVPSYMDGSRQRENEEDA CG57109-04 Protein Sequence KAETPDVTIRSYEIYSLPWNRQQGVCDHSLEYLΞSRISERKLQGΞWLPASRGNLEKPF LGPRGPWPLFCPRNGLHSAHPENSPLKPRWTWKLGGQRPRKITLLLNRRSVQTFE QLLADISEALGSPRWKNDRVRKLFNLKGREIRSVSDFFREGDAFIAMGKEPLTLKSIQ VAVEELYPNKARALTLAQHSRAPSPRLRSRLFSKALKGDHRCGETETPKSCSEVAGCK AAMRHQGKIPEELSLDDRARTQKKWGRGKWEPEPSSKPPREATLEERHARGEKHLGVE IEKTSGEIIRCEKCKRERELQQSLERERLSLGTSELD GKGPMYDVEKKPCMSGGRRM TLRDDQPAKLEKEPKTRPEENKPERPSGRKPRPMGIIAANVEKHYETGRVIGDGNFAV VKECRHRETRQAYAMKIIDKSRLKGKEDMVDSEILIIQSLSHPNIVKLHEVYETDMEI YLILEYVQGGDLFDAIIESVKFPEPDAALMIMDLCKALVHMHDKSIVHRDLKPENLLV QRNEDKSTTLKIJ^FGI-AKHVVRPIFTVCGTPTYVAPEILSEKGYGLEVDMWAAGVIL YILLCGFPPFRSPERDQDELFNIIQLGHFEFLPPYWDNISDTAAKDLVSRLLWDPKK RYTAHQVLQHPWIETAGKTNTVKRQKQVSPSSEGHFRSQHKRWEQVS SEQ ID NO: 59 2133 bp

NOV21e, T GACCGTGTGAGGAAACTGTTTAACCTCAAGGGCAGGGAAATCAGGAGCGTCTCTGA CG57109-05 DNA Sequence TTTC-TC-ASCffiAAGGGGATGC TTCATAGCTATGGGaU-AGAACCACTGACACTGAAG AGOVTTCΑGGTGGCTGTAGAAGAACTGTACCCC_AAC-AAAGCCCGGGCCCTGACACTGG CCC-AGCAC-AGCCGTGCCCCTTCTCαΛGGCTGAGGAGCAGGCTGTTTAGCAAGGCTCT GAAAGGAGACCACCGCTGTGGGGAGACCGAGACCCCCAAGAGCTGCAGCGAAGTTGCA GGATGCAAGGCAGCCATGAGGCACCAGGGGAAGATCCCCGAGGAGCTTTCACTAGATG ACAGAGCGAGGACCCAGAAGAAGTGGGGGAGGGGGAAATGGGAGCCAGAACCCAGTAG CAAGCCCCCCAGGGAAGCCACTCTGGAAGAGAGGCACGCAAGGGGAGAGAAGCATCTT GGGGTGGAGATTGAAAAGACCTCGGGTGAAATTATCAGATGCGAGAAGTGCAAGAGAG AGAGGGAGCTCCAGCAGAGCCTGGAGCGTGAGAGGCTTTCTCTGGGGACCAGTGAGCT GGATATGGGGAAGGGCCCAATGTATGATGTGGAGAAGCTGGTGAGGACCAGAAGCTGC AGGAGGTCTCCCGAGGCAAATCCTGCAAGTGGGGAGGAAGGGTGGAAGGGTGACAGCC ACAGGAGCAGCCCCAGGAATCCCACTCAAGAGCTGAGGAGACCCAGCAAGAGCATGGA CAAGAAAGAGGACAGAGGCCCAGAGGATCAAGAAAGCCATGCTCAGGGAGCGGCCAAG GCCAAGAAGGACCTTGTGGAAGTTCTTCCTGTCACAGAGGAGGGGCTGAGAGAGGTGA AGAAGGACACCAGGCCCATGAGCAGGAGCAAACATGGTGGCTGGCTCCTGAGAGAGCA CCAGGCGGGCTTTGAGAAGCTCCGCAGGACCCGAGGAGAAGAGAAGGAGGCAGAGAAG GAGAAAAAGCCATGTATGTCTGGAGGCAGAAGGATGACTCTCAGAGACGACCAACCTG CAAAGCTAGAAAAGGAGCCCAAGACGAGGCCAGAAGAGAACAAGCCAGAGCGGCCCAG CGGTCGGAAGCCACGGCCCATGGGCATCATTGCCGCCAATGTGGAAAAGCATTATGAG ACTGGCCGGGTCATTGGGGATGGGAACTTTGCTGTCGTGAAGGAGTGCAGACACCGCG AGACCAGGCAGGCCTATGCGATGAAGATCATTGACAAGTCCAGACTCAAGGGCAAGGA GGACATGGTGGACAGTGAGATCTTGATCATCCAGAGCCTCTCTCACCCCAACATCGTG AAATTGCATGAAGTCTACGAAACAGACATGGAAATCTACCTGATCCTGGAGTACGTGC AGGGAGGAGACCTTTTTGACGCCATCATAGAAAGTGTGAAGTTCCCGGAGCCCGATGC TGCCCTCATGATCATGGACTTATGCAAAGCCCTCGTCCACATGCACGACAAGAGCATT GTCCACCGGGACCTCAAGCCGGAAAACCTTTTGGTTCAGCGAAATGAGGACAAATCTA CTACCTTGAAATTGGCTGATTTTGGACTTGCAAAGCATGTGGTGAGACCTATATTTAC TGTGTGTGGGACCCCAACTTACGTAGCTCCCGAAATTCTTTCTGAGAAAGGTTATGGA CTGGAGGTGGACATGTGGGCTGCTGGCGTGATCCTCTATATCCTGCTGTGTGGCTTTC CCCCATTCCGCAGCCCTGAGAGGGACCAGGACGAGCTCTTTAACATCATCCAGCTGGG CCACTTTGAGTTCCTCCCCCCTTACTGGGACAATATCTCTGATGCTGCTAAAGATCTG GTGAGCCGGTTGCTGGTGGTAGACCCCAAAAAGCGCTACACAGCTCATCAGGTTCTTC AGCACCCCTGGATCGAAACAGCTGGCAAGACCAATACAGTGAAACGACAGAAGCAGGT GTCCCCCAGCAGCGAGGGTCACTTCCGGAGCCAGCACAAGAGGGTTGTGGAGCAGGTA TCATAGTCACCACCTTGGGAATCTGTCCAGCCCCCAGTTCTGCTCAAGGACAGAGAAA AGGATAGAAGTTTGAGAGAAAAACAATGAAAGAGGCTTCTTCACA

ORF Start: ATG at 90 ORF Stop: TAG at 2034

SEQ ID NO: 60 648 aa MW at 73813.6kD

NOV21e, MGKEPLTLKSIQVAVEELYPNKARALTLAQHSRAPSPRLRSRLFSKALKGDHRCGETE CG57109-05 Protein Sequence TPKSCSEVAGCKAAMRHQGKIPEELSLDDRARTQKKWGRGKWEPEPSSKPPREATLEE RHARGEKHLGVEIEKTSGEIIRCEKCKRERELQQSLERERLSLGTSELDMGKGPMYDV EKLVRTRSCRRSPEANPASGEEGWKGDSHRSSPRNPTQELRRPSKSMDKKEDRGPEDQ ESHAQGAAKA.KDLVEVLPVTEEGLREVKKDTRPMSRSKHGGWLLREHQAGFEKLRRT RGEEKEAEKEKKPCMSGGRRMTLRDDQPAKLEKEPKTRPEENKPERPSGRKPRPMGII AANVEKHYETGRVIGDGNFAVVKECRHRETRQAYAMKIIDKSRLKGKEDMVDSEILII QSLSHPNIVKLHEVYETDMEIYLILEYVQGGDLFDAIIESVKFPEPDAALMIMDLCKA LVHMHDKSIVHRDLKPE.H-LVQRNEDKSTTLKI-ADFGI-AKHVVRPIFTVCGTPTYVAP EILSEKGYGLEVDMWAAGVILYILLCGFPPFRSPERDQDELFNIIQLGHFEFLPPYWD NISDAAKDLVSRLLVVDPKKRYTAHQVLQHPWIETAGKTNTVKRQKQVSPSSEGHFRS QHKRWEQVS' SEQ ID NO: 61 2720 bp

NOV21f, GGACACTGACATGGACTGAAGGAGTAGAAAAGAAGCCTTGGGCTCTCCCAGATGGAAG CG57109-06 DNA Sequence AATGACCGTGTGAGGAAACTGTTTAACCTCAAGGGCAGGGAAATCAGGAGCGTCTCTG ATTTCTTCAGGGAAGGGGATGCTTTCATAGCTATGGGCAAAGAACCACTGACACTGAA GAGCATTCAGGTGGCTGTAGAAGAACTGTACCCCAACAAAGCCCGGGCCCTGACACTG GCCCAGCACAGCCGTGCCCCTTCTCCAAGGCTGAGGAGCAGGCTGTTTAGCAAGGCTC TGAAAGGAGACCACCGCTGTGGGGAGACCGAGACCCCCAAGAGCTGCAGCGAAGTTGC AGGATGCAAGGCAGCTATGAGGCACCAGGGGAAGATCCCCGAGGAGCTTTCACTAGAT GACAGAGCGAGGACCCAGAAGAAGTGGGGGAGGGGGAAATGGGAGCCAGAACCCAGTA GCAAGCCCCCCAGGGAAGCCACTCTGGAAGAGAGGCACGCAAGGGGAGAGAAGCATCT TGGGGTGGAGATTGAAAAGACCTCGGGTGAAATTATCAGATGCGAGAAGTGCAAGAGA GAGAGGGAGCTTCAGCAGAGCCTGGAGCGTGAGAGGCTTTCTCTGGGGACCAGTGAGC TGGATATGGGGAAGGGCCCAATGTATGATGTGGAGAAGCTGGTGAGGACCAGAAGCTG CAGGAGGTCTCCCGAGGCAAATCCTGCAAGTGGGGAGGAAGGGTGGAAGGGTGACAGC CACAGGAGCAGCCCCAGGAATCCCACTCAAGAGCTGAGGAGACCCAGCAAGAGCATGG ACAAGAAAGAGGACAGAGGCCCAGAGGATCAAGAAAGCCATGCTCAGGGAGCAGCCAA GGCCAAGAAGGACCTTGTGGAAGTTCTTCCTGTCACAGAGGAGGGGCTGAGGGAGGTG AAGAAGGACACCAGGCCCATGAGCAGGAGCAAACATGGTGGCTGGCTCCTGAGAGAGC ACCAGGCGGGCTTTGAGAAGCTCCGCAGGACCCGAGGAGAAGAGAAGGAGGCAGAGAA GGAGAAAAAGCCATGTATGTCTGGAGGCAGAAGGATGACTCTCAGAGATGACCAACCT GCAAAGCTAGAAAAGGAGCCCAAGACGAGGCCAGAAGAGAACAAGCCAGAGCGGCCCA GCGGTCGGAAGCCACGGCCCATGGGCATCATTGCCGCCAATGTGGAAAAGCATTATGA GACTGGCCGGGTCATTGGGGATGGGAACTTTGCTGTCGTGAAGGAGTGCAGACACCGC GAGACCAGGCAGGCCTATGCGATGAAGATCATTGACAAGTCCAGACTCAAGGGCAAGG AGGACATGGTGGACAGTGAGATCTTGCATGAAGTCTACGAAACAGACATGGAAATCTA CCTGATCCTGGAGTACGTGCAGGGAGGAGACCTTTTTGACGCCATCATAGAAAGTGTG AAGTTCCCGGAGCCCGATGCTGCCCTCATGATCATGGACTTATGCAAAGCCCTCGTCC ACATGCACGACAAGAGCATTGTCCACCGGGACCTCAAGCCGGAAAACCTTTTGGTTCA GCGAAATGAGGACAAATCTACTACCTTGAAATTGGCTGATTTTGGACTTGCAAAGCAT GTGGTGAGACCTATATTTACTGTGTGTGGGACCCCAACTTACGTAGCTCCCGAAATTC TTTCTGAGAAAGGTAAGTGTTACACATCGATCTGTGGGACTCTAGTTCCCTTACTAAC AAATGTTTCATTTGTCATATTTACTAGTTTTCAATATGGAATAAATCTCAGAGAACTG ACACTTAGGCTTGGATTTGGACTTCAATGAAAATATTTGAAGTAGGCTTGACCAAAGC

ATGAGAGCTTTCTCCTCATTAGGGCTGCCCTTGTTACAGTCAATGGATCAGTGTGTGT GCATGTGTGTGTGTGTGTGTGTGTTTATTGTGTTTAGGCAGGACAGTGAGATGAAAGA TGATGGAGAATTGGGTGGGGAACTCAAGCAAGCAAGGCTACTTGACCCAAGGCTATCT CTAATAGGAGAGAATTGAAGCAGTCCTTATGGTACTTGGTTTAAAAATTTCTTCACCA ACCTTGCATTTAAAGGAAAAGGATCCCATTTTCCTCCATGAACTCTATGAATATTTAT TACCTACTTGTATATTATGCAAGGATCCAATGAGCTGTTTTAGTGACAAACTTTCTAA AACATTTAAAAAGGAAATAATAGTTATGATATGGCTCTAAATATATGAATGACTATTT GACTACTGTGGCACTCCAGGAGAAACCAATTTACCCACCATTGGTAAGATGGGAAGAC TCTCATTGGGTTGCAGGGTTGGTGACAGGGAGAAGGGATGGACGGATAGTTTCCCAGC AGCAGAAGCATCAGGATAATTAAGATGAGGAGATGGCCAGGGATGGTGGCTCATGCCT GTAATCCCAGCTCTTTGGGAGGCTGAGGCAGGTGGATCACCTGAGGTCAGGCGTTTGA AACCATCCTGGCCAACATGGTGAAACCCTGTCTGTACTAAAACTACAAAAAAATTAGC TGGGCGTGGTGGCACATGCCTGTAATCTGAGCTACTCGGGAGGCTGAGGCAGGAGAAT TGCTTGAACCGGGGAGGTGGAGTTTGCAGTGAGCCAAGATCGTGCCATTGCACTCCAG CCTGGGCAACAAGAGTGAAACTTCATCTCAAAAAAAAAAAAAAAAAAAAAAC

ORF Start: ATG at 149 ORF Stop: TGA at 1826

SEQ ID NO: 62 559 aa MW at 63436.9kD

NOV21f, MGKEPLTLKSIQVAVEELYPNKARALTLAQHSRAPSPRLRSRLFSKALKGDHRCGETE CG57109-06 Protein Sequence TPKSCSEVAGCKAAMRHQGKIPEELSLDDRARTQKKWGRGKWEPEPSSKPPREATLEE RHARGEKHLGVEIEKTSGEIIRCEKCKRERELQQSLERERLSLGTSELDMGKGPMYDV EKLVRTRSCRRSPEANPASGEEGWKGDSHRSSPRNPTQELRRPSKSMDKKEDRGPEDQ ESHAQGAAKAKKDLVEVLPVTEEGIiREVKKDTRPMSRSKHGGWLLREHQAGFEKLRRT RGEEKEAEKEKKPCMSGGRRMTLRDDQPAKLEKEPKTRPEENKPERPSGRKPRPMGII AANVEKHYETGRVIGDGNFAWKECRHRETRQAYAMKIIDKSRLKGKED VDSEILHE VYETDMEIYLILEYVQGGDLFDAIIESVKFPEPDAALMIMDLCKALVHMHDKSIVHRD LKPE-πjLVQRNEDKSTTLIXADFGI-AKIrøWPIFTVCGTPTWAPEILSEKGKCYTSI CGTLVPLLTNVSFVIFTSFQYGINLRELTLRLGFGLQ

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 2 IB.

Further analysis of the NOV21a protein yielded the following properties shown in Table 2 IC.

Table 21C. Protein Sequence Properties NOV21a

PSort analysis: 0.7000 probability located in plasma membrane; 0.3000 probability located in microbody (peroxisome); 0.3000 probability located in nucleus; 0.2000 probability located in endoplasmic reticulum (membrane)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV21a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 21 D.

In a BLAST search of public sequence datbases, the NOV2 la protein was found to have homology to the proteins shown in the BLASTP data in Table 2 IE.

PFam analysis predicts that the NOV21a protein contains the domains shown in the Table 2 IF.

Example 22.

The NOV22 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 22A. Table 22A. NOV22 Sequence Analysis

SEQ ID NO: 63 3553 bp

NOV22a, TACATTCTTCATCGTTTAGATCAAGAAGAAGCTTTGCGACAACACCTCACAAAAGAAA -01 DNA Sequence CTGCAGAGATGTTAAATCAACTGCACATTAAAAGCAGTGGATGCTTTCTTTACCTAGA

ACGAGTTTTAGATGGAGTTGTAGAAAATTTTATTATGTTAAGAGAAATTCGTGACATC CCAGGAACTCTAAATGGTTTATATCTCTGGCTGTGCCAAAGACTTTTTGTAAGAAAAC AATTTGCAAAGGTTCAGCCTATTTTGAATGTGATTCTTGCAGCCTGCCGACCTTTGAC CATAACGGAATTATATCACGCAGTATGGACCAAAAACATGTCGTTAACTTTGGAAGAT TTTCAACGCAAGTTAGATATCCTCTCCAAACTTCTTGTTGATGGACTAGGAAATACAA AAATACTGTTTCATTATAGTTTTGCCGAGTGGCTTCTGGATGTGAAACACTGTACTCA GAAGTATTTATGTAATGCAGCAGAAGGACACAGAATGTTGGCTATGAGTTATACCTGT CAAGCCAAGAATTTAACACCATTGGAAGCACAAGAATTTGCATTGCACTTAATTAACT CAAACTTACAATTAGAGACAGCGGAGTTAGCTCTGTGGATGATATGGAATGGTACACC TGTCAGAGATTCCCTTTCTACTTTGATACCCAAGGAACAAGAAGTGCTACAGCTGTTG GTTAAAGCTGGGGCTCATGTCAACAGTGAAGACGATCGCACATCATGCATAGTTCGAC AAGCCTTAGAAAGAGAGGATTCCATTCGGACATTATTAGATAATGGAGCTTCAGTAAA TCAGTGTGATTCAAATGGGAGAACATTATTGGCTAATGCTGCATATAGTGGCAGTCTT GATGTAGTCAATTTACTTGTCTCTAGGGGAGCAGATTTAGAGATAGAAGATGCTCATG GACATACACCACTCACTCTAGCGGCTAGACAGGGACATACCAAGGTGGTTAATTGTTT GATTGGGTGTGGAGCAAATATTAATCATACTGATCAAGATGGTTGGACAGCATTAAGA TCTGCTGCTTGGGGTGGCCATACTGAGGTAGTTTCTGCACTACTTTATGCTGGCGTAA AAGTGGATTGTGCAGATGCTGATAGCCGAACAGCTTTGAGAGCAGCAGCATGGGGAGG ACACGAGGATATTGTACTGAATTTGCTACAACATGGCGCTGAAGTGAACAAAGCTGAT AATGAAGGTAGAACTGCTTTGATAGCAGCAGCATACATGGGACATAGAGAGATTGTGG AACACCTACTGGACCATGGAGCAGAAGTAAATCATGAGGATGTTGATGGCAGGACTGC ACTCTCTGTAGCTGCACTTTGTGTGCCTGCAAGTAAAGGGCACGCATCAGTTGTTAGC CTTTTAATTGATCGAGGTGCTGAAGTAGATCATTGTGATAAAGATGGCATGACTCCAC TGCTGGTAGCTGCCTATGAAGGACATGTTGATGTGGTTGACTTGCTTCTAGAAGGGGG AGCAGATGTAGATCACACAGATAACAATGGCCGTACACCCCTCTTAGCAGCAGCGTCT ATGGGTCATGCATCAGTTGTAAATACACTTTTGTTTTGGGGTGCAGCTGTGGATAGTA TTGATAGTGAAGGTAGGACAGTCCTCAGTATAGCTTCAGCACAAGGAAATGTTGAGGT GGTACGTACTCTACTGGATAGAGGGTTAGATGAAAATCACAGAGATGATGCTGGATGG ACACCTTTGCACATGGCAGCTTTTGAAGGGCACAGATTGATATGTGAAGCACTTATTG AACAAGGTGCTAGAACAAATGAGATTGACAATGATGGACGAATCCCTTTCATATTAGC TTCACAAGAGGGTCATTATGATTGTGTTCAAATATTACTGGAAAACAAATCCAACATT GATCAAAGAGGTTATGATGGAAGAAATGCACTGCGGGTTGCTGCATTAGAAGGGCACA GGGACATTGTTGAATTGCTTTTTAGCCATGGTGCTGATGTTAACTGCAAAGATGCTGA TGGTCGGCCTACACTTTATATCTTGGCCTTAGAAAATCAGCTTACAATGGCCGAATAT TTTTTAGAAAATGGTGCAAACGTAGAAGCAAGTGATGCTGAAGGAAGGACAGCACTTC ATGTGTCTTGTTGGCAAGGCCATATGGAAATGGTGCAGGTCCTGATAGCATACCATGC TGACGTCAATGCTGCAGACAATGAAAAGCGCTCTGCTTTGCAGTCTGCAGCCTGGCAG GGCCATGTAAAAGTGGTTCAGCTTCTGATTGAGCATGGTGCTGTAGTTGACCATACAT GTAACCAAGGTGCAACTGCACTCTGTATTGCAGCCCAGGAAGGGCACATTGATGTTGT TCAGGTCTTATTAGAGCATGGTGCTGATCCAAACCATGCTGATCAATTTGGACGCACT GCTATGCGTGTTGCAGCCAAAAATGGACATTCTCAGATAATTAAATTATTAGAAAAAT ATGGTGCATCTAGTTTGAATGGCTGTTCCCCATCTCCTGTTCACACAATGGAGCAAAA ACCTCTACAGTCATTGTCTTCAAAAGTGCAGTCATTAACAATTAAATCAAATAGCTCT GGTAGTACTGGTGGAGGGGATATGCAGCCTTCGTTACGTGGTTTACCTAATGGGCCTA CTCATGCTTTTAGTTCTCCTTCAGAATCTCCAGATTCTACAGTTGACCGGCAGAAGTC ATCACTGTCAAATAATTCCCTGAAAAGCTCAAAAAATTCATCTTTGAGAACTACTTCA TCTACAGCAACGGCTCAAACAGTGCCAATTGATAGCTTTCATAACTTGTCATTTACAG AACAAATTCAGCAGCATTCATTGCCACGCAGTAGAAGTCGACAGTCAATTGTTTCCCC ATCTTCCACAACACAGTCCTTAGGACAGAGTCATAATTCACCAAGTAGTGAATTTGAG TGGAGTCAAGTAAAGCCCAGTTTGAAGTCAACTAAAGCAAGTAAAGGGGGGAAATCAG AAAATTCTGCCAAGTCTGGATCAGCTGGGAAAAAAGCGAAACAAAGTAATTCTTCACA GCCAAAGGTTTTAGAATATGAAATGACTCAGTTTGATAGAAGAGGACCTATAGCCAAA TCCGGGACTGCTGCACCACCTAAACAAATGCCAGCAGAATCTCAATGCAAAATTATGA TACCTTCAGCTCAGCAGGAAATTGGTCGATCTCAACAGCAGTTTCTTATTCACCAACA AAGTGGGGAACAGAAGAAGAGAAATGGAATAATGACAAATCCAAATTATCATCTTCAG AGCAACCAGGTTTTTCTTGGTAGGGTTTCAGTCCCACGAACAATGCAAGATAGAGGGC ATCAGGAAGTGTTGGAGGGATACCCTTCCTCAGAGACAGAATTAAGCCTTAAACAAGC TCTGAAGCTTCAGATTGAAGGTTCTGACCCTAGCTTCAACTATAAAAAGGAAACACCA TTATAAAAGGTAATATTTTGTCAACATAAAGAGTAAAAAACAAAAGTAGAGTTCCCTC TACTTGGAATGCTCT

Further analysis of the NOV22a protein yielded the following properties shown in Table 22B.

Table 22B. Protein Sequence Properties NOV22a j PSort analysis: 0.4500 probability located in cytoplasm; 0.3000 probability located in microbody

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV22a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 22C.

In a BLAST search of public sequence datbases, the NOV22a protein was found to have homology to the proteins shown in the BLASTP data in Table 22D.

PFam analysis predicts that the NOV22a protein contains the domains shown in the Table 22E.

Example 23.

The NOV23 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 23A. Table 23 A. NOV23 Sequence Analysis

SEQ ID NO: 65 3321 bp

NOV23a, TAACCCGGCGCCCGGCCCTAGCCAGCCCCGGGGCTCGGGGCTGGGGAGATCATGGCCC -01 DNA Sequence GCCTCTTCAGCCCCCGGCCGCCCCCCAGCGAAGACCTCTTCTACGAGACCTACTACAG CCTGAGCCAGCAGTACCCGCTGCTGCTGCTGCTGCTGGGGATCGTGCTCTGTGCGCTC GCGGCGCTGCTCGCAGTGGCCTGGGCCAGCGGCAGGGAGCTGACCTCAGACCCGAGCT TCCTGACCACTGTGCTGTGCGCGCTGGGCGGCTTCTCGCTGCTGCTGGGCCTCGCTTC CCGGGAGCAGCGACTGCAGCGCTGGACGCGTCCCCTGTCCGGCTTGGTATGGGTCGCG CTGCTAGCGCTAGGCCACGCCTTCCTGTTCACCGGGGGCGTGGTGAGCGCCTGGGACC AGGTGTCCTATTTTCTCTTCGTCATCTTCACGGCGTATGCCATGCTGCCCTTGGGCAT GCGGGACGCCGCCGTCGCGGGCCTCGCCTCCTCACTCTCGCATCTGCTGGTCCTCGGG CTGTATCTTGGGCCACAGCCGGACTCACGGCCTGCACTGCTGCCGCAGTTGGCAGCAA ACGCAGTGCTGTTCCTGTGCGGGAACGTGGCAGGAGTGTACCACAAGGCGCTGATGGA GCGCGCCCTGCGGGCCACGTTCCGGGAGGCACTCAGCTCCCTGCACTCACGCCGGCGG CTGGACACCGAGAAGAAGCACCAGGAACACCTTCTCTTGTCCATCCTTCCTGCCTACC TGGCCCGAGAGATGAAGGCAGAGATCATGGCACGGCTGCAGGCAGGACAGGGGTCACG GCCAGAGAGCACTAACAATTTCCACAGCCTCTATGTCAAGAGGCACCAGGGAGTCAGC GTGCTGTATGCTGACATCGTGGGCTTCACGCGGCTGGCCAGCGAGTGTTCCCCTAAGG AGCTGGTGCTCATGCTCAATGAGCTCTTTGGCAAGTTCGACCAGATTGCCAAGGAGCA TGAATGCATGCGGATCAAGATCCTGGGGGACTGTTACTACTGTGTCTCTGGGCTGCCA CTCTCACTGCCAGACCATGCCATCAACTGCGTGCGCATGGGCCTGGACATGTGCCGGG CCATCAGGAAACTGCGGGCAGCCACTGGCGTGGACATCAACATGCGTGTGGGCGTGCA CTCAGGCAGCGTACTGTGTGGAGTCATCGGGCTGCAGAAGTGGCAGTACGACGTTTGG TCACATGATGTCACACTGGCTAACCACATGGAGGCAGGCGGTGTACCAGGGCGAGTGC ACATCACAGGGGCTACCCTGGCCCTGCTGGCAGGGGCTTATGCTGTGGAGGACGCAGG CATGGAGCATCGGGACCCCTACCTTCGGGAGCTAGGGGAGCCTACCTATCTGGTCATC GATCCACGGGCAGAGGAGGAGGATGAGAAGGGCACTGCAGGAGGCTTGCTGTCCTCGC TTGAGGGCCTCAAGATGCGTCCATCACTGCTGATGACCCGTTACCTGGAGTCCTGGGG CGCAGCCAAGCCTTTTGCCCACCTGAGCCACGGAGACAGCCCTGTGTCCACCTCCACC CCTCTCCCGTGGCTCTCACTGTGCAGGAGCCGTACCCCCCGGGGACTAGATGATGAAC TGGACACCGGGGATGCCAAGTTCTTCCAGGTCATTGAGCAGCTCAACTCGCAGAAACA GTGGAAGCAGTCGAAGGACTTCAACCCACTGACACTGTACTTCAGAGAGAAGGAGATG GAGAAAGAGTACCGACTCTCTGCAATCCCCGCCTTCAAATACTATGAAGCCTGCACCT TCCTGGTTTTTCTCTCCAACTTCATCATCCAGATGCTAGTGACAAACAGGCCCCCAGC TCTGGCCATCACGTATAGCATCACCTTCCTCCTCTTCCTCCTCATCCTTTTTGTCTGC TTCTCAGAGGACCTGATGAGGTGTGTCCTGAAAGGCCCCAAGATGCTGCACTGGCTGC CTGCACTGTCTGGCCTGGTGGCCACACGACCAGGACTGAGAATAGCCTTGGGCACCGC CACCATCCTCCTTGTCTTTGCCATGGCCATTACCAGCCTGTTCTTCTTCCCAACATCA TCAGACTGCCCTTTCCAAGCTCCCAATGTGTCCTCCATGATTTCCAACCTCTCCTGGG AGCTCCCTGGGTCTCTGCCTCTCATCAGTGTCCCATACTCCATGCACTGCTGCACGCT GGGCTTCCTCTCCTGCTCCCTCTTTCTGCACATGAGCTTCGAGCTGAAGCTGCTGCTG CTCCTGCTGTGGCTGGCGGCATCCTGCTCCCTCTTCCTGCACTCCCATGCCTGGCTGT CGGAATGCCTCATCGTCCGCCTCTATCTGGGCCCCTTGGACTCCAGGCCCGGAGTGCT GAAGGAGCCCAAACTGATGGGTGCTATCTCCTTCTTCATCTTCTTCTTCACCCTCCTT GTCCTGGCTCGCCAGAATGAGTACTACTGCCGCCTGGACTTCCTGTGGAAGAAGAAGC TGAGGCAGGAGAGGGAGGAGACAGAGACGATGGAGAACCTGACTCGGCTGCTCTTGGA GAACGTGCTCCCTGCACACGTGGCCCCCCAGTTCATTGGCCAGAACCGGCGCAACGAG GATCTCTACCACCAGTCCTATGAATGCGTTTGTGTCCTCTTCGCCTCAGTCCCAGACT TCAAGGAGTTCTACTCTGAATCCAACATCAATCATGAGGGCCTAGAGTGTCTGAGGCT GCTCAATGAGATAATTGCTGATTTTGATGAGCTGCTCTCCAAGCCCAAGTTCAGTGGG GTGGAGAAGATCAAGACCATCGGCAGCACCTACATGGCAGCCACAGGCTTAAATGCCA CCTCTGGACAGGATGCACAACAGGATGCTGAACGGAGCTGCAGCCACCTTGGCACTAT GGTGGAATTTGCCGTGGCCCTGGGGTCTAAGCTGGACGTCATCAACAAGCATTCATTC AACAACTTCCGCCTGCGAGTGGGGTTGAACCATGGACCCGTAGTAGCTGGAGTTATTG GGGCCCAGAAGCCGCAATATGACATTTGGGGCAACACAGTGAACGTGGCCAGCCGCAT GGAGAGTACAGGAGTCCTTGGCAAAATCCAAGTGACTGAGGAGACAGCATGGGCCCTA CAGTCCCTGGGCTACACCTGCTACAGCCGGGGTGTCATCAAGGTGAAAGGCAAAGGGC AGCTCTGCACCTACTTCCTGAACACAGACTTGACACGAACTGGACCTCCTTCAGCTAC CCTAGGCTGAGATTGCACTCGCCTTCTAAGAACCTCAATAAAGAGACTCTGGGGTGTC TGGAGCCCATTGATG

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 23 B.

Further analysis of the NOV23a protein yielded the following properties shown in Table 23C.

Table 23C. Protein Sequence Properties NOV23a

PSort analysis: 0.8000 probability located in plasma membrane; 0.4000 probability located in Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome)

I SignalP analysis: Cleavage site between residues 51 and 52

A search of the NOV23a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 23D.

In a BLAST search of public sequence datbases, the NOV23a protein was found to have homology to the proteins shown in the BLASTP data in Table 23E.

PFam analysis predicts that the NOV23a protein contains the domains shown in the Table 23F.

Example 24.

The NOV24 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 24A. Table 24A. NOV24 Sequence Analysis

SEQ ID NO: 69 997 bp

NOV24a, TTCTAATCTGTGGTTTCTTCACATCAACTGAAACAATGCAGCAAAATAACAGTGTGAC CG59955-01 DNA Sequence TGAATTCATACTGTTAGGATTAACACAGGATCCCTTGAGGCAGAAAATAGTGTTTGTA ATCTTCTTAATTTTCTATATGGGAACTGTGGTGGGGAATATGCTCATTATTGTGACCA TCAAGTCCAGCCGGACACTAGGAAGCCCCATGTACTTCTTTCTATTTTATTTGTCCTT TGCAGATTCTTGCTTTTCAACTTCCACAGCCCCTAGATTAATTGTGGATGCTCTCTCT GAAAAGAAAATTATAACCTACAATGAGTGCATGACACAAGTCTTTGCACTACATTTAT TTGGCTGCATGGAGATCTTTGTCCTCATTCTCATGGCTGTTGATCGCTATGTGGCCAT CTGTAAGCCCTTGCGTTACCCAACCATCATGAGCCAGCAGGTCTGCATCATCCTGATT GTTCTTGCCTGGATAGGGTCTTTAATACACTCTACAGCTCAGATTATCCTGGCCTTAA GATTGCCTTTCTGTGGACCCTATTTGATTGATCATTATTGCTGTGATTTGCAGCCCTT GTTGAAACTTGCCTGCATGGACACTTACATGATCAACCTGCTGTTGGTGTCTAACAGT GGGGCAATTTGCTCAAGTAGTTTCATGATTTTGATAATTTCATATATTGTCATCTTGC ATTCACTGAGAAACCACAGTGCCAAAGGGAAGAAAAAGGCTCTCTCCGCTTGCACGTC TCACATAATTGTAGTCATCTTATTCTTTGGCCCATGTATATTCATATATACACGCCCC CCGACCACTTTCCCCATGGACAAGATGGTGGCAGTATTTTATACTATTGGACCACCCT TTCTCAATCCACTCATCTACACACTGAGGAATGCAGAAGTGAAAAATGCCATGAGAAA GTTATGGCATGGCAAAATTATTTCAGAAAACAAAGGATAAATTGAGGGCCTGACCTGA TTACTTTTTCA

ORF Start: ATG at 36 ORF Stop: TAA at 966

SEQ ID NO: 70 i l O aa MW at 35002.7kD

NOV24a, MQQNNSVTEFILLGLTQDPLRQKIVFVIFLIFYMGTWGNMLIIVTIKSSRTLGSPMY JCG59955-01 Protein Sequence FFLFYLSFADSCFSTSTAPRLIVDALSEKKIITY ECMTQVFALHLFGCMEIFVLIL AVDRYVAICKPLRYPTIMSQQVCIILIVLAWIGSLIHSTAQIILALRLPFCGPYLIDH YCCDLQPLLKLACMDTYMINLLLVSNSGAICSSSFMILIISYIVILHSLRNHSAKGKK KASACTSHIIWILFFGPCIFIYTRPPTTFPMDKMVAVFYTIGPPFLNPLIYTLRNA EVKNA RKL HGKIISENKG

Further analysis of the NOV24a protein yielded the following properties shown in Table 24B.

Table 24B. Protein Sequence Properties NOV24a

PSort analysis: 0.6000 probability located in plasma membrane; 0.4000 probability located in Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.0300 probability located in mitochondrial inner membrane

I SignalP analysis: Cleavage site between residues 40 and 41

A search of the NOV24a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 24C.

In a BLAST search of public sequence datbases, the NOV24a protein was found to have homology to the proteins shown in the BLASTP data in Table 24D.

PFam analysis predicts that the NOV24a protein contains the domains shown in the Table 24E.

Example 25.

The NOV25 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 25A.

Further analysis of the NOV25a protein yielded the following properties shown in Table 25B.

Table 25B. Protein Sequence Properties NOV25a

PSort analysis: 0.6850 probability located in endoplasmic reticulum (membrane); 0.6400 probability located in plasma membrane; 0.4600 probability located in Golgi body;

0.1000 probability located in endoplasmic reticulum (lumen)

SignalP analysis: Cleavage site between residues 59 and 60

A search of the NOV25a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 25C.

In a BLAST search of public sequence datbases, the NOV25a protein was found to have homology to the proteins shown in the BLASTP data in Table 25D.

PFam analysis predicts that the NOV25a protein contains the domains shown in the Table 25E.

Example 26.

The NOV26 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 26A.

Further analysis of the NOV26a protein yielded the following properties shown in Table 26B.

Table 26B. Protein Sequence Properties NOV26a

PSort analysis: 0.4500 probability located in cytoplasm; 0.3000 probability located in microbody j (peroxisome): 0.1000 probability located in mitochondrial matrix space; 0.1000 J probability located in lysosome (lumen)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV26a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 26C.

In a BLAST search of public sequence datbases, the NOV26a protein was found to have homology to the proteins shown in the BLASTP data in Table 26D.

PFam analysis predicts that the NOV26a protein contains the domains shown in the Table 26E.

Example 27.

The NOV27 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 27A.

Further analysis of the NOV27a protein yielded the following properties shown in Table 27B.

Table 27B. Protein Sequence Properties NOV27a

PSort analysis: 0.6000 probability located in plasma membrane; 0.4000 probability located in Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome)

SignalP analysis: Cleavage site between residues 45 and 46

A search of the NOV27a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 27C.

In a BLAST search of public sequence datbases, the NOV27a protein was found to have homology to the proteins shown in the BLASTP data in Table 27D.

PFam analysis predicts that the NOV27a protein contains the domains shown in the Table 27E.

Example 28.

The NOV28 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 28 A. Table 28A. NOV28 Sequence Analysis

SEQ ID NO: 77 2856 bp

NOV28a, GGGCGGCGCGGGGTCTGCGCTGGGGCCATGGCTCCGCCGCGCCGCTTCGTCCTGGAGC CG94235-01 DNA Sequence TTCCCGACTGCACCCTGGCTCACTTCGCCCTAGGCGCCGACGCCCCCGGCGACGCAGA CGCCCCCGACCCCCGCCTGGCGGCGCTGCTGGGGCCCCCGGAGCGCAGCTACTCGCTG TGCGTGCCCGTGACCCCGGACGCCGGCTGCGGGGCCCGGGTCCGGGCGGCGCGGCTGC ACCAGCGCCTGCTGCACCAGCTGCGCCGCGGCCCCTTCCAGCGGTGCCAGCTGCTCAG GCTGCTCTGCTACTGCCCGGGCGGCCAGGCCGGCGGCGCACAGCAAGGCTTCCTGCTG CGCGACCCCCTGGATGACCCTGACACCCGGCAAGCGCTGCTCGAGCTGCTGGGCGCCT GTCAGGAGGCACCACGCCCGCACTTGGGCGAGTTCGAGGCCGACCCGCGCGGCCAGCT GTGGCAGCGCCTCTGGGAGGTGCAAGACGGCAGGCGGCTGCAGGTGGGCTGCGCACAG GTCGTGCCCGTCCCGGAGCCCCCGCTGCACCCGGTGGTGCCAGACTTGCCCAGTTCCG TGGTCTTCCCGGACCGGGAAGCCGCCCGGGCCGTTTTGGAGGAGTGTACCTCCTTTAT TCCTGAAGCCCGGGCAGTGCTTGACCTGGTCGACCAGTGCCCAAAACAGATCCAGAAA GGAAAGTTCCAGGTTGTTGCCATCGAAGGACTGGATGCCACGGGTGGTAAAACCACGG TGACCCAGTCAGTGGCAGATTCACTTAAGGCTGTCCTCTTAAAGTCACCACCCTCTTG CATTGGCCAGTGGAGGAAGATCTTTGATGATGAACCAACTATCATTAGAAGAGCTTTT TACTCTTTGGGCAATTATATTGTGGCCTCCGAAATAGCTAAAGAATCTGCCAAATCTC CTGTGATTGTAGACAGGCACAGCACGGCCACCTATGCCATAGCCACTGAGGTGAGTGG GGGTCTCCAGCACCTGCCCCCAGCCCATCACCCTGTGTACCAGTGGCCAGAGGACCTG CTCAAACCTGACCTTATCCTGCTGCTCACTGTGAGTCCTGAGGAGAGGTTGCAGAGGC TGCAGGGCCGGGGCATGGAGAAGACCAGGGAAGAAGCAGAACTTGAGGCCAACAGTGT GTTTCGTCAAAAGGTAGAAATGTCCTACCAGCGGATGGAGAATCCTGGCTGCCATGTG GTTGATGCCAGCCCCTCCAGAGAAAAGGTCCTGCAGACGGTATTAAGCCTAATCCAGA ATAGTTTTAGTGAACCGTAGTTACTCTGGCCAGGTGCCACGTCTAACTAGATTAGATG TTGTTTGAAACATCTACATCCACCATTTGTTATGCAGTGTTCCCAAATTTCTGTTCTA CAAGCATGTTGTGTGGCAGAAAACTGGAGACCAGGCATCTTAATTTTACTTCAGCCAT CGTACCCTCTTCTGACTGATGGACCCGTCATCACAAAGGTCCCTCTCATCATGTTCCA GTGAGAGGCCAGCGATTGCTTTCTTCCTGGCATAGTAAACATTTTCTTGGAACATATG TTTCACTTAATCACTACCAAATATCTGGAAGACCTGTCTTACTCAGACAGCACCAGGT GTACAGAAGCAGCAGACAAGATCTTCCAGATCAGCAGGGAGACCCCGGAGCCTCTGCT TCTCCTACACTGGCATGCTGATGAGATCGTGACATGCCCACATTGGCTTCTTCCACAT CTGGTTGCACTCGTCATGATGGGCTCGCTGCATCTCCCTCAGTCCCAAATTCTAGAGC CAAGTGTTCCTGCAGAGGCTGTCTATGTGTCCTGGCTGCCCAAGGACACTCCTGCAGA GCCATTTTTGGGTAAGGAACACTTACAAAGAAGGCATTGATCTTGTGTCTGAGGCTCA GAGCCCTTTTGATAGGCTTCTGAGTCATATATAAAGACATTCAAGCCAAGATGCTCCA ACTGCAAATATACCAACCTTCTCTGAATTATATTTTGCTTATTTATATTTCTTTTCTT TTTTTCTAAAGTATGGCTCTGAATAGAATGCACATTTTCCATTGAACTGGATGCATTT CATTTAGCCAATCCAGTAATTTATTTATATTAATCTATACATAATATGTTTCCTCAGC ATAGGAGCTATGATTCATTAATTAAAAGTGGAGTCAAAACGCTAAATGCAATGTTTGT TGTGTATTTTCATTACACAAACTTAATTTGTCTTGTTAAATAAGTACAGTGGATCTTG GAGTGGGATTTCTTGGTAAATTATCTTGCACTTGAATGTCTCATGATTACATATGAAA TCGCTTTGACATATCTTTAGACAGAAAAAAGTAGCTGAGTGAGGGGGAAATTATAGAG CTGTGTGACTTTAGGGAGTAGGTTGAACCAGGTGATTACCTAAAATTCCTTCCAGTTC AAAGGCAGATAAATCTGTAAATTATTTTATCCTATCTACCATTTCTTAAGAAGACATT ACTCCAAAATAATTAAATTTAAGGCTTTATCAGGTCTGCATATAGAATCTTAAATTCT AATAAAGTTTCATGTTAATGTCATAGGATTTTTAAAAGAGCTATAGGTAATTTCTATA TAATATGTGTATATTAAAATGTAATTGATTTCAGTTGAAAGTATTTTAAAGCTGATAA ATAGCATTAGGGTTCTTTGCAATGTGGTATCTAGCTGTATTATTGGTTTTATTTACTT TAAACATTTTGAAAAGCTTATACTGGCAGCCTAGAAAAACAAACAATTAATGTATCTT TATGTCCCTGGCACATGAATAAACTTTGCTGTGGTTTACTAATCTAAAAAAAAAAAAA AAAGGGCGGCCGCT

ORF Start: ATG at 28 ORF Stop: TAG at 1294

SEQ ID NO: 78 422 aa MW at 46476.6kD

NOV28a, MAPPRRFVLELPDCTLAHFALGADAPGDADAPDPRLAALLGPPERSYSLCVPVTPDAG CG94235-01 Protein Sequence CGARVRAAR HQRLLHQLRRGPFQRCQLLRL CYCPGGQAGGAQQGFL RDPLDDPDT RQALLEL GACQEAPRPHLGEFEADPRGQLWQRL EVQDGRRLQVGCAQWPVPEPP HPWPDLPSSWFPDREAARAVLEECTSFIPEARAVLD VDQCPKQIQKGKFQWAIE GLDATGGKTTVTQSVADS KAVLLKSPPSCIGQ RKIFDDEPTIIRRAFYSLGNYIVA SEIAKESAKSPVIVDRHSTATYAIATEVSGGLQHLPPAHHPVYQWPED KPDLILLL TVSPEERLQR QGRGMEKTREEAELEANSVFRQKVE SYQRMENPGCHWDASPSREK VLQTV SLIQNSFSEP 03/01032

SEQ ID NO: 79 2331 bp

NOV28b, GTCTGCGCTGGGGCCATGGCTCCGCCGCGCCGCTTCGTCCTGGAGCTTCCTGACTGCA CG94235-02 DNA Sequence CCCTGGCTCACTTCGCCCTAGGCGCCGTTTTGGAGGAGTGTACCTCCTTTATTCCTGA AGCCCGGGCAGTGCTTGACCTGGTCGACCAGTGCCCAAAACAGATCCAGAAAGGAAAG TTCCAGGTTGTTGCCATCGAAGGACTGGATGCCACGGGTAAAACCACGGTGACCCAGT CAGCGGCAGATTCACTTAAGGCTGTCCTCTTAAAGTCACCACCCTCTTGCATTGGCCA GTGGAGGAAGATCTTTGATGATGAACCAACTATCATTAGAAGAGCTTTTTACTCTTTG GGCAATTATATTGTGGCCTCCGAAATAGCTAAAGAATCTGCCAAATCTCCTGTGATTG TAGACAGGTACTGGCACAGCACGGCCACCTATGCCATAGCCACTGAGGTGAGTGGGGG TCTCCAGCACCTGCCCCCAGCCCATCACCCTGTGTACCAGTGGCCAGAGGACCTGCTC AAACCTGACCTTATCCTGCTGCTCACTGTGAGTCCTGAGGAGAGGTTGCAGAGGCTGC AGGGCCGGGGCATGGAGAAGACCAGGGAAGAAGCAGAACTTGAGGCCAACAGTGTGTT TCGTCAAAAGGTAGAAATGTCCTACCAGCGGATGGAGAATCCTGGCTGCCATGTGGTT GATGCCAGCCCCTCCAGAGAAAAGGTCCTGCAGACGGTATTAAGCCTAATCCAGAATA GTTTTAGTGAACCGTAGTTACTCTGGCCAGGTGCCACGTCTAACTAGATTAGATGTTG TTTGAAACATCTACATCCACCATTTGTTATGCAGTGTTCCCAAATTTCTGTTCTACAA GCATGTTGTGTGGCAGAAAACTGGAGACCAGGCATCTTAAGTTTACTTCAGCCATCGT ACCCTCTTCTGACTGATGGACCCGTCATCACAAAGGTCCCTCTCATCATGTTCCAGTG AGAGGCCAGCGATTGCTTTCTTCCTGGCATAGTAAACATTTTCTTGGAACATATGTTT CACTTAATCACTACCAAATATCTGGAAGACCTGTCTTACTCAGACAGCACCAGGTGTA CAGAAGCAGCAGACAAGATCTTCCAGATCAGCAGGGAGACCCCGGAGCCTCTGCTTCT CCTACACTGGCATGCTGATGAGATCGTGACATGCCCACATTGGCTTCTTCCACATCTG GTTGCACTCGTCATGATGGGCTCGCTGCATCTCCCTCAGTCCCAAATTCTAGAGCCAA GTGTTCCTGCAGAGGCTGTCTATGTGTCCTGGCTGCCCAAGGACACTCCTGCAGAGCC ATTTTTGGGTAAGGAACACTTACAAAGAAGGCATTGATCTTGTGTCTGAGGCTCAGAG CCCTTTTGATAGGCTTCTGAGTCATATATAAAGACATTCAAGCCAAGATGCTCCAACT GCAAATATACCAACCTTCTCTGAATTATATTTTGCTTATTTATATTTCTTTTCTTTTT TTCTAAAGTATGGCTCTGAATAGAATGCACATTTTCCATTGAACTGGATGCATTTCAT TTAGCCAATCCAGTAATTTATTTATATTAATCTATACATAATATGTTTCCTCAGCATA GGAGCTATGATTCATTAATTAAAAGTGGAGTCAAAACGCTAAATGCAATGTTTGTTGT GTATTTTCATTACACAAACTTAATTTGTCTTGTTAAATAAGTACAGTGGATCTTGGAG TGGGATTTCTTGGTAAATTATCTTGCACTTGAATGTCTCATGATTACATATGAAATCG CTTTGACATATCTTTAGACAGAAAAAAGTAGCTGAGTGAGGGGGAAATTATAGAGCTG TGTGACTTTAGGGAGTAGGTTGAACCAGGTGATTACCTAAAATTCCTTCCAGTTCAAA GGCAGATAAATCTGTAAATTATTTTATCCTATCTACCATTTCTTAAGAAGACATTACT CCAAAATAATTAAATTTAAGGCTTTATCAGGTCTGCATATAGAATCTTAAATTCTAAT AAAGTTTCATGTTAATGTCATAGGATTTTTAAAAGAGCTATAGGTAATTTCTGTATAA TATGTGTATATTAAAATGTAATTGATTTCAGTTGAAAGTATTTTAAAGCTGATAAATA GCATTAGGGTTCTTTGCAATGTGGTATCTAGCTGTATTATTGGTTTTATTTACTTTAA ACATTTTGAAAAGCTTATACTGGCAGCCTAGAAAAACAAACAATTAATGTATCTTTAT GTCCCTGGCACATGAATAAACTTTGCTGTGGTTTACTAAAAAAAAAAAAAAAAAAAAA GGGCGGCCGCT

ORF Start: ATG at 16 ORF Stop: TAG at 769

SEQ ID NO: 80 251 aa MW at 27980.8kD

NOV28b, MAPPRRFV ELPDCT AHFA GAVLEECTSFIPEARAV DLVDQCPKQIQKGKFQWA CG94235-02 Protein Sequence IEGLDATGKTTVTQSAADS KAVLLKSPPSCIGQWRKIFDDEPTIIRRAFYSLGNYIV ASEIAKESAKSPVIVDRYWHSTATYAIATEVSGGLQHLPPAHHPVYQWPED LKPD I LLLTVSPEERLQRLQGRGMEKTREEAELEANSVFRQKVEMSYQRMENPGCHWDASPS REKVLQTVLS IQNSFSEP

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 28B.

Further analysis of the NOV28a protein yielded the following properties shown in Table 28C.

Table 28C. Protein Sequence Properties NOV28a

(peroxisome); 0.1939 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV28a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 28D.

In a BLAST search of public sequence datbases, the NOV28a protein was found to have homology to the proteins shown in the BLASTP data in Table 28E.

PFam analysis predicts that the NOV28a protein contains the domains shown in the Table 28F.

Example 29.

The NOV29 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 29A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 29B.

Table 29B. Comparison of NOV29a against NOV29b.

NOV29a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

Further analysis of the NOV29a protein yielded the following properties shown in Table 29C.

Table 29C. Protein Sequence Properties NOV29a

PSort analysis: j 0.7900 probability located in plasma membrane; 0.6400 probability located in microbody (peroxisome); 0.3000 probability located in Golgi body; 0.2000 probability located in endoplasmic reticulum (membrane)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV29a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 29D.

In a BLAST search of public sequence datbases, the NOV29a protein was found to have homology to the proteins shown in the BLASTP data in Table 29E.

PFam analysis predicts that the NOV29a protein contains the domains shown in the Table 29F.

Example 30.

The NOV30 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 30 A.

Further analysis of the NOV30a protein yielded the following properties shown in Table 30B.

Table 30B. Protein Sequence Properties NOV30a

PSort analysis: | 0.6000 probability located in plasma membrane; 0.4000 probability located in Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in mitochondrial inner membrane

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV30a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 30C.

In a BLAST search of public sequence datbases, the NOV30a protein was found to have homology to the proteins shown in the BLASTP data in Table 30D.

PFam analysis predicts that the NOV30a protein contains the domains shown in the Table 30E.

Example 31.

The NOV31 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 31 A. 0

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 3 IB.

Further analysis of the NOV31a protein yielded the following properties shown in Table 3 IC.

Table 31C. Protein Sequence Properties NOV31a i PSort analysis: 0.3000 probability located in nucleus; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen); 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV31 a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3 ID.

In a BLAST search of public sequence datbases, the NO V3 la protein was found to have homology to the proteins shown in the BLASTP data in Table 3 IE.

PFam analysis predicts that the NO V31 a protein contains the domains shown in the Table 3 IF.

Example 32.

The NOV32 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 32 A. Table 32A. NOV32 Sequence Analysis

SEQ ID NO: 95 6224 bp

NOV32a, CCGGCGCGGCCCGCGCGCTCTTCCGCCGCCTCTCGCATGCGCCATGGCCGGCCGGTCC -01 DNA Sequence CACCCGGGCCCGCTGCGGGGCGGCCGCTGCTGCCTCTCCTTGTGGTGGCCGCGTGCGT CCTGCCCGGAGCCGGCGGGACATGCCCGGAGCGCGCGCTGGAGCGGCGCGAGGAGGAG GCGAACGTGGTGCTCACCGGGACGGTGGAGGAGATCCTCAACGTGGACCCGGTGCAGC ACACGTACTCCTGCAAGGTTCGGGTCTGGCGGTACTTGAAGGGCAAAGACCTGGTGGC CCGGGAGAGCCTGCTGGACGGCGGCAACAAGGTGGTGATCAGCGGCTTTGGAGACCCC CTCATCTGTGACAACCAGGTGTCCACTGGGGACACCAGGATCTTCTTTGTGAACCCTG CACCCCCATACCTGTGGCCAGCCCACAAGAACGAGCTGATGCTCAACTCCAGCCTCAT GCGGATCACCCTGCGGAACCTGGAGGAGGTGGAGTTCTGTGTGGAAGATAAACCCGGG ACCCACTTCACTCCAGTGCCTCCGACGCCTCCTGATGCGTGCCGGGGAATGCTGTGCG GCTTCGGCGCCGTGTGCGAGCCCAACGCGGAGGGGCCGGGCCGGGCGTCCTGCGTCTG CAAGAAGAGCCCGTGCCCCAGCGTGGTGGCGCCTGTGTGTGGGTCGGACGCCTCCACC TACAGCAACGAATGCGAGCTGCAGCGGGCGCAGTGCAGCCAGCAGCGCCGCATCCGCC TGCTCAGCCGCGGGCCGTGCGGCTCGCGGGACCCCTGCTCCAACGTGACCTGCAGCTT CGGCAGCACCTGTGCGCGCTCGGCCGACGGGCTGACGGCCTCGTGCCTGTGCCCCGCG ACCTGCCGTGGCGCCCCCGAGGGGACCGTCTGCGGCAGCGACGGCGCCGACTACCCCG GCGAGTGCCAGCTCCTGCGCCGCGCCTGCGCCCGCCAGGAGAATGTCTTCAAGAAGTT CGACGGCCCTTGTGACCCCTGTCAGGGCGCCCTCCCTGACCCGAGCCGCAGCTGCCGT GTGAACCCGCGCACGCGGCGCCCTGAGATGCTCCTACGGCCCGAGAGCTGCCCTGCCC GGCAGGCGCCAGTGTGTGGGGACGACGGAGTCACCTACGAAAACGACTGTGTCATGGG CCGATCGGGGGCCGCCCGGGGTCTCCTCCTGCAGAAAGTGCGCTCCGGCCAGTGCCAG GGTCGAGACCAGTGCCCGGAGCCCTGCCGGTTCAATGCCGTGTGCCTGTCCCGCCGTG GCCGTCCCCGCTGCTCCTGCGACCGCGTCACCTGTGACGGGGCCTACAGGCCCGTGTG TGCCCAGGACGGGCGCACGTATGACAGTGATTGCTGGCGGCAGCAGGCTGAGTGCCGG CAGCAGCGTGCCATCCCCAGCAAGCACCAGGGCCCGTGTGACCAGGCCCCGTCCCCAT GCCTCGGGGTGCAGTGTGCATTTGGGGCGACGTGTGCTGTGAAGAACGGGCAGGCAGC GTGTGAATGCCTGCAGGCGTGCTCGAGCCTCTACGATCCTGTGTGCGGCAGCGACGGC GTCACATACGGCAGCGCGTGCGAGCTGGAGGCCACGGCCTGTACCCTCGGGCGGGAGA TCCAGGTGGCGCGCAAAGGACCCTGTGACCGCTGCGGGCAGTGCCGCTTTGGAGCCCT GTGCGAGGCCGAGACCGGGCGCTGCGTGTGCCCCTCTGAATGCGTGGCTTTGGCCCAG CCCGTGTGTGGCTCCGACGGGCACACGTACCCCAGCGAGTGCATGCTGCACGTGCACG CCTGCACACACCAGATCAGCCTGCACGTGGCCTCAGCTGGACCCTGTGAGACCTGTGG AGATGCCGTGTGTGCTTTTGGGGCTGTGTGCTCCGCAGGGCAGTGTGTGTGTCCCCGG TGTGAGCACCCCCCGCCCGGCCCCGTGTGTGGCAGCGACGGTGTCACCTACGGCAGTG CCTGCGAGCTACGGGAAGCCGCCTGCCTCCAGCAGACACAGATCGAGGAGGCCCGGGC AGGGCCGTGCGAGCAGGCCGAGTGCGGTTCCGGAGGCTCTGGCTCTGGGGAGGACGGT GACTGTGAGCAGGAGCTGTGCCGGCAGCGCGGTGGCATCTGGGACGAGGACTCGGAGG ACGGGCCGTGTGTCTGTGACTTCAGCTGCCAGAGTGTCCCAGGCAGCCCGGTGTGCGG CTCAGATGGGGTCACCTACAGCACCGAGTGTGAGCTGAAGAAGGCCAGGTGTGAGTCA CAGCGAGGGCTCTACGTAGCGGCCCAGGGAGCCTGCCGAGGCCCCGCCTTCGCCCCGC TGCCGCCTGTGGCCCCCTTACACTGTGCCCAGACGCCCTACGGCTGCTGCCAGGACAA TATCACCGCAGCCCGGGGCGTGGGCCTGGCTGGCTGCCCCAGTGCCTGCCAGTGCAAC CCCCATGGCTCTTACGGCGGCACCTGTGACCCAGCCACAGGCCAGTGCTCCTGCCGCC CAGGTGTGGGGGGCCTCAGGTGTGACCGCTGTGAGCCTGGCTTCTGGAACTTTCGAGG CATCGTCACCGATGGCCGGAGTGGCTGTACACCCTGCAGCTGTGATCCCCAAGGCGCC GTGCGGGATGACTGTGAGCAGATGACGGGGCTGTGCTCGTGTAAGCCCGGGGTGGCTG GACCCAAGTGTGGGCAGTGTCCAGACGGCCGTGCCCTGGGCCCCGCGGGCTGTGAAGC TGACGCTTCTGCGCCTGCGACCTGTGCGGAGATGCGCTGTGAGTTCGGTGCGCGGTGC GTGGAGGAGTCTGGCTCAGCCCACTGTGTCTGCCCGATGCTCACCTGTCCAGAGGCCA ACGCTACCAAGGTCTGTGGGTCAGATGGAGTCACATACGGCAACGAGTGTCAGCTGAA GACCATCGCCTGCCGCCAGGGCCTGCAAATCTCTATCCAGAGCCTGGGCCCGTGCCAG GAGGCTGTTGCTCCCAGCACTCACCCGACATCTGCCTCCGTGACTGTGACCACCCCAG GGCTCCTCCTGAGCCAGGCACTGCCGGCCCCCCCCGGCGCCCTCCCCCTGGCTCCCAG CAGTACCGCACACAGCCAGACCACCCCTCCGCCCTCATCGCGACCTCGGACCACTGCC AGCGTCCCCAGGACCACCGTGTGGCCCGTGCTGACGGTGCCCCCCACGGCACCCTCCC CTGCACCCAGCCTGGTGGCGTCCGCCTTTGGTGAATCTGGCAGCACTGATGGAAGCAG CGATGAGGAACTGAGCGGGGACCAGGAGGCCAGTGGGGGTGGCTCTGGGGGGCTCGAG CCCTTGGAGGGCAGCAGCGTGGCCACCCCTGGGCCACCTGTCGAGAGGGCTTCCTGCT ACAACTCCGCGTTGGGCTGCTGCTCTGATGGGAAGACGCCCTCGCTGGACGCAGAGGG CTCCAACTGCCCCGCCACCAAGGTGTTCCAGGGCGTCCTGGAGCTGGAGGGCGTCGAG GGCCAGGAGCTGTTCTACACGCCCGAGATGGCTGACCCCAAGTCAGAACTGTTCGGGG AGACAGCCAGGAGCATTGAGAGCACCCTGGACGACCTCTTCCGGAATTCAGACGTCAA GAAGGATTTCCGGAGTGTCCGCTTGCGGGACCTGGGGCCCGGCAAATCCGTCCGCGCC ATTGTGGATGTGCACTTTGACCCCACCACAGCCTTCAGGGCACCCGACGTGGCCCGGG CCCTGCTCCGGCAGATCCAGGTGTCCAGGCGCCGGTCCTTGGGGGTGAGGCGGCCGCT GCAGGAGCACGTGCGATTTATGGACTTTGACTGGTTTCCTGCGTTTATCACGGGGGCC ACGTCAGGAGCCATTGCTGCGGGAGCCACGGCCAGAGCCACCACTGCATCGCGCCTGC CGTCC^CTGCTGTGACCCCTCGGGCCCCGCaCCCCAGTCACACAAGCCAGCCCGTTGC CAAGACO-CGGCAGCCCCCACCACACGTCGGCCCCCCACCACTGCCCCCAGCCGTGTG CCCGGACGTCGGCCCCCGGCCCCCCAGCAGCCTCCAAAGCCCTGTGACTCACAGCCCT GCTTCCACGGGGGGACCTGCCAGGACTGGGCATTGGGCGGGGGCTTCACCTGCAGCTG CCCGGCAGGCAGGGGAGGCGCCGTCTGTGAGAAGGTGCTTGGCGCCCCTGTGCCGGCC TTCGAGGGCCGCTCCTTCCTGGCCTTCCCCACCCTCCGCGCCTACCACACGCTGCGCC TGGCACTGGAATTCCGGGCGCTGGAGCCTCAGGGGCTGCTGCTGTACAATGGCAACGC CCGGGGCAAGGACTTCCTGGCATTGGCGCTGCTAGATGGCCGCGTGCAGCTCAGGTTT GACACAGGTTCGGGGCCGGCGGTGCTGACCAGTGCCGTGCCGGTAGAGCCGGGCCAGT GGCACCGCCTGGAGCTGTCCCGGCACTGGCGCCGGGGCACCCTCTCGGTGGATGGTGA GACCCCTGTTCTGGGCGAGAGTCCCAGTGGCACCGACGGCCTCAACCTGGACACAGAC CTCTTTGTGGGCGGCGTACCCGAGGACCAGGCTGCCGTGGCGCTGGAGCGGACCTTCG TGGGCGCCGGCCTGAGGGGGTGCATCCGTTTGCTGGACGTCAACAACCAGCGCCTGGA GCTTGGCATTGGGCCGGGGGCTGCCACCCGAGGCTCTGGCGTGGGCGAGTGCGGGGAC CACCCCTGCCTGCCCAACCCCTGCCATGGCGGGGCCCCATGCCAGAACCTGGAGGCTG GAAGGTTCCATTGCCAGTGCCCGCCCGGCCGCGTCGGACCAACCTGTGCCGATGAGAA GAGCCCCTGCCAGCCCAACCCCTGCCATGGGGCGGCGCCCTGCCGTGTGCTGCCCGAG GGTGGTGCTCAGTGCGAGTGCCCCCTGGGGCGTGAGGGCACCTTCTGCCAGACAGCCT CGGGGCAGGACGGCTCTGGGCCCTTCCTGGCTGACTTCAACGGCTTCTCCCACCTGGA GCTGAGAGGCCTGCACACCATTGCACGGGACCTGGGGGAGAAGATGGCGCTGGAGGCC GTGTTCCTGGCACGAGGCCCCAGCGGCCTCCTGCTCTACAACGGGCAGAAGACGGACG GCAAGGGGGACTTCGTGTCGCTGGCACTGCGGGACCGCCGCCTGGAGTTCCGCTACGA CCTGGGCAAGGGGGCAGCGGTCATCAGGAGCAGGGAGCCAGTCACCCTGGGAGCCTGG ACCAGGGTCTCACTGGAGCGAAACGGCCGCAAGGGTGCCCTGCGTGTGGGCGACGGCC CCCGTGTGTTGGGGGAGTCCCCGAAATCCCGCAAGGTTCCGCACACCGTCCTCAACCT GAAGGAGCCGCTCTACGTAGGGGGCGCTCCCGACTTCAGCAAGCTGGCCCGTGCTGCT GCCGTGTCCTCTGGCTTCGACGGTGCCATCCAGCTGGTCTCCCTCGGAGGCCGCCAGC TGCTGACCCCGGAGCACGTGCTGCGGCAGGTGGACGTCACGTCCTTTGCAGGTCACCC CTGCACCCGGGCCTCAGGCCACCCCTGCCTCAATGGGGCCTCCTGCGTCCCGAGGGAG GCTGCCTATGTGTGCCTGTGTCCCGGGGGATTCTCAGGACCGCACTGCGAGAAGGGGC TGGTGGAGAAGTCAGCGGGGGACGTGGATACCTTGGCCTTTGACGGGCGGACCTTTGT CGAGTACCTCAACGCTGTGACCGAGAGCGAGAAGGCACTGCAGAGCAACCACTTTGAA CTGAGCCTGCGCACTGAGGCCACGCAGGGGCTGGTGCTCTGGAGTGGCAAGGCCACGG AGCGGGCAGACTATGTGGCACTGGCCATTGTGGACGGGCACCTGCAACTGAGCTACAA CCTGGGCTCCCAGCCCGTGGTGCTGCGTTCCACCGTGCCCGTCAACACCAACCGCTGG TTGCGGGTCGTGGCACATAGGGAGCAGAGGGAAGGTTCCCTGCAGGTGGGCAATGAGG CCCCTGTGACCGGCTCCTCCCCGCTGGGCGCCACGCAGCTGGACACTGATGGAGCCCT GTGGCTTGGGGGCCTGCCGGAGCTGCCCGTGGGCCCAGCACTGCCCAAGGCCTACGGC ACAGGCTTTGTGGGCTGCTTGCGGGATGTGGTGGTGGGCCGGCACCCGCTGCACCTGC TGGAGGACGCCGTCACCAAGCCAGAGCTGCGGCCCTGCCCCACCCCATGAGCTGGCAC CAGAGCCCCGCGCCCGCT

ORF Start: ATG at 37 ORF Stop: TGA at 6196

SEQ ID NO: 96 2053 aa MW at 215628.0kD

NOV32a, MRHGRPVPPGPAAGRPIiLPLLVVAACT PGAGGTCPERALERREEEANVVLTGTVEEI 01 Protein Sequence Lr^PVQHTϊ^■SC VRWRYLKGKD VARESLIiDGGNKVISGFGDP]-ICDNQVSTGDT RIFFVNPAPPY PAHKNELM SSLMRITLRNLEEVEFCVEDKPGTHFTPVPPTPPD ACRGMLCGFGAVCEPNAEGPGRASCVCKKSPCPSWAPVCGSDASTYSNECE QRAQC SQQRRIR LSRGPCGSRDPCSNVTCSFGSTCARSADGLTASC CPATCRGAPEGTVCG SDGADYPGECQLLRRACARQENVFKKFDGPCDPCQGA PDPSRSCRVNPRTRRPEMLL RPESCPARQAPVCGDDGVTYENDCVMGRSGAARGLL QKVRΞGQCOGRDQCPEPCRFN AVCLSRRGRPRCSCDRVTCDGAYRPVCAQDGRTYDSDC RQQAECRQQRAIPSKHQGP CDQAPSPCLGVQCAFGATCAVKNGQAACECLQACSSLYDPVCGSDGVTYGSACEI.EAT ACTLGREIQVARKGPCDRCGQCRFGALCEAETGRCVCPSECVALAQPVCGSDGHTYPS ECMLHVHACTHQIS HVASAGPCETCGDAVCAFGAVCSAGQCVCPRCEHPPPGPVCGS DGVTYGSACELREAACLQQTQIEEARAGPCEQAECGSGGSGSGEDGDCEQELCRQRGG I DEDSEDGPCVCDFSCQSVPGSPVCGSDGVTYSTECELK ARCESQRGLYVAAQGAC RGPAFAPLPPVAPLHCAQTPYGCCQDNITAARGVG AGCPSACQC PHGSYGGTCDPA TGQCSCRPGVGGLRCDRCEPGFWNFRGIVTDGRSGCTPCSCDPQGAVRDDCEQMTGLC SCKPGVAGPKCGQCPDGRA GPAGCEADASAPATCAEMRCEFGARCVEESGSAHCVCP MLTCPEANATKVCGSDGVTYGNECQLKTIACRQG QISIQS GPCQEAVAPSTHPTSA SVTVTTPGLLLSQA PAPPGALPLAPSSTAHSQTTPPPSSRPRTTASVPRTTVWPV T VPPTAPSPAPS VASAFGESGSTDGSSDEE SGDQEASGGGSGGLEPLEGSSVATPGP PVERASCY SA GCCSDGKTPS DAEGSNCPATKVFQGVLELEGVEGQELFYTPEMAD PKSELFGETARSIESTLDDLFRNSDVKKDFRSVR RDLGPGKSVRAIVDVHFDPTTAF RAPDVARALLRQIQVSRRRSLGVRRPLQEHVRFMDFDWFPAFITGATSGAIAAGATAR ATTASRLPSSAVTPRAPHPSHTSQPVAKTTAAPTTRRPPTTAPSRVPGRRPPAPQQPP KPCDSQPCFHGGTCQDALGGGFTCSCPAGRGGAVCEKV GAPVPAFEGRSF AFPTL RAYHTLRI-ALEFRALEPQG LLY GNARGKDFIALA DGRVQ RFDTGSGPAVLTSA VPVEPGQWHR ELSRHWRRGT SVDGETPVLGESPSGTDGLNLDTDLFVGGVPEDQAA VALERTFVGAGIiRGCIRL D-VNNQRLE GIGPGAATRGSGVGECGDHPCLPNPCHGGA PCQNLEAGRFHCQCPPGRVGPTCADEKSPCQPNPCHGAAPCRλ/LPEGGAQCECPLGRE GTFCQTASGQ0GSGPF ADFNGFSHLELRG3-HTIARDLGEKMA EAVF ARGPSG LL Y GQKTDGKGDFVSLALRDRR EFRYDLGKGAAVIRSREPVT GAWTRVSLERNGRKG ALRVGDGPRVLGESPKSRKVPHTVI-OT.KEPLYVGGAPDFS.α-ARAAAVSSGFDGAIQL VSLGGRQLLTPEHVLRQVDVTSFAGHPCTRASGHPC NGASCVPREAAYVC CPGGFS GPHCEKGLVEKSAGDVDTLAFDGRTFVEYLNAVTEΞEKALQSNHFE SLRTEATQGLV SG ATERADYVALAIλ/DGHLQLSYNLGSQPVVLRSTVPVNTNR LRλWAHREQREG SLQVGNEAPVTGSSPLGATQLDTDGAL GGLPELPVGPALPKAYGTGFVGCLRD W GRHPLHLLEDAVTKPELRPCPTP

SEQ ID NO: 97 4760 bp

NOV32b, CCGGCGCGGCCCGCGCGCTCTTCCGCCGCCTCTCGCATGCGCCATGGCCGGCCGGTCC -02 DNA Sequence CACCCGGGCCCGCTGCGGGGCGGCCGCTGCTGCCTCTCCTTGTGGTGGCCGCGTGCGT CCTGCCCGGAGCCGGCGGGACATGCCCGGAGCGCGCGCTGGAGCGGCGCGAGGAGGAG GCGAACGTGGTGCTCACCGGGACGGTGGAGGAGATCCTCAACGTGGACCCGGTGCAGC ACACGTACTCCTGCAAGGTTCGGGTCTGGCGGTACTTGAAGGGCAAAGACCTGGTGGC CCGGGAGAGCCTGCTGGACGGCGGCAACAAGGTGGTGATCAGCGGCTTTGGAGACCCC CTCATCTGTGACAACCAGGTGTCCACTGGGGACACCAGGATCTTCTTTGTGAACCCTG CACCCCCATACCTGTGGCCAGCCCACAAGAACGAGCTGATGCTCAACTCCAGCCTCAT GCGGATCACCCTGCGGAACCTGGAGGAGGTGGAGTTCTGTGTGGAAGATAAACCCGGG ACCCACTTCACTCCAGTGCCTCCGACGCCTCCTGATGCGTGCCGGGGAATGCTGTGCG GCTTCGGCGCCGTGTGCGAGCCCAACGCGGAGGGGCCGGGCCGGGCGTCCTGCGTCTG CAAGAAGAGCCCGTGCCCCAGCGTGGTGGCGCCTGTGTGTGGGTCGGACGCCTCCACC TACAGCAACGAATGCGAGCTGCAGCGGGCGCAGTGCAGCCAGCAGCGCCGCATCCGCC TGCTCAGCCGCGGGCCGTGCGGCTCGCGGGACCCCTGCTCCAACGTGACCTGCAGCTT CGGCAGCACCTGTGCGCGCTCGGCCGACGGGCTGACGGCCTCGTGCCTGTGCCCCGCG ACCTGCCGTGGCGCCCCCGAGGGGACCGTCTGCGGCAGCGACGGCGCCGACTACCCCG GCGAGTGCCAGCTCCTGCGCCGCGCCTGCGCCCGCCAGGAGAATGTCTTCAAGAAGTT CGACGGCCCTTGTGACCCCTGTCAGGGCGCCCTCCCTGACCCGAGCCGCAGCTGCCGT GTGAACCCGCGCACGCGGCGCCCTGAGATGCTCCTACGGCCCGAGAGCTGCCCTGCCC GGCAGGCGCCAGTGTGTGGGGACGACGGAGTCACCTACGAAAACGACTGTGTCATGGG CCGATCGGGGGCCGCCCGGGGTCTCCTCCTGCAGAAAGTGCGCTCCGGCCAGTGCCAG GGTCGAGACCAGTGCCCGGAGCCCTGCCGGTTCAATGCCGTGTGCCTGTCCCGCCGTG GCCGTCCCCGCTGCTCCTGCGACCGCGTCACCTGTGACGGGGCCTACAGGCCCGTGTG TGCCCAGGACGGGCGCACGTATGACAGTGATTGCTGGCGGCAGCAGGCTGAGTGCCGG CAGCAGCGTGCCATCCCCAGCAAGCACCAGGGCCCGTGTGACCAGGCCCCGTCCCCAT GCCTCGGGGTGCAGTGTGCATTTGGGGCGACGTGTGCTGTGAAGAACGGGCAGGCAGC GTGTGAATGCCTGCAGGCGTGCTCGAGCCTCTACGATCCTGTGTGCGGCAGCGACGGC GTCACATACGGCAGCGCGTGCGAGCTGGAGGCCACGGCCTGTACCCTCGGGCGGGAGA TCCAGGTGGCGCGCAAAGGACCCTGTGACCGCTGCGGGCAGTGCCGCTTTGGAGCCCT GTGCGAGGCCGAGACCGGGCGCTGCGTGTGCCCCTCTGAATGCGTGGCTTTGGCCCAG CCCGTGTGTGGCTCCGACGGGCACACGTACCCCAGCGAGTGCATGCTGCACGTGCACG CCTGCACACACCAGATCAGCCTGCACGTGGCCTCAGCTGGACCCTGTGAGACCTGTGG AGATGCCGTGTGTGCTTTTGGGGCTGTGTGCTCCGCAGGGCAGTGTGTGTGTCCCCGG TGTGAGCACCCCCCGCCCGGCCCCGTGTGTGGCAGCGACGGTGTCACCTACGGCAGTG CCTGCGAGCTACGGGAAGCCGCCTGCCTCCAGCAGACACAGATCGAGGAGGCCCGGGC AGGGCCGTGCGAGCAGGCCGAGTGCGGTTCCGGAGGCTCTGGCTCTGGGGAGGACGGT GACTGTGAGCAGGAGCTGTGCCGGCAGCGCGGTGGCATCTGGGACGAGGACTCGGAGG ACGGGCCGTGTGTCTGTGACTTCAGCTGCCAGAGTGTCCCAGGCAGCCCGGTGTGCGG CTCAGATGGGGTCACCTACAGCACCGAGTGTGAGCTGAAGAAGGCCAGGTGTGAGTCA CAGCGAGGGCTCTACGTAGCGGCCCAGGGAGCCTGCCGAGGCCCCGCCTTCGCCCCGC TGCCGCCTGTGGCCCCCTTACACTGTGCCCAGACGCCCTACGGCTGCTGCCAGGACAA TATCACCGCAGCCCGGGGCGTGGGCCTGGCTGGCTGCCCCAGTGCCTGCCAGTGCAAC CCCCATGGCTCTTACGGCGGCACCTGTGACCCAGCCACAGGCCAGTGCTCCTGCCGCC CAGGTGTGGGGGGCCTCAGGTGTGACCGCTGTGAGCCTGGCTTCTGGAACTTTCGAGG CATCGTCACCGATGGCCGGAGTGGCTGTACACCCTGCAGCTGTGATCCCCAAGGCGCC GTGCGGGATGACTGTGAGCAGATGACGGGGCTGTGCTCGTGTAAGCCCGGGGTGGCTG GACCCAAGTGTGGGCAGTGTCCAGACGGCCGTGCCCTGGGCCCCGCGGGCTGTGAAGC TGACGCTTCTGCGCCTGCGACCTGTGCGGAGATGCGCTGTGAGTTCGGTGCGCGGTGC GTGGAGGAGTCTGGCTCAGCCCACTGTGTCTGCCCGATGCTCACCTGTCCAGAGGCCA ACGCTACCAAGGTCTGTGGGTCAGATGGAGTCACATACGGCAACGAGTGTCAGCTGAA GACCATCGCCTGCCGCCAGGGCCTGCAAATCTCTATCCAGAGCCTGGGCCCGTGCCAG GAGGCTGTTGCTCCCAGCACTCACCCGACATCTGCCTCCGTGACTGTGACCACCCCAG GGCTCCTCCTGAGCCAGGCACTGCCGGCCCCCCCCGGCGCCCTCCCCCTGGCTCCCAG CAGTACCGCACACAGCCAGACCACCCCTCCGCCCTCATCGCGACCTCGGACCACTGCC AGCGTCCCCAGGACCACCGTGTGGCCCGTGCTGACGGTGCCCCCCACGGCACCCTCCC CTGCACCCAGCCTGGTGGCGTCCGCCTTTGGTGAATCTGGCAGCACTGATGGAAGCAG CGATGAGGAACTGAGCGGGGACCAGGAGGCCAGTGGGGGTGGCTCTGGGGGGCTCGAG CCCTTGGAGGGCAGCAGCGTGGCCACCCCTGGGCCACCTGTCGAGAGGGCTTCCTGCT ACAACCCCTGCCATGGGGCGGCGCCCTGCCGTGTGCTGCCCGAGGGTGGTGCTCAGTG CGAGTGCCCCCTGGGGCGTGAGGGCACCTTCTGCCAGACAGCCTCGGGGCAGGACGGC TCTGGGCCCTTCCTGGCTGACTTCAACGGCTTCTCCCACCTGGAGCTGAGAGGCCTGC ACACCATTGCACGGGACCTGGGGGAGAAGATGGCGCTGGAGGCCGTGTTCCTGGCACG AGGCCCCAGCGGCCTCCTGCTCTACAACGGGCAGAAGACGGACGGCAAGGGGGACTTC

NOV32c, MRHGRPVPPGPAAGRPLLPLLWAACV PGAGGTCPERA ERREEEANWLTGTVEEI CG94946-03 Protein Sequence I-NVDPVQHTYSCKVRVWRYLKGKDIiVARESLLDGGNKVVISGFGDPLICDNQVSTGDT RIFFVNPAPPYLWPAHKNELVLWSGKATERADYVA AIVDGHLQLSYNLGSQPVVLRS TVPVNTNR LRWAHREQREGSLQVGNEAPVTGSSPLGATQ DTDGALWLGG PELPV GPALPKAYGTGFVGCLRDWVGRHPLHLLEDAVTKPELRPCPTP

SEQ ID NO: 101 1931 bp

NOV32d, CCGGCGCGGCCCGCGCGCTCTTCCGCCGCCTCTCGCATGCGCCATGGCCGGCCGGTCC CG94946-04 DNA Sequence CACCCGGGCCCGCTGCGGGGCGGCCGCTGCTGCCTCTCCTTGTGGTGGCCGCGTGCGT CCTGCCCGGAGCCGGCGGGACATGCCCGGAGCGCGCGCTGGAGCGGCGCGAGGAGGAG GCGAACGTGGTGCTCACCGGGACGGTGGAGGAGATCCTCAACGTGGACCCGGTGCAGC ACACGTACTCCTGCAAGGTTCGGGTCTGGCGGTACTTGAAGGGCAAAGACCTGGTGGC CCGGGAGAGCCTGCTGGACGGCGGCAACAAGGTGGTGATCAGCGGCTTTGGAGACCCC CTCATCTGTGACAACCAGGTGTCCACTGGGGACACCAGGATCTTCTTTGTGAACCCTG CACCCCCATACCTGTGGCCAGCCCACAAGAACGAGCTGATGCTCAACTCCAGCCTCAT GCGGATCACCCTGCGGAACCTGGAGGAGGTGGAGTTCTGTGTGGAAGATAAACCCGGG ACCCACTTCACTCCAGTGCCTCCGACGCCTCCTGATGCGTGCCGGGGAATGCTGTGCG GCTTCGGCGCCGTGTGCGAGCCCAACGCGGAGGGGCCGGGCCGGGCGTCCTGCGTCTG CAAGAAGAGCCCGTGCCCCAGCGTGGTGGCGCCTGTGTGTGGGTCGGACGCCTCCACC TACAGCAACGAATGCGAGCTGCAGCGGGCGCAGTGCAGCCAGCAGCGCCGCATCCGCC TGCTCAGCCGCGGGCCGTGCGGCTCGCGGGACCCCTGCTCCAACGTGACCTGCAGCTT CGGCAGCACCTGTGCGCGCTCGGCCGACGGGCTGACGGCCTCGTGCCTGTGCCCCGCG ACCTGCCGTGGCGCCCCCGAGGGGACCGTCTGCGGCAGCGACGGCGCCGACTACCCCG GCGAGTGCCAGCTCCTGCGCCGCGCCTGCGCCCGCCAGGAGAATGTCTTCAAGAAGTT CGACGGCCCTTGTGACCCCTGTCAGGGCGCCCTCCCTGACCCGAGCCGCAGCTGCCGT GTGAACCCGCGCACGCGGCGCCCTGAGATGCTCCTACGGCCCGAGAGCTGCCCTGCCC GGCAGGCGCCAGTGTGTGGGGACGACGGAGTCACCTACGAAAACGACTGTGTCATGGG CCGATCGGGGGCCGCCCGGGGTCTCCTCCTGCAGAAAGTGCGCTCCGGCCAGTGCCAG GGTCGAGACCAGTGCCCGGAGCCCTGCCGGTTCAATGCCGTGTGCCTGTCCCGCCGTG GCCGTCCCCGCTGCTCCTGCGACCGCGTCACCTGTGACGGGGCCTACAGGCCCGTGTG TGCCCAGGACGGGCGCACGTATGACAGTGATTGCTGGCGGCAGCAGGCTGAGTGCCGG CAGCAGCGTGCCATCCCCAGCAAGCACCAGGGCCCGTGTGACCAGGCCCCGTCCCCAT GCCTCGGGGTGCAGTGTGCATTTGGGGCGACGTGTGCTGTGAAGAACGGGCAGGCAGC GTGTGAATGCCTGCAGGCGTGCTCGAGCCTCTACGATCCTGTGTGCGGCAGCGACGGC GTCACATACGGCAGCGCGTGCGAGCTGGAGGCCACGGCCTGTACCCTCGGGCGGGAGA TCCAGGTGGCGCGCAAAGGACCCTGTGACCGCTGCGGGCAGTGCCGCTTTGGAGCCCT GCCTGTGACCGGCTCCTCCCCGCTGGGCGCCACGCAGCTGGACACTGATGGAGCCCTG TGGCTTGGGGGCCTGCCGGAGCTGCCCGTGGGCCCAGCACTGCCCAAGGCCTACGGCA CAGGCTTTGTGGGCTGCTTGCGGGATGTGGTGGTGGGCCGGCACCCGCTGCACCTGCT GGAGGACGCCGTCACCAAGCCAGAGCTGCGGCCCTGCCCCACCCCATGAGCTGGCACC AGAGCCCCGCGCCCGCT

ORF Start: ATG at 37 ORF Stop: TGA at 1903

SEQ ID NO: 102 622 aa MW at 66353.9kD

NOV32d, MRHGRPVPPGPAAGRPIi PL VVAACV PGAGGTCPERALERREEEANVVLTGTVEEI CG94946-04 Protein Sequence LNVDPVQHTYSCKVRVWRYLKGKD VARESL DGGNKWISGFGDPLICDNQVSTGDT RIFFVNPAPPYLWPAHKNE MLNSSLMRITLRNLEEVEFCVEDKPGTHFTPVPPTPPD ACRGMLCGFGAVCEPNAEGPGRASCVCKKSPCPSWAPVCGSDASTYSNECELQRAQC SQQRRIR SRGPCGSRDPCStrVTCSFGSTCARSADG TASCLCPATCRGAPEGTVCG SDGADYPGECQ RRACARQENVFKKFDGPCDPCQGALPDPSRSCRVNPRTRRPEMLL RPESCPARQAPVCGDDGVTYENDCVMGRSGAARGLLLQKVRSGQCQGRDQCPEPCRFN AVC SRRGRPRCSCDRλTCDGAYRPVCAQDGRTYDSDCWRQQAECRQQRAIPSKHQGP CDQAPSPCLGVQCAFGATCAVKNGQAACECLQACSS YDPVCGSDGVTYGSACELEAT ACTLGREIQVARKGPCDRCGQCRFGALPVTGSSPLGATQLDTDGALWLGGLPE PVGP A PKAYGTGFVGCLRDVWGRHPLHLLEDAVTKPELRPCPTP SEQ ID NO: 103 4697 bp

NOV32e, CCGGCGCGGCCCGCGCGCTCTTCCGCCGCCTCTCGCATGCGCCATGGCCGGCCGGTCC -05 DNA Sequence CACCCGGGCCCGCTGCGGGGCGGCCGCTGCTGCCTCTCCTTGTGGTGGCCGCGTGCGT CCTGCCCGGAGCCGGCGGGACATGCCCGGAGCGCGCGCTGGAGCGGCGCGAGGAGGAG GCGAACGTGGTGCTCACCGGGACGGTGGAGGAGATCCTCAACGTGGACCCGGTGCAGC ACACGTACTCCTGCAAGGTTCGGGTCTGGCGGTACTTGAAGGGCAAAGACCTGGTGGC CCGGGAGAGCCTGCTGGACGGCGGCAACAAGGTGGTGATCAGCGGCTTTGGAGACCCC CTCATCTGTGACAACCAGGTGTCCACTGGGGACACCAGGATCTTCTTTGTGAACCCTG CACCCCCATACCTGTGGCCAGCCCACAAGAACGAGCTGATGCTCAACTCCAGCCTCAT GCGGATCACCCTGCGGAACCTGGAGGAGGTGGAGTTCTGTGTGGAAGATAAACCCGGG ACCCACTTCACTCCAGTGCCTCCGACGCCTCCTGATGCGTGCCGGGGAATGCTGTGCG GCTTCGGCGCCGTGTGCGAGCCCAACGCGGAGGGGCCGGGCCGGGCGTCCTGCGTCTG CAAGAAGAGCCCGTGCCCCAGCGTGGTGGCGCCTGTGTGTGGGTCGGACGCCTCCACC TACAGCAACGAATGCGAGCTGCAGCGGGCGCAGTGCAGCCAGCAGCGCCGCATCCGCC TGCTCAGCCGCGGGCCGTGCGGCTCGCGGGACCCCTGCTCCAACGTGACCTGCAGCTT CGGCAGCACCTGTGCGCGCTCGGCCGACGGGCTGACGGCCTCGTGCCTGTGCCCCGCG ACCTGCCGTGGCGCCCCCGAGGGGACCGTCTGCGGCAGCGACGGCGCCGACTACCCCG GCGAGTGCCAGCTCCTGCGCCGCGCCTGCGCCCGCCAGGAGAATGTCTTCAAGAAGTT CGACGGCCCTTGTGACCCCTGTCAGGGCGCCCTCCCTGACCCGAGCCGCAGCTGCCGT GTGAACCCGCGCACGCGGCGCCCTGAGATGCTCCTACGGCCCGAGAGCTGCCCTGCCC GGCAGGCGCCAGTGTGTGGGGACGACGGAGTCACCTACGAAAACGACTGTGTCATGGG CCGATCGGGGGCCGCCCGGGGTCTCCTCCTGCAGAAAGTGCGCTCCGGCCAGTGCCAG GGTCGAGACCAGTGCCCGGAGCCCTGCCGGTTCAATGCCGTGTGCCTGTCCCGCCGTG GCCGTCCCCGCTGCTCCTGCGACCGCGTCACCTGTGACGGGGCCTACAGGCCCGTGTG TGCCCAGGACGGGCGCACGTATGACAGTGATTGCTGGCGGCAGCAGGCTGAGTGCCGG CAGCAGCGTGCCATCCCCAGCAAGCACCAGGGCCCGTGTGACCAGGCCCCGTCCCCAT GCCTCGGGGTGCAGTGTGCATTTGGGGCGACGTGTGCTGTGAAGAACGGGCAGGCAGC GTGTGAATGCCTGCAGGCGTGCTCGAGCCTCTACGATCCTGTGTGCGGCAGCGACGGC GTCACATACGGCAGCGCGTGCGAGCTGGAGGCCACGGCCTGTACCCTCGGGCGGGAGA TCCAGGTGGCGCGCAAAGGACCCTGTGACCGCTGCGGGCAGTGCCGCTTTGGAGCCCT GTGCGAGGCCGAGACCGGGCGCTGCGTGTGCCCCTCTGAATGCGTGGCTTTGGCCCAG CCCGTGTGTGGCTCCGACGGGCACACGTACCCCAGCGAGTGCATGCTGCACGTGCACG CCTGCACACACCAGATCAGCCTGCACGTGGCCTCAGCTGGACCCTGTGAGACCTGTGG AGATGCCGTGTGTGCTTTTGGGGCTGTGTGCTCCGCAGGGCAGTGTGTGTGTCCCCGG TGTGAGCACCCCCCGCCCGGCCCCGTGTGTGGCAGCGACGGTGTCACCTACGGCAGTG CCTGCGAGCTACGGGAAGCCGCCTGCCTCCAGCAGACACAGATCGAGGAGGCCCGGGC AGGGCCGTGCGAGCAGGCCGAGTGCGGTTCCGGAGGCTCTGGCTCTGGGGAGGACGGT GACTGTGAGCAGGAGCTGTGCCGGCAGCGCGGTGGCATCTGGGACGAGGACTCGGAGG ACGGGCCGTGTGTCTGTGACTTCAGCTGCCAGAGTGTCCCAGGCAGCCCGGTGTGCGG CTCAGATGGGGTCACCTACAGCACCGAGTGTGAGCTGAAGAAGGCCAGGTGTGAGTCA CAGCGAGGGCTCTACGTAGCGGCCCAGGGAGCCTGCCGAGGCCCCGCCTTCGCCCCGC TGCCGCCTGTGGCCCCCTTACACTGTGCCCAGACGCCCTACGGCTGCTGCCAGGACAA TATCACCGCAGCCCGGGGCGTGGGCCTGGCTGGCTGCCCCAGTGCCTGCCAGTGCAAC CCCCATGGCTCTTACGGCGGCACCTGTGACCCAGCCACAGGCCAGTGCTCCTGCCGCC CAGGTGTGGGGGGCCTCAGGTGTGACCGCTGTGAGCCTGGCTTCTGGAACTTTCGAGG CATCGTCACCGATGGCCGGAGTGGCTGTACACCCTGCAGCTGTGATCCCCAAGGCGCC GTGCGGGATGACTGTGAGCAGATGACGGGGCTGTGCTCGTGTAAGCCCGGGGTGGCTG GACCCAAGTGTGGGCAGTGTCCAGACGGCCGTGCCCTGGGCCCCGCGGGCTGTGAAGC TGACGCTTCTGCGCCTGCGACCTGTGCGGAGATGCGCTGTGAGTTCGGTGCGCGGTGC GTGGAGGAGTCTGGCTCAGCCCACTGTGTCTGCCCGATGCTCACCTGTCCAGAGGCCA ACGCTACCAAGGTCTGTGGGTCAGATGGAGTCACATACGGCAACGAGTGTCAGCTGAA GACCATCGCCTGCCGCCAGGGCCTGCAAATCTCTATCCAGAGCCTGGGCCCGTGCCAG GAGGCTGTTGCTCCCAGCACTCACCCGACATCTGCCTCCGTGACTGTGACCACCCCAG GGCTCCTCCTGAGCCAGGCACTGCCGGCCCCCCCCGGCGCCCTCCCCCTGGCTCCCAG CAGTACCGCACACAGCCAGACCACCCCTCCGCCCTCATCGCGACCTCGGACCACTGCC AGCGTCCCCAGGACCACCGTGTGGCCCGTGCTGACGGTGCCCCCCACGGCACCCTCCC CTGCACCCAGCCTGGTGGCGTCCGCCTTTGGTGAATCTGGCAGCACTGATGGAAGCAG CGATGAGGAACTGAGCGGGGACCAGGAGGCCAGTGGGGGTGGCTCTGGGGGGCTCGAG CCCTTGGAGGGCAGCAGCGTGGCCACCCCTGGGCCACCTGTCGAGAGGGCTTCCTGCT ACAACTCCGCGTTGGGCTGCTGCTCTGATGGGAAGACGCCCTCGCTGGACGCAGAGGG CTCCAACTGCCCCGCCACCAAGGTGTTCCAGGGCGTCCTGGAGCTGGAGGGCGTCGAG GGCCAGGAGCTGTTCTACACGCCCGAGATGGCTGACCCCAAGTCAGAACTGTTCGGGG AGACAGCCAGGAGCATTGAGAGCACCCTGGACGACCTCTTCCGGAATTCAGACGTCAA GAAGGATTTCCGGAGTGTCCGCTTGCGGGACCTGGGGCCCGGCAAATCCGTCCGCGCC ATTGTGGATGTGCACTTTGACCCCACCACAGCCTTCAGGGCACCCGACGTGGCCCGGG CCCTGCTCCGGCAGATCCAGGTGTCCAGGCGCCGGTCCTTGGGGGTGAGGCGGCCGCT GCAGGAGCACGTGCGATTTATGGACTTTGACTGGTTTCCTGCGTTTATCACGGGGGCC ACGTCAGGAGCCATTGCTGCGGGAGCCACGGCCAGAGCCACCACTGCATCGCGCCTGC CGTCCTCTGCTGTGACCCCTCGGGCCCCGCACCCCAGTCACACAAGCCAGCCCGTTGC CAAGACCACGGCAGCCCCCACCACACGTCGGCCCCCCACCACTGCCCCCAGCCGTGTG CCCGGACGTCGGCCCCCGGCCTCCTGCGTCCCGAGGGAGGCTGCCTATGTGTGCCTGT

GTGCGAGGCCGAGACCGGGCGCTGCGTGTGCCCCTCTGAATGCGTGGCTTTGGCCCAG CCCGTGTGTGGCTCCGACGGGCACACGTACCCCAGCGAGTGCATGCTGCACGTGCACG CCTGCACACACCAGATCAGCCTGCACGTGGCCTCAGCTGGACCCTGTGAGACCTGTGG AGATGCCGTGTGTGCTTTTGGGGCTGTGTGCTCCGCAGGGCAGTGTGTGTGTCCCCGG TGTGAGCACCCCCCGCCCGGCCCCGTGTGTGGCAGCGACGGTGTCACCTACGGCAGTG CCTGCGAGCTACGGGAAGCCGCCTGCCTCCAGCAGACACAGATCGAGGAGGCCCGGGC AGGGCCGTGCGAGCAGGCCGAGTGCGGTTCCGGAGGCTCTGGCTCTGGGGAGGACGGT GACTGTGAGCAGGAGCTGTGCCGGCAGCGCGGTGGCATCTGGGACGAGGACTCGGAGG ACGGGCCGTGTGTCTGTGACTTCAGCTGCCAGAGTGTCCCAGGCAGCCCGGTGTGCGG CTCAGATGGGGTCACCTACAGCACCGAGTGTGAGCTGAAGAAGGCCAGGTGTGAGTCA CAGCGAGGGCTCTACGTAGCGGCCCAGGGAGCCTGCCGAGGCCCCGCCTTCGCCCCGC TGCCGCCTGTGGCCCCCTTACACTGTGCCCAGACGCCCTACGGCTGCTGCCAGGACAA TATCACCGCAGCCCGGGGCGTGGGCCTGGCTGGCTGCCCCAGTGCCTGCCAGTGCAAC CCCCATGGCTCTTACGGCGGCACCTGTGACCCAGCCACAGGCCAGTGCTCCTGCCGCC CAGGTGTGGGGGGCCTCAGGTGTGACCGCTGTGAGCCTGGCTTCTGGAACTTTCGAGG CATCGTCACCGATGGCCGGAGTGGCTGTACACCCTGCAGCTGTGATCCCCAAGGCGCC GTGCGGGATGACTGTGAGCAGATGACGGGGCTGTGCTCGTGTAAGCCCGGGGTGGCTG GACCCAAGTGTGGGCAGTGTCCAGACGGCCGTGCCCTGGGCCCCGCGGGCTGTGAAGC TGACGCTTCTGCGCCTGCGACCTGTGCGGAGATGCGCTGTGAGTTCGGTGCGCGGTGC GTGGAGGAGTCTGGCTCAGCCCACTGTGTCTGCCCGATGCTCACCTGTCCAGAGGCCA ACGCTACCAAGGTCTGTGGGTCAGATGGAGTCACATACGGCAACGAGTGTCAGCTGAA GACCATCGCCTGCCGCCAGGGCCTGCAAATCTCTATCCAGAGCCTGGGCCCGTGCCAG GAGGCTGTTGCTCCCAGCACTCACCCGACATCTGCCTCCGTGACTGTGACCACCCCAG GGCTCCTCCTGAGCCAGGCACTGCCGGCCCCCCCCGGCGCCCTCCCCCTGGCTCCCAG CAGTACCGCACACAGCCAGACCACCCCTCCGCCCTCATCGCGACCTCGGACCACTGCC AGCGTCCCCAGGACCACCGTGTGGCCCGTGCTGACGGTGCCCCCCACGGCACCCTCCC CTGCACCCAGCCTGGTGGCGTCCGCCTTTGGTGAATCTGGCAGCACTGATGGAAGCAG CGATGAGGAACTGAGCGGGGACCAGGAGGCCAGTGGGGGTGGCTCTGGGGGGCTCGAG CCCTTGGAGGGCAGCAGCGTGGCCACCCCTGGGCCACCTGTCGAGAGGGCTTCCTGCT ACAACTCCGCGTTGGGCTGCTGCTCTGATGGGAAGACGCCCTCGCTGGACGCAGAGGG CTCCAACTGCCCCGCCACCAAGGTGTTCCAGGGCGTCCTGGAGCTGGAGGGCGTCGAG GGCCAGGAGCTGTTCTACACGCCCGAGATGGCTGACCCCAAGTCAGAACTGTTCGGGG AGACAGCCAGGAGCATTGAGAGCACCCTGGACGACCTCTTCCGGAATTCAGACGTCAA GAAGGATTTCCGGAGTGTCCGCTTGCGGGACCTGGGGCCCGGCAAATCCGTCCGCGCC ATTGTGGATGTGCACTTTGACCCCACCACAGCCTTCAGGGCACCCGACGTGGCCCGGG CCCTGCTCCGGCAGATCCAGGTGTCCAGGCGCCGGTCCTTGGGGGTGAGGCGGCCGCT GCAGGAGCACGTGCGATTTATGGACTTTGACTGGTTTCCTGCGTTTATCACGGGGGCC ACGTCAGGAGCCATTGCTGCGGGAGCCACGGCCAGAGCCACCACTGCATCGCGCCTGC CGTCCTCTGCTGTGACCCCTCGGGCCCCGCACCCCAGTCACACAAGCCAGCCCGTTGC CAAGACCACGGCAGCCCCCACCACACGTCGGCCCCCCACCACTGCCCCCAGCCGTGTG CCCGGACGTCGGCCCCCGGCCCCCCAGCAGCCTCCAAAGCCCTGTGACTCACAGCCCT GCTTCCACGGGGGGACCTGCCAGGACTGGGCATTGGGCGGGGGCTTCACCTGCAGCTG CCCGGCAGGCAGGGGAGGCGCCGTCTGTGAGAAGGTGCTTGGCGCCCCTGTGCCGGCC TTCGAGGGCCGCTCCTTCCTGGCCTTCCCCACCCTCCGCGCCTACCACACGCTGCGCC TGGCACTGGAATTCCGGGCGCTGGAGCCTCAGGGGCTGCTGCTGTACAATGGCAACGC CCGGGGCAAGGACTTCCTGGCATTGGCGCTGCTAGATGGCCGCGTGCAGCTCAGGTTT GACACAGGTTCGGGGCCGGCGGTGCTGACCAGTGCCGTGCCGGTAGAGCCGGGCCAGT GGCACCGCCTGGAGCTGTCCCGGCACTGGCGCCGGGGCACCCTCTCGGTGGATGGTGA GACCCCTGTTCTGGGCGAGAGTCCCAGTGGCACCGACGGCCTCAACCTGGACACAGAC CTCTTTGTGGGCGGCGTACCCGAGGACCAGGCTGCCGTGGCGCTGGAGCGGACCTTCG TGGGCGCCGGCCTGAGGGGGTGCATCCGTTTGCTGGACGTCAACAACCAGCGCCTGGA GCTTGGCATTGGGCCGGGGGCTGCCACCCGAGGCTCTGGCGTGGGCGAGTGCGGGGAC CACCCCTGCCTGCCCAACCCCTGCCATGGCGGGGCCCCATGCCAGAACCTGGAGGCTG GAAGGTTCCATTGCCAGTGCCCGCCCGGCCGCGTCGGACCAACCTGTGCCGATGAGAA GAGCCCCTGCCAGCCCAACCCCTGCCATGGGGCGGCGCCCTGCCGTGTGCTGCCCGAG GGTGGTGCTCAGTGCGAGTGCCCCCTGGGGCGTGAGGGCACCTTCTGCCAGACAGCCT CGGGGCAGGACGGCTCTGGGCCCTTCCTGGCTGACTTCAACGGCTTCTCCCACCTGGA GCTGAGAGGCCTGCACACCATTGCACGGGACCTGGGGGAGAAGATGGCGCTGGAGGCC GTGTTCCTGGCACGAGGCCCCAGCGGCCTCCTGCTCTACAACGGGCAGAAGACGGACG GCAAGGGGGACTTCGTGTCGCTGGCACTGCGGGACCGCCGCCTGGAGTTCCGCTACGA CCTGGGCAAGGGGGCAGCGGTCATCAGGAGCAGGGAGCCAGTCACCCTGGGAGCCTGG ACCAGGGTCTCACTGGAGCGAAACGGCCGCAAGGGTGCCCTGCGTGTGGGCGACGGCC CCCGTGTGTTGGGGGAGTCCCCGAAATCCCGCAAGGTTCCGCACACCGTCCTCAACCT GAAGGAGCCGCTCTACGTAGGGGGCGCTCCCGACTTCAGCAAGCTGGCCCGTGCTGCT GCCGTGTCCTCTGGCTTCGACGGTGCCATCCAGCTGGTCTCCCTCGGAGGCCGCCAGC TGCTGACCCCGGAGCACGTGCTGCGGCAGGTGGACGTCACGTCCTTTGCAGGTCACCC CTGCACCCGGGCCTCAGGCCACCCCTGCCTCAATGGGGCCTCCTGCGTCCCGAGGGAG GCTGCCTATGTGTGCCTGTGTCCCGGGGGATTCTCAGGACCGCACTGCGAGAAGGGGC TGGTGGAGAAGTCAGCGGGGGACGTGGATACCTTGGCCTTTGACGGGCGGACCTTTGT CGAGTACCTCAACGCTGTGACCGAGAGCGAGAAGGCACTGCAGAGCAACCACTTTGAA CTGAGCCTGCGCACTGAGGCCACGCAGGGGCTGGTGCTCTGGAGTGGCAAGGCCACGG AGCGGGCAGACTATGTGGCACTGGCCATTGTGGACGGGCACCTGCAACTGAGCTACAA CCTGGGCTCC(_AGCCCGTGGTGCTGCGTTCCACCGTGCCCGTCAACACCAACCGCTGG TTGCGGGTCGTGGCACATAGGGAGCAGAGGGAAGGTTCCCTGCAGGTGGGCAATGAGG CCCCTGTGACCGGCTCCTCCCCGCTGGGCGCCACGCAGCTGGACACTGATGGAGCCCT GTGGCTTGGTGAGTGTTTTGGGGAGACTAGAGAGGGATGCCCAAGGGTCTCAGATATC CGAGGGACAGACTCCACCCCCCAGCGCCCACCCTTGAGTCAGGGTGCATGTGAGCCGG CGGGCTGGGCTCTCTTCTCCCGCTGTAGCCCCTGCAGTTCCCAGTGCTGTGGGGCCGG GAGGCGGGTGCCCAGGTGTGGGCCCCCTGCTGGTCACCTGCTCGTTGGGGTGCCCATC AGCATCACTGAGTCACAGCCGGGTGACTCCCACTGTCTGTGCTGCAGGGGCCTGCCGG AGCTGCCCGTGGGCCCAGCACTGCCCAAGGCCTACGGCACAGGCTTTGTGGGCTGCTT GCGGGATGTGGTGGTGGGCCGGCACCCGCTGCACCTGCTGGAGGACGCCGTCACCAAG CCAGAGCTGCGGCCCTGCCCCACCCCATGAGCTGGCACCAGAGCCCCGCGCCCGCT

ORF Start: ATG at 37 ORF Stop: TGA at 6466

SEQ ID NO: 106 2143 aa MW at 225054.6kD j NOV32f, MRHGRPVPPGPAAGRPLLPLLWAACVLPGAGGTCPERALERREEEANWLTGTVEEI

^! CG94946-06 Protein Sequence LNVDPVQHTYSC VRV RY KGKDLVARESLLDGGN WISGFGDPLICDNQVSTGDT RIFFVNPAPPYL PAHKNELMLNSS MRITLRN EEVEFCVEDKPGTHFTPVPPTPPD ACRGMLCGFGAVCEPNAEGPGRASCVCKKSPCPSWAPVCGSDASTYΞNECELQRAQC SQQRRIR LSRGPCGSRDPCSNVTCSFGSTCARSADGLTASCLCPATCRGAPEGTVCG SDGADYPGECQLLRRACARQENVFKKFDGPCDPCQGALPDPΞRSCRVNPRTRRPEMLL RPESCPARQAPVCGDDGVTYENDCVMGRSGAARGIi LQKVRSGQCQGRDQCPEPCRFN AVCLSRRGRPRCSCDRVTCDGAYRPVCAQDGRTYDSDCWRQQAECRQQRAIPSKHQGP CDQAPSPC GVQCAFGATCAVK GQAACECLQACSSLYDPVCGSDGVTYGSACELEAT ACTLGREIQVARKGPCDRCGQCRFGALCEAETGRCVCPSECVALAQPVCGSDGHTYPS EC HVHACTHQIS HVASAGPCETCGDAVCAFGAVCSAGQCVCPRCEHPPPGPVCGS DGVTYGSACELREAAC QQTQIEEARAGPCEQAECGSGGSGSGEDGDCEQELCRQRGG IWDEDSEDGPCVCDFSCQSVPGSPVCGSDGVTYSTECELKKARCESQRGLYVAAQGAC RGPAFAPLPPVAPLHCAQTPYGCCQDNITAARGVG AGCPSACQCNPHGSYGGTCDPA TGQCSCRPGVGGLRCDRCEPGFWNFRGIVTDGRSGCTPCSCDPQGAVRDDCEQMTG C SCKPGVAGPKCGQCPDGRA GPAGCEADASAPATCAEMRCEFGARCVEESGΞAHCVCP LTCPEANATKVCGSDGVTYGNECQLKTIACRQGLQISIQSLGPCQEAVAPSTHPTSA SVTVTTPG SQALPAPPGA PLAPSSTAHSQTTPPPSSRPRTTASVPRTTVWPV T VPPTAPSPAPSLVASAFGESGSTDGSSDEELSGDQEASGGGSGG EPLEGSSVATPGP PVERASCYNSALGCCSDGKTPSLDAEGSNCPATKVFQGV E EGVEGQELFYTPEMAD PKSE FGETARSIESTLDDLFRNSDVKKDFRSVR RDLGPGKSVRAIVDVHFDPTTAF RAPDVARAL RQIQVΞRRRS GVRRP QEHVRF DFDWFPAFITGATSGAIAAGATAR ATTASRLPSSAVTPRAPHPSHTSQPVAKTTAAPTTRRPPTTAPSRVPGRRPPAPQQPP KPCDSQPCFHGGTCQDWALGGGFTCSCPAGRGGAVCEKV GAPVPAFEGRSF AFPTL RAYHTLRLA EFRALEPQGL LYNGNARGKDFLALA DGRVQLRFDTGSGPAVLTSA VPVEPGQ HRLELSRHWRRGT SVDGETPVLGEΞPSGTDGLN DTD FVGGVPEDQAA VALERTFVGAGLRGCIRLLDVNQRLELGIGPGAATRGSGVGECGDHPCLPNPCHGGA PCQNLEAGRFHCQCPPGRVGPTCADEKSPCQPNPCHGAAPCRVLPEGGAQCECP GRE GTFCQTASGQDGSGPF ADFNGFSHLELRGLHTIARD GEKMALEAVFLARGPSG LL YNGQKTDGKGDFVSLALRDRRLEFRYDLGKGAAVIRSREPVTLGAWTRVSLER GRKG ALRVGDGPRVLGESPKSRKVPHTVLNIJKEPLYVGGAPDFSKLARAAAVSSGFDGAIQL VSLGGRQL TPEHV RQVDVTSFAGHPCTRASGHPC NGASCVPREAAYVCLCPGGFS GPHCEKGLVEKSAGDVDTLAFDGRTFVEYLNAVTESEKALQSNHFE SLRTEATQGLV L SGKATERADYVALAIVDGHLQLSYNLGSQPVVLRSTVPVNTNR LRWAHREQREG S QVGNEAPVTGSSP GATQLDTDGALWLGECFGETREGCPRVSDIRGTDSTPQRPPL SQGACEPAGWA FSRCSPCSSQCCGAGRRVPRCGPPAGH LVGVPISITESQPGDSHC CCRGLPE PVGPA PKAYGTGFVGC1.RDVWGRHPLHLLEDAVTKPE RPCPTP

SEQ ID NO: 107 5688 bp

NOV32g, CCGGCGCGGCCCGCGCGCTCTTCCGCCGCCTCTCGCATGCGCCATGGCCGGCCGGTCC CG94946-07 DNA Sequence CACCCGGGCCCGCTGCGGGGCGGCCGCTGCTGCCTCTCCTTGTGGTGGCCGCGTGCGT CCTGCCCGGAGCCGGCGGGACATGCCCGGAGCGCGCGCTGGAGCGGCGCGAGGAGGAG GCGAACGTGGTGCTCACCGGGACGGTGGAGGAGATCCTCAACGTGGACCCGGTGCAGC ACACGTACTCCTGCAAGGTTCGGGTCTGGCGGTACTTGAAGGGCAAAGACCTGGTGGC CCGGGAGAGCCTGCTGGACGGCGGCAACAAGGTGGTGATCAGCGGCTTTGGAGACCCC CTCATCTGTGACAACCAGGTGTCCACTGGGGACACCAGGATCTTCTTTGTGAACCCTG CACCCCCATACCTGTGGCCAGCCCACAAGAACGAGCTGATGCTCAACTCCAGCCTCAT GCGGATCACCCTGCGGAACCTGGAGGAGGTGGAGTTCTGTGTGGAAGATAAACCCGGG ACCCACTTCACTCCAGTGCCTCCGACGCCTCCTGATGCGTGCCGGGGAATGCTGTGCG GCTTCGGCGCCGTGTGCGAGCCCAACGCGGAGGGGCCGGGCCGGGCGTCCTGCGTCTG CAAGAAGAGCCCGTGCCCCAGCGTGGTGGCGCCTGTGTGTGGGTCGGACGCCTCCACC TACAGCAACGAATGCGAGCTGCAGCGGGCGCAGTGCAGCCAGCAGCGCCGCATCCGCC TGCTCAGCCGCGGGCCGTGCGGCTCGCGGGACCCCTGCTCCAACGTGACCTGCAGCTT CGGCAGCACCTGTGCGCGCTCGGCCGACGGGCTGACGGCCTCGTGCCTGTGCCCCGCG ACCTGCCGTGGCGCCCCCGAGGGGACCGTCTGCGGCAGCGACGGCGCCGACTACCCCG GCGAGTGCCAGCTCCTGCGCCGCGCCTGCGCCCGCCAGGAGAATGTCTTCAAGAAGTT CGACGGCCCTTGTGACCCCTGTCAGGGCGCCCTCCCTGACCCGAGCCGCAGCTGCCGT GTGAACCCGCGCACGCGGCGCCCTGAGATGCGCCTACGGCCCGAGAGCTGCCCTGCCC GGCAGGCGCCAGTGTGTGGGGACGACGGAGTCACCTACGAAAACGACTGTGTCATGGG CCGATCGGGGGCCGCCCGGGGTCTCCTCCTGCAGAAAGTGCGCTCCGGCCAGTGCCAG GGTCGAGACCAGTGCCCGGAGCCCTGCCGGTTCAATGCCGTGTGCCTGTCCCGCCGTG GCCGTCCCCGCTGCTCCTGCGACCGCGTCACCTGTGACGGGGCCTACAGGCCCGTGTG TGCCCAGGACGGGCGCACGTATGACAGTGATTGCTGGCGGCAGCAGGCTGAGTGCCGG CAGCAGCGTGCCATCCCCAGCAAGCACCAGGGCCCGTGTGACCAGGCCCCGTCCCCAT GCCTCGGGGTGCAGTGTGCATTTGGGGCGACGTGTGCTGTGAAGAACGGGCAGGCAGC GTGTGAATGCCTGCAGGCGTGCTCGAGCCTCTACGATCCTGTGTGCGGCAGCGACGGC GTCACATACGGCAGCGCGTGCGAGCTGGAGGCCACGGCCTGTACCCTCGGGCGGGAGA TCCAGGTGGCGCGCAAAGGACCCTGTGACCGCTGCGGGCAGTGCCGCTTTGGAGCCCT GTGCGAGGCCGAGACCGGGCGCTGCGTGTGCCCCTCTGAATGCGTGGCTTTGGCCCAG CCCGTGTGTGGCTCCGACGGGCACACGTACCCCAGCGAGTGCATGCTGCACGTGCACG CCTGCACACACCAGATCAGCCTGCACGTGGCCTCAGCTGGACCCTGCGAGACCTGTGG AGATGCCGTGTGTGCTTTTGGGGCTGTGTGCTCCGCAGGGCAGTGTGTGTGTCCCCGG TGTGAGCACCCCCCGCCCGGCCCCGTGTGTGGCAGCGACGGTGTCACCTACGGCAGTG CCTGCGAGCTACGGGAAGCCGCCTGCCTCCAGCAGACACAGATCGAGGAGGCCCGGGC AGGGCCGTGCGAGCAGGCCGAGTGCGGTTCCGGAGGCTCTGGCTCTGGGGAGGACGGT GACTGTGAGCAGGAGCTGTGCCGGCAGCGCGGTGGCATCTGGGACGAGGACTCGGAGG ACGGGCCGTGTGTCTGTGACTTCAGCTGCCAGAGTGTCCCAGGCAGCCCGGTGTGCGG CTCAGATGGGGTCACCTACAGCACCGAGTGTGAGCTGAAGAAGGCCAGGTGTGAGTCA CAGCGAGGGCTCTACGTAGCGGCCCAGGGAGCCTGCCGAGGCCCCACCTTCGCCCCGC TGCCGCCTGTGGCCCCCTTACACTGTGCCCAGACGCCCTACGGCTGCTGCCAGGACAA TATCACCGCAGCCCGGGGCGTGGGCCTGGCTGGCTGCCCCAGTGCCTGCCAGTGCAAC CCCCATGGCTCTTACGGCGGCACCTGTGACCCAGCCACAGGCCAGTGCTCCTGCCGCC CAGGTGTGGGGGGCCTCAGGTGTGACCGCTGTGAGCCTGGCTTCTGGAACTTTCGAGG CATCGTCACCGATGGCCGGAGTGGCTGTACACCCTGCAGCTGTGATCCCCAAGGCGCC GTGCGGGATGACTGTGAGCAGATGACGGGGCTGTGCTCGTGTAAGCCCGGGGTGGCTG GACCCAAGTGTGGGCAGTGTCCAGACGGCCGTGCCCTGGGCCCCGCGGGCTGTGAAGC TGACGCTTCTGCGCCTGCGACCTGTGCGGAGATGCGCTGTGAGTTCGGTGCGCGGTGC GTGGAGGAGTCTGGCTCAGCCCACTGTGTCTGCCCGATGCTCACCTGTCCAGAGGCCA ACGCTACCAAGGTCTGTGGGTCAGATGGAGTCACATACGGCAACGAGTGTCAGCTGAA GACCATCGCCTGCCGACGGTGTCACCTACGCCAGGGCCTGCAAATCTCTATCCAGAGC CTGGGCCCGTGCCAGGAGGCTGTTGCTCCCAGCACTCACCCGACATCTGCCTCCGTGA CTGTGACCACCCCAGGGCTCCTCCTGAGCCAGGCACTGCCGGCCCCCCCCGGCGCCCT CCCCCTGGCTCCCAGCAGTACCGCACACAGCCAGACCACCCCTCCGCCCTCATCGCGA CCTCGGACCACTGCCAGCGTCCCCAGGACCACCGTGTGGCCCGTGCTGACGGTGCCCC CCACGGCACCCTCCCCTGCACCCAGCCTGGTGGCGTCCGCCTTTGGTGAATCTGGCAG CACTGATGGAAGCAGCGATGAGGAACTGAGCGGGGACCAGGAGGCCAGTGGGGGTGGC TCTGGGGGGCCCGAGCCCTTGGAGGGCAGCAGCGTGGCCACCCCTGGGCCACCTGTCG AGAGGGCTTCCTGCTACAACCCCTGCCATGGGGCGGCGCCCTGCCGTGTGCTGCCCGA GGGTGGTGCTCAGTGCGAGTGCCCCCTGGGGCGTGAGGGCACCTTCTGCCAGACAGCC TCGGGGCAGGACGGCTCTGGGCCCTTCCTGGCTGACTTCAACGGCTTCTCCCACCTGG AGCTGAGAGGCCTGCACACCTTTGCACGGGACCTGGGGGAGAAGATGGCGCTGGAGGT CGTGTTCCTGGCACGAGGCCCCAGCGGCCTCCTGCTCTACAACGGGCAGAAGACGGAC GGCAAGGGGGACTTCGTGTCGCTGGCACTGCGGGACCGCCGCCTGGAGTTCCGCTACG ACCTGGGCAAGGGGGCAGCGGTCATCAGGAGCAGGGAGCCAGTCACCCTGGGAGCCTG GACCAGGGTCTCACTGGAGCGAAACGGCCGCAAGGGTGCCCTGCGTGTGGGCGACGGC CCCCGTGTGTTGGGGGAGTCCCCGGTTCCGCACACCGTCCTCAACCTGAAGGAGCCGC TCTACGTAGGGGGCGCTCCCGACTTCAGCAAGCTGGCCCGTGCTGCTGCCGTGTCCTC TGGCTTCGACGGTGCCATCCAGCTGGTCTCCCTCGGAGGCCGCCAGCTGCTGACCCCG GAGCACGTGCTGCGGCAGGTGGACGTCACGTCCTTTGCAGGTCACCCCTGCACCCGGG CCTCAGGCCACCCCTGCCTCAATGGGGCCTCCTGCGTCCCGAGGGAGGCTGCCTATGT GTGCCTGTGTCCCGGGGGATTCTCAGGACCGCACTGCGAGAAGGGGCTGGTGGAGAAG TCAGCGGGGGACGTGGATACCTTGGCCTTTGACGGGCGGACCTTTGTCGAGTACCTCA ACGCTGTGACCGAGAGCGAGAAGGCACTGCAGAGCAACCACTTTGAACTGAGCCTGCG CACTGAGGCCACGCAGGGGCTGGTGCTCTGGAGTGGCAAGGCCACGGAGCGGGCAGAC TATGTGGCACTGGCCATTGTGGACGGGCACCTGCAACTGAGCTACAACCTGGGCTCCC AGCCCGTGGTGCTGCGTTCCACCGTGCCCGTCAACACCAACCGCTGGTTGCGGGTCGT GGCACATAGGGAGCAGAGGGAAGGTTCCCTGCAGGTGGGCAATGAGGCCCCTGTGACC GGCTCCTCCCCGCTGGGCGCCACGCAGCTGGACACTGATGGAGCCCTGTGGCTTGGGG GCCTGCCGGAGCTGCCCGTGGGCCCAGCACTGCCCAAGGCCTACGGCACAGGCTTTGT GGGCTGCTTGCGGGATGTGGTGGTGGGCCGGCACCCGCTGCACCTGCTGGAGGACGCC GTCACCAAGCCAGAGCTGCGGCCCTGCCCCACCCCATGAGCTGGCACCAGAGCCCCGC GCCCGCTGTAATTATTTTCTATTTTTGTAAACTTGTTGCTTTTTGATATGATTTTCTT GCCTGAGTGTTGGCCGGAGGGACTGCTGGCCCGGCCTCCCTTCCGTCCAGGCAGCCGT GCTGCAGACAGACCTAGTGCTGAGGGATGGACAGGCGAGGTGGCAGCGTGGAGGGCTC GGCGTGGATGGCAGCCTCAGGACACACACCCCTGCCTCAAGGTGCTGAGCCCCCGCCT TGCACTGCGCCTGCCCCACGGTGTCCCCGCCGGGAAGCAGCCCCGGCTCCTGAATCAC CCTCGCTCCGTCAGGCGGGACTCGTGTCCCAAAAAGGAAGGGGCTGCTGAGGTCTGAT GGGGCCCTTCCTCCGGGTGACCCCACAGGGCCTTTCCAAGCCCCTATTTGAGCTGCTC CTTCCTGTGTGTGCTCTGGACCCTGCCTCGGCCTCCTGCGCCAATACTGTGACTTCCA AACAATGTTACTGCTGGGCACAGCTCTGCGTTGCTCCCGTGCTGCCTGCGCCAGCCCC AGGCTGCTGAGGAGCAGAGGCCAGAC^'CAGGGCCGATCTGGGTGTCCTGACCCTCAGCT GGCCCTGCCCAGCCACCCTGGACATGACCGTATCCCTCTGCCACACCCCAGGCCCTGC

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 32B.

Further analysis of the NOV32a protein yielded the following properties shown in Table 32C.

A search of the NOV32a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 32D.

In a BLAST search of public sequence datbases, the NOV32a protein was found to have homology to the proteins shown in the BLASTP data in Table 32E.

PFam analysis predicts that the NOV32a protein contains the domains shown in the Table 32F.

Example 33.

The NOV33 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 33 A.

Table 33A. NOV33 Sequence Analysis

SEQ ID NO: 109 3354 bp

NOV33a, TGTGGCAGGAGGCGATGCGGCGCCGCCGCTACCTGCGGGACCGCTCCGAGGAGGCGGC ^:CG95165-01 DNA Sequence GGGCGGCGGAGACGGGCTGCCGCGGTCCCGGGACTGGCTCTACGAGTCCTACTACTGC ATGAGCCAGCAGCACCCGCTCATCGTCTTCCTGCTGCTCATCGTCATGGGCTCCTGCC TCGCCCTGCTCGCCGTCTTCTTCGCGCTCGGCCTGGAAGTTGAAGACCATGTGGCGTT TCTAATAACAGTTCCAACTGCCCTGGCGATTTTCTTTGCGATATTTATCCTGGTCTGC ATCGAGTCTGTGTTTAAGAAGCTGCTGCGCCTCTTCTCGTTGGTGATATGGATATGCC TTGTTGCCATGGGATACCTGTTCATGTGTTTTGGAGGCACCGTCTCTCCCTGGGACCA GGTATCGTTCTTCCTCTTCATCATCTTCGTGGTGTACACCATGCTGCCCTTCAACATG CGAGACGCCATCATTGCCAGCGTCCTCACCTCCTCCTCCCACACCATCGTGCTAAGCG TCTGCCTGTCTGCAACACCGGGAGGCAAGGAGCACCTGGTCTGGCAGATCCTGGCCAA TGTGATCATTTTCATCTGTGGGAACCTGGCGGGAGCCTACCATAAGCACCTCATGGAA CTCGCTCTTCAGCAAACATATCAGGACACCTGTAATTGCATCAAGTCGCGGATCAAGT TGGAATTTGAAAAACGTCAACAGGAGCGGCTTCTGCTCTCCCTGCTGCCGGCCCACAT CGCCATGGAGATGAAAGCGGAGATCATCCAGAGGCTGCAGGGCCCCAAGGCGGGCCAG ATGGAGAACACAAATAACTTCCACAACCTGTATGTGAAGCGGCATACAAACGTGAGCA TCTTATACGCTGACATCGTTGGCTTTACCCGGCTGGCAAGTGACTGCTCCCCGGGAGA ACTAGTCCACATGCTGAATGAGCTCTTTGGAAAGTTTGATCAAATTGCAAAGGAGAAT GAATGCATGAGAATTAAAATTTTAGGAGACTGCTACTACTGTGTATCTGGACTCCCTA TATCTCTCCCTAACCATGCCAAGAACTGTGTGAAAATGGGGCTGGACATGTGTGAAGC CATAAAGAAAGTGAGGGATGCTACTGGAGTTGATATCAACATGCGCGTGGGCGTGCAT TCTGGGAATGTCCTGTGTGGCGTGATTGGTCTGCAGAAGTGGCAATATGATGTGTGGT CACATGATGTGACCTTGGCCAACCACATGGAAGCTGGAGGGGTCCCTGGACGTGTTCA CATTTCTTCTGTCACCCTGGAGCACTTGAATGGCGCTTATAAAGTGGAGGAGGGAGAT GGTGACATTAGGGACCCATATTTAAAACAGCACCTGGTGAAAACCTACTTTGTGATCA ACCCCAAGGGAGAACGACGGAGCCCCCAGCATCTCTTCAGACCTCGCCACACCCTTGA TGGAGCCAAAATGAGGGCCTCGGTCCGCATGACCCGGTACTTGGAGTCCTGGGGGGCA GCCAAGCCCTTTGCACACCTACATCACAGGGACAGCATGACCACAGAGAACGGCAAGA TCAGCACCACGGATGTACCCATGGGTCAGCATAATTTTCAAAATCGCACCTTAAGAAC CAAGTCACAAAAGAAGAGATTTGAAGAAGAATTGAATGAAAGGATGATTCAAGCAATT GATGGGATTAATGCACAGAAGCAATGGCTCAAGTCTGAAGACATTCAGAGAATCTCAC TGCTTTTCTATAACAAAGTACTAGAAAAAGAGTACCGGGCCACGGCACTGCCAGCGTT CAAGTATTATGTGACTTGTGCCTGTCTCATATTCTTCTGCATCTTCATTGTGCAGATT CTCGTGCTGCCAAAAACGTCTGTCCTGGGCATCTCCTTTGGGGCTGCGTTTCTCTTGC TGGCCTTCATCCTCTTCGTCTGCTTTGCTGGACAGCTTCTGCAATGCAGCAAAAAAGC CTCTCCCCTGCTCATGTGGCTTTTGAAGTCCTCGGGCATCATTGCCAACCGCCCCTGG CCACGGATCTCTCTCACGATCATCACCACAGCCATCATATTAATGATGGCCGTGTTCA ACATGTTTTTCCTGAGTGACTCAGAGGAAACAATCCCTCCAACTGCCAACACAACAAA CACAAGCTTTTCAGCCTCAAATAATCAGGTGGCGATTCTGCGTGCGCAGAATTTATTT TTCCTCCCGTACTTTATCTACAGCTGCATTCTGGGACTGATATCCTGTTCCGTGTTCC TGCGGGTAAACTATGAGCTGAAGATGTTGATCATGATGGTGGCCTTGGTGGGCTACAA CACCATCCTACTCCACACCCACGCCCACGTCCTGGGCGACTACAGCCAGGTCTTATTT GAGAGACCAGGCATTTGGAAAGACCTGAAGACCATGGGCTCTGTGTCTCTCTCTATAT TCTTCATCACACTGCTTGTTCTGGGTAGACAGAATGAATATTACTGTAGGTTAGACTT CTTATGGAAGAACAAATTCAAAAAAGAGCGGGAGGAGATAGAGACCATGGAGAACCTG AACCGCGTGCTGCTGGAGAACGTGCTTCCCGCGCACGTGGCTGAGCACTTCCTGGCCA GGAGCCTGAAGAATGAGGAGCTATACCACCAGTCCTATGACTGCGTCTGTGTCATGTT TGCCTCCATTCCGGATTTCAAAGAATTTTATACAGAATCCGACGTGAACAAGGAGGGC TTGGAATGCCTTCGGCTCCTGAACGAGATCATCGCTGACTTTGATGATCTTCTTTCCA AGCCAAAATTCAGTGGAGTTGAAAAGATTAAGACCATTGGCAGCACATACATGGCAGC AACAGGTCTGAGCGCTGTGCCCAGCCAGGAGCACTCCCAGGAGCCCGAGCGGCAGTAC ATGCACATTGGCACCATGGTGGAGTTTGCTTTTGCCCTGGTAGGGAAGCTGGATGCCA TCAACAAGCACTCCTTCAACGACTTCAAATTGCGAGTGGGTATTAACCATGGACCTGT GATAGCTGGTGTGATTGGAGCTCAGAAGCCACAATATGATATCTGGGGCAACACTGTC

Further analysis of the NOV33a protein yielded the following properties shown in

Table 33B.

Table 33B. Protein Sequence Properties NOV33a

SignalP analysis: Cleavage site between residues 65 and 66

A search of the NOV33a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 33C. 03/010327

In a BLAST search of public sequence datbases, the NOV33a protein was found to have homology to the proteins shown in the BLASTP data in Table 33D.

Table 33D. Public BLASTP Results for NOV33a

Identities/

Protein NOV33a

Similarities for Expect

Accession Prote in/Organ i sm/Length Residues/ the Matched Value

Number Match Residues

Portion

P26769 Adenylate cyclase, type II (EC 1..1086 1039/1090 (95%) 0.0

4.6.1.1 ) (ATP pyrophosphate-lyase) I ..1090 1062/1090 (97%)

(Adenylyl cyclase) - Rattus norvegicus (Rat), 1090 aa.

Q08462 Adenylate cyclase, type 11 (EC 200- 1086 887/887 (100%) 0.0

4.6.1.1) (ATP pyrophosphate-lyase) 1..887 887/887 (100%)

(Adenylyl cyclase) - Homo sapiens

(Human), 887 aa (fragment).

Q91 WF3 SIMILAR TO ADENYLYL 22..1082 612/1074 (56%) 0.0

CYCLASE 4 (ADENYLYL I 0..1075 780/1074 (71 %)

CYCLASE TYPE 4) (EC 4.6.1.1 )

Mus musculus (Mouse), 1077 aa

CAC37757 SEQUENCE 2 FROM PATENT 22..1078 605/1070 (56%) 0.0

WO0125448 - Homo sapiens 10..1069 772/ 1070 (71%)

(Human), 1077 aa

P26770 Adenylate cyclase, type IV (EC 22..1082 609/1072 (56%) 0.0

4.6.1.1 ) (ATP pyrophosphate-lyase) 10..1062 769/1072 (70%)

(Adenylyl cyclase) - Rattus norvegicus (Rat), 1064 aa. J

PFam analysis predicts that the NOV33a protein contains the domains shown in the Table 33E.

Example 34.

The NOV34 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 34A. Table 34A. NOV34 Sequence Analysis

SEQ ID NO: 1 11 3117 bp

NOV34a, CCTCCCCAGTAGCTGGGACTATGGGAGCGTGCCACCATGCCTGGTTAATTTTTGTATT -01 DNA Sequence TTTAGTAGAGATGGGGTTTCACCATGTTGGCCAGGCTTGTCTTCCCCTCTCCTTAGTT ATCCTCCTGGATTCCAAAGCCTCCCAGGCCGAGCTGGGCTGGACTGCACTGCCAAGTA ATGGGTGGGAGGAGATCAGCGGCGTGGATGAACACGACCGTCCCATCCGCACGTACCA AGTGTGCAATGTGCTGGAGCCCAACCAGGACAACTGGCTGCAGACTGGCTGGATAAGC CGTGGCCGCGGGCAGCGCATCTTCGTGGAACTGCAGTTCACACTCCGTGACTGCAGCA GCATCCCTGGCGCCGCGGGTACCTGCAAGGAGACCTTCAACGTCTACTACCTGGAAAC TGAGGCCGACCTGGGCCGTGGGCGTCCCCGCCTAGGCGGCAAAATCGACACGATCGCG GCGGACGAGAGCTTCACGCAGGGCGACCTGGGTGAGCGCAAGATGAAGCTGAACACAG AGGTGCGCGAGATCGGACCGCTCAGCCGGCGGGGTTTCCACCTGGCCTTTCAGGACGT GGGCGCATGCGTGGCGCTTGTCTCGGTGCGCGTCTACTACAAGCAGTGCCGCGCCACC GTGCGGGGCCTGGCCACGTTCCCAGCCACCGCAGCCGAGAGCGCCTTCTCCACACTGG TGGAAGTGGCCGGAACGTGCGTGGCGCACTCGGAAGGGGAGCCTGGCAGCCCCCCACG CATGCACTGCGGCGCCGACGGCGAGTGGCTGGTGCCTGTGGGCCGCTGCAGCTGCAGC GCGGGATTCCAGGAGCGTGGTGACTTCTGCGAAGGTATCTGTCCCCCAGGGTTTTACA AGGTGTCCCCGCGGCGGCCCCTCTGCTCACCGTGCCCAGAGCACAGCCGGGCCCTGGA AAACGCCTCCACCTTCTGCGTGTGCCAGGACAGCTATGCGCGCTCACCCACCGACCCG CCCTCGGCTTCCTGCACCCGTCCGCCGTCGGCGCCGCGGGACCTGCAGTACAGCCTGA GCCGCTCGCCGCTGGTGCTGCGACTGCGCTGGCTGCCGCCGGCCGACTCGGGAGGCCG CTCGGACGTCACCTACTCGCTGCTGTGCCTGCGCTGCGGCCGCGAGGGCCCGGCGGGC GCCTGCGAGGGGCCGCGCGTGGCCTTCCTACCGCGCCAGGCAGGGCTGCGGGAGCGAG CCGCCACGCTGCTGCACCTGCGGCCCGGCGCGCGCTACACCGTGCGCGTGGCCGCGCT CAACGGCGTCTCGGGCCCGGCGGCCGCCGCGGGAACCACCTACGCGCAGGTCACCGTC TCCACCGGGCCCGGGGGTAAGGCCGTCCGCGCCCCCCACCCCGAGGCCACCGCGCCTG CCGCCCCTGCGCCCTCTTGGGGCCGCCCCGTCGGTCCTGCGGGATCAGCGCCCTGGGA GGAGGATGAGATCCGCAGGGACCGAGTGGAACCCCAGAGCGTGTCCCTGTCGTGGCGG GAGCCCATCCCTGCCGGAGCCCCTGGGGCCAATGACACGGAGTACGAGATCCGATACT ACGAGAAGGTGAGTGCGCAGAGTGAGCAGACTTACTCCATGGTGAAGACAGGGGCGCC CACAGTCACCGTGATTTTCCTCCCAGCTGCCTCAGGGTCCAGGGACCAGAGCCCCGCC ATTGTCGTCACCGTAGTGACCATCTCGGCCCTCCTCGTCCTGGGCTCCGTGATGAGTG TGCTGGCCATTTGGAGGAGGAGGCCCTGCAGCTATGGCAAAGGAGGAGGGGATGCCCA TGATGAAGAGGAGCTGTATTTCCACTGTGAGTTGGCTGGGAAAGTCCCAACACGTCGC ACATTCCTGGACCCCCAGAGCTGTGGGGACCTGCTGCAGGCTGTGCATCTGTTCGCCA AGGAACTGGATGCGAAAAGCGTCACGCTGGAGAGGAGCCTTGGAGGAGGCAAGCTGGG CGGGCGGTTTGGGGAGCTGTGCTGTGGCTGCTTGCAGCTCCCCGGTCGCCAGGAGCTG CTCGTAGCCGTGCACATGCTGAGGGACAGCGCCTCCGACTCACAGAGGCTCGGCTTCC TGGCCGAGGCCCTCACGCTGGGCCAGTTTGACCATAGCCACATCGTGCGGCTGGAGGG CGTTGTTACCCGAGGTAGGGGAAGCACCTTGATGATTGTCACCGAGTACATGAGCCAT GGGGCCCTGGACGGCTTCCTCAGGCAGCGGCACGAGGGGCAGCTGGTGGCTGGGCAAC TGATGGGGTTGCTGCCTGGGCTGGCATCAGCCATGAAGTATCTGTCAGAGATGGGCTA CGTTCACCGGGGCCTGGCAGCTCGCCATGTGCTGGTCAGCAGCGACCTTGTCTGCAAG ATCTCTGGCTTCGGGCGGGGCCCCCGGGACCGATCAGAGGCTGTCTACACCACTATGG TGAGGCTACAGAGTGGCCGGAGCCCAGCGCTATGGGCCGCTCCCGAGACACTTCAGTT TGGCCACTTCAGCTCTGCCAGTGACGTGTGGAGCTTCGGCATCATCATGTGGGAGGTG ATGGCCTTTGGGGAGCGGCCTTACTGGGACATGTCTGGCCAAGACGTGGTGATCAAGG CTGTGGAGGATGGCTTCCGGCTGCCACCCCCCAGGAACTGTCCTAACCTTCTGCACCG ACTAATGCTCGACTGCTGGCAGAAGGACCCAGGTGAGCGGCCCAGGTTCTCCCAGATC CACAGCATCCTGAGCAAGATGGTGCAGGACCCAGAGCCCCCCAAGTGTGCCCTGACTA CCTGTCCCAGGCCTCTGACCCGCAGGCCTCCCACTCCACTAGCCGACCGTGCCTTCTC CACCTTCCCCTCCTTTGGCTCTGTGGGCGCGTGGCTGGAGGCCCTGGACCTGTGCCGC TACAAGGACAGCTTCGCGGCTGCTGGCTATGGGAGCCTGGAGGCCGTGGCCGAGATGA CTAGCCAGGACCTGGTGAGCCTAGGCATCTCTTTGGCTGAACATCGAGAGGCCCTCCT CAGCGGGATCAGCGCCCTGCAGGCACGAGTGCTCCAGCTGCAGGGCCAGGGGGTGCAG GTGTGAGTGGACCCCATTCTTCCAAGGCAGGACTCCGGTGGGG

Further analysis of the NOV34a protein yielded the following properties shown in Table 34B.

A search of the NOV34a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 34C.

In a BLAST search of public sequence datbases, the NOV34a protein was found to have homology to the proteins shown in the BLASTP data in Table 34D.

PFam analysis predicts that the NOV34a protein contains the domains shown in the Table 34E.

Example 35.

The NO V35 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 35 A.

Further analysis of the NOV35a protein yielded the following properties shown in Table 35B.

Table 35B. Protein Sequence Properties NOV35a

PSort analysis: 0.5500 probability located in endoplasmic reticulum (membrane); 0.3592 probability located in lysosome (lumen); 0.2463 probability located in microbody

(peroxisome); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP analysis: Cleavage site between residues 14 and 15

A search of the NOV35a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 35C.

In a BLAST search of public sequence datbases, the NOV35a protein was found to have homology to the proteins shown in the BLASTP data in Table 35D.

PFam analysis predicts that theNOV35a protein contains the domains shown in the Table 35E.

Table 35E. Domain Analysis of NOV35a

Identities/

Pfam Domain NOV35a Match Region Similarities Expect Value for the Matched Region

No Significant Matches Found

Example 36.

The NOV36 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 36 A. Table 36A. NOV36 Sequence Analysis

SEQ ID NO: 115 3500 bp

NOV36a, GCGCTGCAGTTCTCCCGGCTATGCATGGGCTGCGGCTCCGGCTCTAGCACAGGCACCA -01 DNA Sequence GCCGCCGCCGCACCCGGCCCCAGCGCCCACCGTCTGCATGTGCCCGCCGTAGCCGTCT GCCCAGCCCGCAGCCCGCGCTCCACGGAGCGCTGGAGACCACCGTGGGGGGCCCCTTC TGCCCTCGAGAGAAGCGGTCTTGGAGGTATGGATTTAGGTGGTTGGATTTTTTCCGTG GATCTATCAATTCACAATTCGAATTTGGAAGAAAGAAGGAAAACATGACGTCTCCAGC CAAATTCAAAAAGGATAAGGAGATCATAGCAGAGTACGATACTCAGGTCAAAGAGATC CGTGCTCAGCTCACAGAGCAGATGAAATGCCTGGACCAGCAGTGTGAGCTTCGGGTGC AACTGTTGCAGGACCTCCAGGACTTCTTCCGAAAGAAGGCAGAGATTGAGATGGACTA CTCCCGCAACCTGGAGAAGCTGGCAGAACGCTTCCTGGCCAAGACACGCAGCACCAAG GACCAGCAATTCAAGAAGGATCAGAATGTTCTCTCTCCAGTCAACTGCTGGAATCTCC TCTTAAACCAGGTGAAGCGGGAAAGCAGGGACCATACCACCCTGAGTGACATCTACCT GAATAATATCATTCCTCGATTTGTACAAGTCAGCGAGGACTCAGGAAGACTCTTTAAA AAGAGTAAAGAAGTCGGCCAGCAGCTCCAAGATGATTTGATGAAGGTCCTGAACGAGC TCTACTCGGTCATGAAGACATATCACATGTACAATGCCGACAGCATCAGTGCTCAGAG CAAACTAAAGGAGGCGGAGAAGCAGGAGGAGAAGCAAATTGGTAAATCGGTAAAGCAG GAGGACCGGCAGACCCCACGCTCCCCTGACTCCACGGCCAACGTTCGCATTGAGGAGA AACATGTCCGGAGGAGCTCAGTGAAGAAGATTGAGAAGATGAAGGAGAAGCACCAAGC CAAGTACACGGAGAATAAGCTGAAGGCCATCAAAGCCCGGAATGAGTACTTGCTGGCT TTGGAGGCAACCAATGCATCTGTCTTCAAGTACTACATCCATGACCTATCTGACCTTA TTGATCAGTGTTGTGACTTAGGCTACCATGCAAGTCTGAACCGGGCTCTACGCACCTT CCTCTCTGCTGAGTTAAACCTGGAACAGTCGAAGCATGAGGGTCTGGATGCCATCGAG AATGCAGTAGAAAACCTGGATGCCACCAGTGACAAGCAGCGCCTCATGGAGATGTACA ACAACGTCTTCTGCCCCCCTATGAAGTTTGAGTTTCAGCCCCACATGGGGGATATGGC TTCCCAGCTCTGTGCCCAGCAGCCTGTCCAGAGTGAGCTGGTACAGAGATGCCAACAA CTGCAGTCTCGCTTATCCACTCTAAAGATTGAAAACGAAGAGGTAAAGAAGACAATGG AGGCCACCCTGCAAACCATCCAGGACATTGTGACTGTCGAGGACTTTGATGTGTCTGA CTGCTTCCAGTACAGCAACTCCATGGAGTCCGTCAAGTCCACGGTCTCTGAAACCTTC ATGGGCAAGCCCAGCATTGCTAAGAGGAGAGCCAACCAGCAAGAGACAGAGCAGTTTT ATTTCACAAAAATGAAAGAGTACCTGGAGGGCAGGAACCTCATCACCAAGTTACAAGC CAAGCATGACCTTCTGCAGAAAACCCTGGGAGAAAGTCAGCGGACAGATTGCAGTCTA GCCAGGCGCAGCTCAACTGTGAGGAAACAGGACTCCAGCCAGGCAATTCCTCTAGTGG TGGAAAGCTGTATCCGGTTTATCAGCAGACACGGACTACAGCATGAAGGAATTTTCCG GGTGTCAGGATCCCAGGTGGAAGTGAATGACATCAAAAATGCCTTTGAGAGAGGAGAG GACCCCCTGGCTGGGGACCAGAACGACCATGACATGGATTCCATAGCTGGTGTCCTGA AGCTTTACTTCCGGGGGCTGGAACACCCTCTCTTCCCCAAGGACATCTTTCATGACCT GATGGCCTGCGTCACAATGGACAACCTGCAGGAGAGAGCTCTGCACATCCGGAAAGTC CTCCTAGTCCTGCCCAAAACCACTCTGATTATCATGAGATACCTCTTTGCCTTCCTCA ATCATTTATCACAGTTCAGTGAAGAGAACATGATGGACCCCTACAACCTCGCCATCTG CTTCGGGCCCTCGCTAATGTCAGTGCCAGAGGGCCACGACCAGGTGTCCTGCCAAGCC CACGTGAATGAGCTGATCAAAACCATCATCATCCAGCATGAGAACATCTTCCCAAGCC CCAGGGAGCTGGAGGGCCCTGTCTACAGCAGAGGAGGAAGCATGGAGGATTACTGTGA TAGCCCTCATGGAGAGACTACCTCGGTTGAAGACTCAACCCAGGATGTGACCGCAGAG CACCACACGAGCGATGACGAATGTGAGCCCATCGAGGCCATTGCCAAGTTTGACTACG TGGGCCGGACAGCCCGAGAGCTGTCCTTTAAGAAGGGAGCATCCCTGCTGCTTTACCA GCGGGCTTCCGACGACTGGTGGGAAGGCCGGCACAATGGCATCGACGGACTCATCCCC CATCAGTACATCGTGGTCCAAGACACCGAGGACGGTGTCGTGGAGAGGTCCAGCCCCA AGTCTGAGATTGAGGTCATTTCTGAGCCACCTGAAGAAAAGGTGACAGCCAGAGCGGG GGCCAGCTGTCCCAGTGGGGGTCATGTAGCCGATATTTATCTTGCAAACATCAACAAG CAAAGGAAGCGTCCAGAATCTGGGAGCATCCGGAAAACTTTTCGGAGTGACAGCCATG GGCTGAGCAGTTCCCTGACTGACTCCTCCTCCCCAGGGGTGGGGGCTAGCTGCCGCCC ATCCTCCCAGCCCATCATGAGCCAGAGCCTCCCCAAAGAAGGGCCAGATAAGTGTTCC ATCAGTGGGCACGGGAGCCTCAACTCCATCAGCCGCCACTCATCCCTGAAGAATCGGC TGGATAGTCCACAGATCCGGAAGACTGCCACAGCGGGAAGGTCAAAAAGCTTCAATAA CCATCGGCCCATGGACCCTGAGGTCATTGCTCAGGATATTGAGGCAACAATGAACTCG GCCCTGAATGAGCTACGGGAACTAGAACGGCAGAGCAGTGTCAAACACACCCCTGACG TGGTTCTGGACACCTTGGAGCCCCTCAAAACCTCCCCAGTGGTGGCCCCCACGTCAGA GCCCTCCAGCCCTCTGCACACCCAGCTCCTCAAGGACCCCGAGCCCGCCTTCCAGCGC AGCGCCAGTACTGCTGGGGACATCGCCTGCGCCTTCCGGCCTGTCAAGTCTGTCAAGA TGGCTGCCCCGGTCAAACCACCAGCCACACGGCCCAAGCCCACTGTCTTCCCCAAAAC AAATGCCACTAGCCCTGGTGTCAACTCATCAACTTCCCCACAGTCTACTGACAAGTCT TGTACTGTCTGAGGGATAAT

Further analysis of the NOV36a protein yielded the following properties shown in Table 36B.

Table 36B. Protein Sequence Properties NOV36a

PSort analysis: 0.9400 probability located in nucleus; 0.4936 probability located in mitochondrial matrix space; 0.3000 probability located in microbody (peroxisome); 0.2087 probability located in mitochondrial inner membrane

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV36a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 36C.

In a BLAST search of public sequence datbases, the NOV36a protein was found to have homology to the proteins shown in the BLASTP data in Table 36D.

PFam analysis predicts that the NOV36a protein contains the domains shown in the Table 36E.

Example 37.

The NOV37 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 37 A. Table 37A. NOV37 Sequence Analysis

SEQ ID NO: 117 3790 bp

NOV37a, CAAACAGCGATGTCCCAGACGCAGGACTACGAGTGCAGGAGCCATAATGTCGACCTGC JCG95824-01 DNA Sequence CGGAGTCGAGGATTCCAGGGTCGAACACTCGGTTGGAGTGGGTGGAGATCATCGAACC GCGCACCCGCGAGCGCATGTACGCCAACCTGGTCACCGGTGAGTGCGTGTGGGACCCG CCGGCCGGCGTCCGCATCAAGCGCACCAGCGAGAACCAGTGGTGGGAGCTGTTCGACC CCAACACGTCCCGCTTCTACTACTACAATGCCAGCACGCAGCGCACGGTGTGGCACCG GCCGCAGGGCTGCGACATCATCCCGCTGGCCAAGCTGCAGACGCTGAAGCAGAACACG GAGTCCCCGCGCGCCTCGGCGGAGAGCAGCCCCGGGCGCGGCAGCAGCGTCAGCCGTG AGGGCAGCACCAGCTCCTCCCTGGAGCCCGAGCCCGACACTGAGAAAGCGCAGGAGTT GCCAGCGAGGGCCGGGCGGCCCGCGGCGTTTGGGACAGTGAAGGAGGACAGCGGCAGC TCTTCACCACCAGGAGTGTTCCTTGAGAAGGACTATGAGATTTACCGGGATTACAGTG CGGACGGCCAGCTTCTTCACTACAGGACCTCCTCGCTGCGGTGGAACTCGGGCGCCAA AGAGCGCATGCTCATCAAGGTCGCTGATCGGGAGCCCAGCTTCCTCGCCGCCCAGGGC AATGGCTACGCCCCAGACGGCCCACCTGGGGTCCGCTCCCGCAGACCCTCCGGCAGCC AGCACTCACCCAGCCTGCAGACCTTCGCCCCGGAGGCTGACGGCACCATCTTCTTCCC AGAGAGGAGGCCGTCACCCTTCCTGAAGAGGGCCGAGCTCCCAGGGAGCAGCTCCCCG CTGCTGGCCCAGCCCCGAAAGCCCTCCGGGGACTCGCAGCCCTCCTCCCCGCGCTATG GCTATGAACCCCCGCTCTACGAGGAGCCCCCAGTGGAGTACCAGGCCCCCATCTACGA TGAGCCCCCCATGGACGTGCAATTCGAGGCTGGCGGGGGCTACCAGGCCGGCTCTCCC CAGCGGTCGCCGGGCCGTAAGCCCCGGCCGTTCCTCCAGCCCAACAAGCAGGGCCCCC CCTCGCCCTGCCAGCAGCTGGTGCTCACCAAGCAGAAGTGTCCCGAGCGCTTCCTGAG CCTGGAGTACAGTCCCGCCGGCAAGGAGTACGTGCGGCAGCTGGTCTACGTGGAGCAG GCGGGCTCCAGCCCCAAGCTGCGCGCCGGCCCGCGGCACAAGTACGCGCCCAACCCCG GCGGTGGTTCGTACTCCTTGCAGCCCAGCCCCTGCCTGCTGAGGGACCAGCGCCTGGG CGTCAAGTCCGGAGACTACAGCACCATGGAGGGACCTGAGCTGCGGCACAGCCAGCCG CCCACGCCGCTGCCACAGGCCCAGGAGGATGCCATGTCCTGGTCCAGCCAGCAGGACA CCCTGTCCTCCACAGGCTACTCCCCGGGCACGCGCAAGCGGAAGAGCAGAAAGCCCTC TTTGTGCCAAGCCACCAGCGCCACCCCCACTGAGGGCCCCGGGGACCTGCTTGTGGAG CAGCCCCTGGCCGAGGAACAGCCCCCGTGCGGGACCAGCCTCGCCCCCGTGAAGCGAG CGGAAGGTGAGGCCGAAGGGGCGCGGGGCGCGGCCGAGCCCTTCCTGGCGCAGGCTCG GCTGGCCTGGGAGGCGCAGCAGGCCCACTTCCACATGAAGCAGAGGAGCAGCTGGGAC TCCCAGCAGGACGGCTCTGGCTACGAGAGCGACGGCGCCCTGCCACTGCCCATGCCCG GGCCGGTGGTGCGGGCCTTCAGCGAGGACGAGGCGCTGGCCCAGCAGGAGAACAGGCA CTGGAGGAGGGGCACCTTCGAGAAGCTAGGCTTCCCCCAGATCCTGCTGGAGAAGAGC GTCTCCGTGCAGACCAACCTGGCCTCACCAGAGCCCTACCTCCACCCCTCACAGTCTG AGGACCTCGCTGCCTGTGCCCAGTTCGAGAGCAGCCGGCAGAGCCGCAGCGGCGTTCC CAGCTCCAGCTGCGTCTTCCCCACTTTCACGCTGCGCAAGCCCTCCTCGGAGACGGAC ATCGAGAACTGGGCCTCCAAGCACTTCAACAAGCACACGCAGGGCCTCTTCCGGCGGA AGGTGTCCATCGCCAACATGCTGGCCTGGAGCAGCGAGTCCATCAAGAAGCCCATGAT CGTGACAAGCGACCGGCACGTGAAGAAGGAGGCCTGCGAGCTCTTCAAGCTGATCCAG ATGTACATGGGTGACCGGCGGGCCAAGGCCGACCCACTGCACGTGGCCCTGGAGGTGG CCACCAAGGGCTGGAGCGTGCAGGGCCTGCGGGACGAGCTCTACATCCAGCTGTGCCG GCAGACCACCGAGAACTTCCGCCTGGAGAGCCTGGCCCGCGGCTGGGAGCTCATGGCC ATCTGCCTGGCCTTTTTCCCGCCCACCCCCAAGTTCCACTCCTACCTGGAAGGCTACA TCTACCGGCACATGGACCCCGTCAATGACACTAAAGGGGTGGCGATAAGCACGTATGC CAAGTACTGTTACCACAAGCTACAGAAGGCAGCCCTGACCGGGGCCAAGAAGGGGCTG AAGAAGCCCAACGTGGAGGAGATCCGGCATGCCAAGAACGCCGTGTTCAGCCCGTCCA TGTTCGGCAGCGCACTGCAGGAGGTCATGGGCATGCAGAGAGAGCGCTACCCCGAGCG CCAGCTGCCCTGGGTGCAGACACGGCTCTCTGAGGAGGTGCTGGCGCTCAACGGTGAC CAGACAGAGGGCATCTTCAGGGTCCCTGGGGACATTGACGAGGTGAATGCCCTGAAGC TGCAGGTGGACCAGTGGAAGGTGCCCACAGGCCTGGAAGACCCCCACGTCCCTGCGTC CCTGCTGAAGCTGTGGTACCGGGAGCTGGAGGAGCCCCTGATCCCGCACGAGTTCTAC GAGCAGTGCATCGCGCACTACGACAGCCCCGAGGCGGCGGTGGCCGTGGTGCACGCGC TGCCCCGCATCAACCGCATGGTGCTGTGCTACCTCATCCGCTTCCTGCAGGTCTTCGT GCAGCCGGCCAACGTCGCGGTCACCAAGATGGATGTCAGCAACCTGGCCATGGTGATG GCGCCCAACTGCTTGCGCTGCCAGTCCGACGACCCGCGCGTCATCTTCGAGAACACCC GCAAGGAGATGTCCTTCCTGCGGGTGCTCATCCAGCACCTGGACACCAGCTTCATGGA GGGTGTGCTGGAGCGGGGGCGCCCGGGGACAGGAGGGATGTCCTGCCGCCCCCAGCCA GGCCGAACTCCGCACTCGCTCTCCCGGCAGAGGGGCCAGAATCGCCCGGCCCAGCCCT GGAGCCCCCTCCACTCCCCCAGGCCCCTGGCCCCGGCGCTCCCCACGTCTTCTGCCTG GTCTGAGGGTGCAGCCAGGGCACAGCAGCGGCGGGGAGGGCGCCTCTGGCCCCCCACC TCACGGCCAGTTCCCGCGGGCACCGCCTCGCCCTCCGCTGGCCGCGGGTCAGCTCCGA GAAAGTGCCTTCTGTGTCCTGGAGCCGAGCGACGCTGCCTCCTTGGGGCCGGGCTGCC TCCCTGTGGCTCCTGCGCGCCCTGGCCTGGGCCTTGCCCAGCCGCCCCGGTCTCTCCT TCCCTTTCTCCTGTCCTCGTCCTGGCCTGCAGCTCTTCCCAGCCCCGAGAGAGCTTCC CGACCTGTCCCCGCCTCCTCTCCCTCCCTCGGCCCGTGGTCCCCAGCTGGTGACTGCT CAGGAGTTTGGGGGCTCCAG

Further analysis of the NOV37a protein yielded the following properties shown in

Table 37B.

Table 37B. Protein Sequence Properties NOV37a

PSort analysis: 0.7000 probability located in nucleus; 0.3000 probability located in microbody

(peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen) j SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV37a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 37C.

In a BLAST search of public sequence datbases, the NOV37a protein was found to have homology to the proteins shown in the BLASTP data in Table 37D.

PFam analysis predicts that the NOV37a protein contains the domains shown in the Table 37E.

Example 38.

The NOV38 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 38 A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 38B.

Table 38B. Comparison of NOV38a against NOV38b.

NOV38a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV38b 43. 2J 214/291 (73%) 86. ,369 219/291 (74%)

Further analysis of the NOV38a protein yielded the following properties shown in

Table 38C.

Table 38C. Protein Sequence Properties NOV38a

PSort analysis: j 0.6000 probability located in plasma membrane; 0.4000 probability located in Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome)

SignalP analysis: Cleavage site between residues 70 and 71

A search of the NOV38a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 38D.

In a BLAST search of public sequence datbases, the NOV38a protein was found to have homology to the proteins shown in the BLASTP data in Table 38E.

PFam analysis predicts that the NOV38a protein contains the domains shown in the Table 38F.

Table 38F. Domain Analysis of NOV38a

Identities/

Pfam Domain NOV38a Match Region Similarities j Expect Value for the Matched Region

7tm 66-319 60/287 (21%) 9.7e-41 191/287 (67%)

Example 39.

The NOV39 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 39 A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 39B.

Further analysis of the NOV39a protein yielded the following properties shown in Table 39C.

Table 39C. Protein Sequence Properties NOV39a

PSort analysis: 0.3000 probability located in nucleus; 0.2271 probability located in lysosome

(lumen); 0.1 109 probability located in microbody (peroxisome); 0.1000 probability located in mitochondrial matrix space

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV39a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 39D.

In a BLAST search of public sequence datbases, the NOV39a protein was found to have homology to the proteins shown in the BLASTP data in Table 39E.

PFam analysis predicts that the NOV39a protein contains the domains shown in the Table 39F.

Example 40.

The NOV40 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 40A.

Further analysis of the NOV40a protein yielded the following properties shown in Table 40B.

Table 40B. Protein Sequence Properties NOV40a

PSort analysis: 0.8200 probability located in endoplasmic reticulum (membrane); 0.2222 probability located in microbody (peroxisome); 0.1900 probability located in plasma membrane;

0.1000 probability located in endoplasmic reticulum (lumen)

; SignalP analysis: Cleavage site between residues 27 and 28

A search of the NOV40a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 40C.

In a BLAST search of public sequence datbases, the NOV40a protein was found to have homology to the proteins shown in the BLASTP data in Table 40D.

PFam analysis predicts that the NOV40a protein contains the domains shown in the Table 40E.

Example 41.

The NOV41 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 41 A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 4 IB.

Further analysis of the NOV41a protein yielded the following properties shown in Table 41 C.

Table 41C. Protein Sequence Properties NOV41a

PSort analysis: 0.6400 probability located in microbody (peroxisome); 0.3600 probability located in mitochondrial matrix space; 0.3000 probability located in mitochondrial intermembrane space; 0.2883 probability located in lysosome (lumen)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV41a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 4 ID.

03/010327

In a BLAST search of public sequence datbases, the NOV41a protein was found to have homology to the proteins shown in the BLASTP data in Table 4 IE.

PFam analysis predicts that the NOV4 la protein contains the domains shown in the Table 4 IF.

Example 42.

The NOV42 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 42A.

Further analysis of the NOV42a protein yielded the following properties shown in Table 42B.

Table 42B. Protein Sequence Properties NOV42a

PSort analysis: 0.6400 probability located in microbody (peroxisome); 0.4500 probability located in cytoplasm; 0.2809 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV42a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 42C.

In a BLAST search of public sequence datbases, the NOV42a protein was found to have homology to the proteins shown in the BLASTP data in Table 42D.

PFam analysis predicts that the NOV42a protein contains the domains shown in the Table 42E.

Example 43.

The NOV43 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 43 A.

Further analysis of the NOV43a protein yielded the following properties shown in Table 43B. Table 43B. Protein Sequence Properties NOV43a

PSort analysis: 0.4010 probability located in microbody (peroxisome); 0.3000 probability located in nucleus; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

', SignalP analysis: Cleavage site between residues 16 and 17

A search of the NOV43a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 43 C.

In a BLAST search of public sequence datbases, the NOV43a protein was found to have homology to the proteins shown in the BLASTP data in Table 43D.

PFam analysis predicts that the NOV43a protein contains the domains shown in the Table 43E.

Table 43E. Domain Analysis of NOV43a

Identities/

Pfam Domain NOV43a Match Region Similarities Expect Value for the Matched Region

No Significant Matches Found

Example 44.

The NOV44 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 44A.

Table 44A. NOV44 Sequence Analysis

SEQ ID NO: 137 999 bp NOV44a, GGTTTTAATGCTTCCGGGTTGCCACTGCAGTGGCATTTCTGACTGTGGGAGCCTCAGT CG96501-01 DNA Sequence TTCCCAGTC-ATTGATGAGCCTGAGCAGCAGCAAAGTACCACTGTAAGCCATGAGATGT CTCGTCTGAACTGGAAACCCTTTGTATATGACGCCCTTGCCTCTATCACTGCTGAGTT TGGAACTTTCCCCaTGGACCTTGCCAAAAClACGA_TTCAGGTAC_AAGGCCAAAGCATT GATGTCCGTTTCAAAGAAACAAAATATAGACGGATGTTTCATGCTTTGTTTTGGATCT ATAAAGCGGAGGGGGGATTGGCTCTGTATTCAGGAATTGCTCCTGTTTTGCAAAGACA AGCATCATATGGCACCATTAAAATTGGGATTTACCAAAGCTTGAAGCAATTATCTGTA GAACGTTTAGAAGATGAAACTCTTTTAATCAACATGATCTGTGGGGTAGTGTCAGGGG TGATATTTTCCACTATAGCCAATCCCACCGATGTTCTAAAGATTCGAATGCAGGCTCA AGGAAGTTTGTTCCAAGGGAGCATGATTGGCAGCTTCATCGATATATACCAACAGGAA GGCACCAGGGGTCTGTGGAGGAGTGTGGTTCCAACTGCTCAGCATGCTGCCATCGTTG TGGGAGTAGAGCTACCAGTCTATGATTTTACTAAGAAGCACTTAATATTGTCAGGAAT GATGGAAGACACAACTTTAACTCACTTTGTTTCCAGCTTTACATATGGTTTGGCTGGG GCTCTTGCCTCTAATCCAGGTGATGTGGCAGGCACTCACGTGATGAACCAGAGGGCAA TCGTGGGACATGTGGATCTCTATAAGGGCACTTTGGATGGTATTTTAAAAATGTGGAA ACATGAGGGCTTTTTTTTGTATTCTAAAGGATTTTGGCCAAACTGGCTTTGGCGTGGA CCCTGGAACATCATTCTTAAAATTACATATGAGAAGCTCAAGAGGCTTTAAATCTAAG GACTGAATTATAT

Further analysis of the NOV44a protein yielded the following properties shown in Table 44B.

Table 44B. Protein Sequence Properties NOV44a

PSort analysis: j 0.7480 probability located in microbody (peroxisome); 0.7000 probability located in plasma membrane; 0.2000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in mitochondrial inner membrane

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV44a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 44C.

In a BLAST search of public sequence datbases, the NOV44a protein was found to have homology to the proteins shown in the BLASTP data in Table 44D.

PFam analysis predicts that the NOV44a protein contains the domains shown in the Table 44E.

Example 45.

The NOV45 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 45A.

Further analysis of the NOV45a protein yielded the following properties shown in

Table 45B. Table 45B. Protein Sequence Properties NOV45a

PSort analysis: 0.8673 probability located in mitochondrial matrix space; 0.5542 probability located in mitochondrial inner membrane; 0.5542 probability located in mitochondrial intermembrane space; 0.5542 probability located in mitochondrial outer membrane

SignalP analysis: Cleavage site between residues 17 and 18

A search of the NOV45a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 45C.

In a BLAST search of public sequence datbases, the NOV45a protein was found to have homology to the proteins shown in the BLASTP data in Table 45D.

PFam analysis predicts that the NOV45a protein contains the domains shown in the Table 45E.

Table 45E. Domain Analysis of NOV45a

Identities/

Pfam Domain NOV45a Match Region Similarities Expect Value for the Matched Region

No Significant Matches Found

Example 46.

The NOV46 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 46A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 46B. Table 46B. Comparison of NOV46a against NO 46b.

NOV46a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV46b 1..259 258/259 (99%) 1..259 258/259 (99%)

Further analysis of the NOV46a protein yielded the following properties shown in Table 46C.

Table 46C. Protein Sequence Properties NOV46a

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV46a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 46D.

In a BLAST search of public sequence datbases, the NOV46a protein was found to have homology to the proteins shown in the BLASTP data in Table 46E.

PFam analysis predicts that the NOV46a protein contains the domains shown in the Table 46F.

Table 46F. Domain Analysis of NOV46a

Identities/

Pfam Domain NOV46a Match Region Similarities Expect Value for the Matched Region

No Significant Matches Found

Example 47.

The NON47 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 47A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 47B.

Further analysis of the NOV47a protein yielded the following properties shown in Table 47C.

Table 47C. Protein Sequence Properties NOV47a

0.1000 probability located in endoplasmic reticulum (lumen)

SignalP analysis: Cleava-τe site between residues 44 and 45

A search of the NOV47a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 47D.

In a BLAST search of public sequence datbases, the NOV47a protein was found to have homology to the proteins shown in the BLASTP data in Table 47E.

PFam analysis predicts that the NOV47a protein contains the domains shown in the Table 47F.

Table 47F. Domain Analysis of NOV47a

Identities/

Pfam Domain NOV47a Match Region Similarities ] Expect Value for the Matched Region

No Significant Matches Found

Example 48. The NOV48 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 48A. 03/010327

Further analysis of the NOV48a protein yielded the following properties shown in Table 48B.

Table 48B. Protein Sequence Properties NOV48a

SignalP analysis: Cleavage site between residues 29 and 30

A search of the NOV48a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 48C.

In a BLAST search of public sequence datbases, the NOV48a protein was found to have homology to the proteins shown in the BLASTP data in Table 48D.

PFam analysis predicts that the NOV48a protein contains the domains shown in the Table 48E.

Example 49.

The NOV49 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 49A.

Further analysis of the NOV49a protein yielded the following properties shown in Table 49B.

Table 49B. Protein Sequence Properties NOV49a

PSort analysis: 0.9200 probability located in mitochondrial matrix space; 0.6000 probability located in mitochondrial inner membrane; 0.6000 probability located in mitochondrial intermembrane space; 0.6000 probability located in mitochondrial outer membrane

SignalP analysis: Cleavage site between residues 19 and 20

A search of the NOV49a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 49C.

In a BLAST search of public sequence datbases, the NOV49a protein was found to have homology to the proteins shown in the BLASTP data in Table 49D.

PFam analysis predicts that the NOV49a protein contains the domains shown in the Table 49E.

Example 50.

The NOV50 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 50A.

Further analysis of the NOV50a protein yielded the following properties shown in Table 50B.

Table 50B. Protein Sequence Properties NOV50a

PSort analysis: 0.6500 probability located in cytoplasm; 0.1586 probability located in lysosome

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV50a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 50C.

In a BLAST search of public sequence datbases, the NOV50a protein was found to have homology to the proteins shown in the BLASTP data in Table 50D.

PFam analysis predicts that the NOV50a protein contains the domains shown in the Table 50E.

Example 51.

The NOV51 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 51 A. Table 51A. NOV51 Sequence Analysis

SEQ ID NO: 155 4297 bp

NOV51a, GCAGGGCCCCTGAAGACTGGCGATCCCGCGCCCGACTACCTTGGTCGTCCGGATATGC -01 DNA Sequence TCCATCGCAAGGAGACGTCAGCCGGCAGCCGGTCTCACAGGCGTACCATACGGCTACA GAAACAGGGCGGTGACAGCGACAGAGAGCAAGCGGGAACTCCCTCCACCAGCCAGCGC CGCGCGTCTGCCTGCCTCGAGTCCCCCGGGAGGCCGCGGGGTTTGGGGAAGTGTTTCT AGGAGACGGCGCTCACCGGCTGCACCTGCGCCGTTGACGCCACCGGGGCCGGCAGACA GACCCGCGGCGCTGGCTGGTGGAGGGAGTTCCCGCTTGCTCTCTGTCGCTGTCACCGC CCTGTTTCTGTAGCCGTATGGTACGCCTGTGAGACCGGCTGCCGGGTGACGTCTCCTT GCGATGGAGCATATCCGGACGACCAAGGTCGAACAAGTAAAATTACTTGACCGATTCA GTACCAGCAACAAGTCATTAACAGGAACACTGTATCTTACGGCTACACATCTATTATT TATCGACTCTCATCAAAAAGAAACCTGGATATTACACCACCATATTGCCTCAGTAGAG AAACTTGCTTTGACTACTTCTGGATGCCCCCTTGTGATACAGTGCAAGAACTTCAGAA CTGTGCATTTCATTGTTCCCAGAGAAAGAGATTGCCATGATATTTACAACTCTTTGCT ACAACTGTCAAAACAAGCAAAATATGAAGATCTCTATGCATTTTCTTATAATCCCAAA CAAAATGATTCAGAACGACTACAAGGCTGGCAGCTCATTGATCTCGCTGAGGAATATA AGAGGATGGGAGTGCCAAACTCACACTGGCAGTTGTCTGATGCCAACCGGGACTACAA GATTTGTGAAACTTACCCCAGAGAACTTTATGTTCCCCGGATAGCAAGCAAACCAATA ATTGTTGGTAGTTCCAAGTTCCGGAGCAAGGGAAGATTCCCAGTTCTTTCCTACTATC ATCAAGATAAGGAGGCTGCCATTTGTCGATGTAGTCAGCCACTCTCTGGATTCAGTGC CAGGTGCCTGGAGGATGAACATTTGCTTCAAGCCATTAGTAAAGCCAATCCAGTCAAT CGCTATATGTACGTCATGGATACCAGGCCAAAACTGAATGCAATGGCCAACAGAGCAG CTGGAAAAGGTTATGAAAATGAAGACAACTATTCCAATATTAGATTTCAGTTTGTTGG AATTGAAAATATTCATGTCATGAGGTCCAGCCTTCAGAAATTATTGGAAGTCAATGGC ACTAAAGGGCTTTCTGTCAATGATTTCTACTCCGGTTTGGAGAGCTCGGGATGGCTTC GCCATATCAAAGCTGTTATGGATGCTGCAGTCTTCTTGGCCAAAGCAATAACAGTTGA AAATGCAAGTGTGTTGGTGCATTGTTCCGATGGTTGGGATAGGACTTCCCAGGTTTGT TCCCTGGGTTCTCTTTTATTGGATTCCTACTACAGGACAATCAAAGGATTCATGGTTT TAATAGAAAAGGATTGGATCTCTTTTGGACATAAATTTTCAGAGAGGTGTGGCCAGTT GGATGGTGACCCAAAGGAAGTCTCACCAGTGTTTACTCAGTTCTTGGAATGTGTGTGG CATTTGACCGAACAGTTTCCACAAGCCTTTGAATTCAGTGAAGCATTTCTTCTTCAGA TCCATGAGCATATTCATTCATGCCAGTTTGGAAACTTCCTTGGAAATTGTCCCAAGGA AAGAGAAGAGCTCAAGTTGAAGGAGAAGACTTATTCCCTGTGGCCATTTCTTTTGGAA GACCAAAAGAAGTACTTAAATCCTCTCTACAGTTCCGAATCTCACAGATTTACAGTTT TGGAGCCAAATACAGTATCTTTCAATTTTAAGTTTTGGAGGAACATGTACCATCAGTT TGATCGAACACTGCATCCTAGGCAGTCTGTATTTAATATAATTATGAATATGAATGAG CAAAATAAACAATTAGAGAAAGATATTAAAGACCTAGAATCTAAAATTAAACAACGCA AAAATAAGCAAACAGATGGCATCCTCACCAAGGAATTGTTACATTCAGTTCATCCTGA ATCACCTAACCTCAAAACTTCCCTGTGTTTTAAAGAGCAGACTCTGCTACCCGTAAAT GATGCTCTTCGAACTATAGAGGGCAGCAGCCCGGCAGATAATCGTTATAGTGAATATG CAGAAGAGTTTTCTAAATCAGAACCTGCTGTGGTCAGCTTAGAGTATGGTGTGGCAAG AATGACTTGTTAGACTCATAGAGTTTTTTCTGCAATGATTGCAGTACAAGAAAAGGAT TATTGTGAGGATGGTCTGTAAGCATAACCAAAAGGAATTTGTCTAATAACAATTTTAG GGTTTAACAGTAGGCTAATAGTTGAAGGAAGGATAATAACTACCCTTGTGAGAGAAAT ATGTCATTTTAATTGCATTTCCAGCAAGGAATGACATTCAGTTCTGTAAGAAATGAGT GGTATTTGATGTATTTACTCAAAACACAATTTGCACTGTACACTAGTGAATTGACGTT TATGATTTATGTTAATTCAGCCAAACATAAATAACCTTCCTTAAGTACAATTTAACTT CAAGAAAACAAAATTTGACAACATAGTTTCTTAATAAATGATATGGCATGTACTTTCA ATTATGTAGCTTTGTAACTATGAATATTTACATATTTTGCCTTTTAGTGATATTTAAT GTTAAAGTGCCATGAAAAATATTTCTAAGAAAGCCTTAAATTCCCAGTGGATTCTTTA CCCTTAAGTTTTACAGCCTACAACAAGATTTTTTGTTTTGTTTTTCTTCTGGTCAGCC TTGTTTTGTTTGTAAAGAATTGTGCTCTCATTACTGCTGGGGGTGCATGCTACAATAC TTCTATATAAACACTTGTAGAAGTACACTGTTCACGTTTAGCCTGCCCCACTTTTGTA TTCAAAATTAATGAAACTGAAGGTTTATTCTGATCATAATTTGTTTAGTGCTACATTT GATAATTTATTATTTACAGCTTAGAATATTGATTTCTTGAATACGTATAAGCACATTT GACTGTCTTTTATATATGGATTACTGCATTCCATTGATTCTTATTTTGTGGTTGGCTT TATTTCTTTCACAACTGTGTAAGTTTAAAGAGCTAAAGCTCTAAAACTGTTCTGAGAA ACAATGAATAGTACATGTATATGTATATTTTTAAACTGCCTTATTGCTCAATGAGTTG CTGTTCCTGGAGTATCTAACTTTCAGTTTACTCAAAAACTTTTGGGTAAATAAAAAAG GGAAGTACAGATAGTTTAGGTTGTGCATGGTTGCATGAATTTTGAAGTCATTTCTATG TGGAGCATTATTTTTCTTCTTGTTAAATATAGAAAAAAAAAGAGATTCTAGTACAAAG TTACTGTTTAACAAAAGCAACATAAACTCTGGGAAAGATTTCATTTTGCCATGTTATA TTTACTGTTTATTCTGTGTACTAGTACATATCTTTAAATTACCAAAAAACAAGAAACA AAACATAAAAACCCCAAAACTATCACTTGGAATTAGCAATATCACCCAACTGGCTTTA AAATTGAAAATTTAAATAACATGGTGGCATGAAGTACAATTCGAGTATTAGGCAATTT GCATAGTGTTCCTCATGCTACTTTCTGTTACACCTCTATTATATTAGTTTTGAATATA AACATCTTTTTCAGACCAAAAAAAACTTTATTGTATGAGAGCTTATCTTATCCTGTTT ATTTTTCCAATGCTTTTCTGTAATACATTATGTAATTTAAAAAATATTCCTTTTTAAA CAGCAACAGAAATGCACTATAAAATATAGTATGTGATTAACCAATCCTGCTTCCATAT

Further analysis of the NOV51a protein yielded the following properties shown in Table 51B.

Table 51B. Protein Sequence Properties NOV51a

PSort analysis: 0.3600 probability located in mitochondrial matrix space; 0.1723 probability located in microbody (peroxisome); 0.1000 probability located in lysosome (lumen); 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV51a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 51 C.

In a BLAST search of public sequence datbases, the NOV5 la protein was found to have homology to the proteins shown in the BLASTP data in Table 5 ID.

PFam analysis predicts that the NO V51 a protein contains the domains shown in the Table 5 IE.

Table 51E. Domain Analysis of NOV51a

Identities/

Pfam Domain NOV51a Match Region Similarities Expect Value for the Matched Region

No Significant Matches Found

Example 52.

The NOV52 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 52A.

Further analysis of the NOV52a protein yielded the following properties shown in Table 52B.

Table 52B. Protein Sequence Properties NOV52a

PSort analysis: 0.5500 probability located in endoplasmic reticulum (membrane); 0.2632 probability located in lysosome (lumen); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside

SignalP analysis: Cleavage site between residues 22 and 23

A search of the NOV52a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 52C.

In a BLAST search of public sequence datbases, the NOV52a protein was found to have homology to the proteins shown in the BLASTP data in Table 52D.

PFam analysis predicts that the NOV52a protein contains the domains shown in the Table 52E.

Example 53.

The NOV53 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 53A.

Further analysis of the NOV53a protein yielded the following properties shown in Table 53B.

Table 53B. Protein Sequence Properties NOV53a

0.1000 probability located in endoplasmic reticulum (lumen)

SignalP analysis: Cleavage site between residues 22 and 23

A search of the NOV53a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 53C.

In a BLAST search of public sequence datbases, the NOV53a protein was found to have homology to the proteins shown in the BLASTP data in Table 53D.

PFam analysis predicts that the NOV53a protein contains the domains shown in the Table 53E.

Example 54.

The NOV54 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 54A. Table 54A. NOV54 Sequence Analysis

SEQ ID NO: 161 2049 bp

NOV54a, TACACATTTTCCCTCATCTCTCTCACTGACACACACAAAACTTTTGGCCATCCTGGGG CG97528-01 DNA Sequence AATTCTGTGACTCTATCCTCTAATTGCAAAAGACTGGAAATTCTAATTCATTCCAACT CTTCCCTTGCAGACAAGAGAACAATGCCCTGGACATGGCTCCAGAGATCCACATGACA GGCCCAATGTGCCTCATTGAGAACACTAATGGGGAACTGGTGGCGAATCCAGAAGCTC TGAAAATCCTGTCTGCCATTACACAGCCTGTGGTGGTGGTGGCAATTGTGGGCCTCTA CCGCACAGGAAAATCCTACCTGATGAACAAGCTAGCTGGGAAGAATAAGGGCTTCTCT CTGGGCTCCACAGTGAAATCTCACACCAAAGGAATCTGGATGTGGTGTGTGCCTCACC CCAAAAAGCCAGAACACACCTTAGTCCTGCTTGACACTGAGGGCCTGGGAGATGTAAA GAAGGGTGACAACCAGAATGACTCCTGGATCTTCACCCTGGCCGTCCTCCTGAGCAGC ACTCTCGTGTACAATAGCATGGGAACCATCAACCAGCAGGCTATGGACCAACTGCAGT ATGTGACAGAGCTGACACATCGAATCCGATCAAAATCCTCACCTGATGAGAATGAGAA TGAGGATTCAGCTGACTTTGTGAGCTTCTTCCCAGATTTTGTGTGGACACTGAGAGAT TTCTCCCTGGACTTGGAAGCAGATGGACAACCCCTCACACCAGATGAGTACCTGGAGT ATTCCCTGAAGCTAACGCAAGGTACCAGTCAAAAAGATAAAAATTTTAATCTGCCCCG ACTCTGTATCCGGAAGTTCTTCCCAAAGAAAAAATGTTTTGTCTTCGATCTGCCCATT CACCGCAGGAAGCTTGCCCAGCTTGAGAAACTACAAGATGAAGAGCTGGACCCTGAAT TTGTGCAACAAGTAGCAGACTTCTGTTCCTACATCTTTAGCAATTCCAAAACTAAAAC TCTTTCAGGAGGCATCAAGGTCAATGGGCCTCGTCTAGAGAGCCTAGTGCTGACCTAT ATCAATGCTATCAGCAGAGGGGATCTGCCCTGCATGGAGAACGCAGTCCTGGCCTTGG CCCAGATAGAGAACTCAGCCGCAGTGCAAAAGGCTATTGCCCACTATGACCAGCAGAT GGGCCAGAAGGTGCAGCTGCCCGCAGAAACCCTCCAGGAGCTGCTGGACCTGCACAGG GTTAGTGAGAGGGAGGCCACTGAAGTCTATATGAAGAACTCTTTCAAGGATGTGGACC ATCTGTTTCAAAAGAAATTAAAGGCCCAGCTAGACAAAAAGCGGGATGACTTTTGTAA ACAGAATCAAGAAGCATCATCAGATCGTTGCTCAGCTTTACTTCAGGTCATTTTCAGT CCTCTAGAAGAAGAAGTGAAGGCGGGAATTTATTCGAAACCAGGGGGCTATTGTCTCT TTATTCAGAAGCTACAAGACCTGGAGAAAAAGTACTATGAGGAACCAAGGAAGGGTCC TAAGGCTGAAGAGATTCTGCAGACATACTTGAAATCCAAGGAGTCTGTGACCGATGCA ATTCTACAGACAGACCAGATTCTCACAGAAAAGGAAAAGGAGATTGAAGGTGTGGAAT GTGTAAAAGCTGAATCTGCACAGGCTTCAGCAAAAATGGTGGAGGAAATGCAAATAAA GTATCAGCAGATGATGGAAGAGAAAGAGAAGAGTTATCAAGAACATGTGAAACAATTG ACTGAGAAGATGGAGAGGGAGAGGGCCCAGTTGCTGGAAGAGCAAGAGAAGACCCTCA CTAGTAAACTTCAGGAACAGGCCCGAGTACTAAAGGAGAGATGCCAAGGTGAAAGTAC CCAACTTCAAAATGAGATACAAAAGCTACAGAAGACCCTGAAAAAAAAAACCAAGAGA TATATGTCGCATAAGCTAAAGATCTAAACAACAGAGCTTTTCTGTCATCCTAACCCAA GGCATAACTGAAACAATTTTAGAATTTGGAACAAGTGTCACTATATTTGATAATAATT AGATCTTGCATCATAACAC

ORF Start: ATG at 151 ORF Stop: TAA at 1939

SEQ ID NO: 162 596 aa MW at 68176.6kD

NOV54a, MAPEIHMTGP CLIENTNGELVANPEALKILSAITQPVWVAIVGLYRTGKSYLMNKL CG97528-01 Protein Sequence AGKNKGFSLGSTVKSHTKGI MWCVPHPKKPEHTLVLLDTEGLGDVKKGDNQNDS IF TLAVLLSSTLVYNSMGTINQQAMDQLQYVTELTHRIRSKSSPDENENEDSADFVSFFP DFVWTLRDFSLDLEADGQPLTPDEYLEYSLKLTQGTSQKDKNFNLPRLCIRKFFPKKK CFVFDLPIHRRKLAQLEKLQDEELDPEFVQQVADFCSYIFSNSKTKTLSGGIKVNGPR LESLVLTYINAISRGDLPCMENAVLALAQIENSAAVQKAIAHYDC2QMGQKVQLPAETL QELLDLHRVSEREATEVYMKNSFKDVDHLFQKKLKAQLDKKRDDFCKQNQEASSDRCS ALLQVIFSPLEEEVKAGIYSKPGGYCLFIQKLQDLEKKYYEEPRKGPKAEEILQTYLK SKESVTDAILQTDQILTEKEKEIEGVECVKAESAQASAKMVEEMQIKYQQMMEEKEKS YQEHVKQLTEKMERERAQLLEEQEKTLTSKLQEQARVLKERCcGESTQLQNEIQKLQ TLKKKTKRYMSHKLKI Further analysis of the NOV54a protein yielded the following properties shown in Table 54B.

Table 54B. Protein Sequence Properties NOV54a

PSort analysis: 0.8000 probability located in nucleus; 0.6000 probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome);

0.1000 probability located in mitochondrial inner membrane j SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV54a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 54C.

In a BLAST search of public sequence datbases, the NOV54a protein was found to have homology to the proteins shown in the BLASTP data in Table 54D.

PFam analysis predicts that the NOV54a protein contains the domains shown in the Table 54E.

Example 55.

The NOV55 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 55 A.

Further analysis of the NOV55a protein yielded the following properties shown in Table 55B.

A search of the NOV55a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 55C.

In a BLAST search of public sequence datbases, the NOV55a protein was found to have homology to the proteins shown in the BLASTP data in Table 55D.

PFam analysis predicts that the NOV55a protein contains the domains shown in the Table 55E.

Example 56.

The NOV56 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 56 A.

Further analysis of the NOV56a protein yielded the following properties shown in Table 56B.

A search of the NOV56a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 56C.

In a BLAST search of public sequence datbases, the NOV56a protein was found to have homology to the proteins shown in the BLASTP data in Table 56D.

PFam analysis predicts that the NOV56a protein contains the domains shown in the Table 56E.

Example 57.

The NOV57 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 57A.

Further analysis of the NOV57a protein yielded the following properties shown in Table 57B.

Table 57B. Protein Sequence Properties NOV57a

PSort analysis: j 0.6000 probability located in plasma membrane; 0.4000 probability located in Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in mitochondrial inner membrane

SignalP analysis: No Known Signal Sequence Predicted A search of the NOV57a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 57C.

In a BLAST search of public sequence datbases, the NOV57a protein was found to have homology to the proteins shown in the BLASTP data in Table 57D.

PFam analysis predicts that the NOV57a protein contains the domains shown in the Table 57E.

Example 58.

The NOV58 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 58A.

Table 58A. NOV58 Sequence Analysis

SEQ ID NO: 169 2937 bp

NOV58a, ATCAGTTCTCCACTATCCTTCTGTTTTTCTAGGTAACTATAACTACCCAATATTGCAG CG97842-01 DNA Sequence CCATGGAGTCCATGCTTAATAAATTGAAGAGTACTGTTACAAAAGTAACAGCTGATGT CACTAGTGCTGTAATGGGAAATCCTGTCACTAGAGAATTTGATGTTGGTCGACACATT GCCAGTGGTGGCAATGGGCTAGCTTGGAAGATTTTTAATGGCACAAAAAAGTCAACAA AGCAGGAAGTGGCAGTTTTTGTCTTTGATAAAAAACTGATTGACAAGTATCAAAAATT TGAAAAGGATCAAATCATTGATTCTCTAAAACGAGGAGTCCAACAGTTAACTCGGCTT CGACACCCTCGACTTCTTACTGTCCAGCATCCTTTAGAAGAATCCAGGGATTGCTTGG CATTTTGTACAGAACCAGTTTTTGCCAGTTTAGCCAATGTTCTTGGTAACTGGGAAAA TCTACCTTCCCCTATATCTCCAGACATTAAGGATTATAAACTTTATGATGTAGAAACC AAATATGGTTTGCTTCAGGTTTCTGAAGGATTGTCATTCTTGCATAGCAGTGTGAAAA TGGTGCATGGAAATATCACTCCTGAAAATATAATTTTGAATAAAAGTGGAGCCTGGAA AATAATGGGTTTTGATTTTTGTGTATCATCAACCAATCCTTCTGAACAAGAGCCTAAA TTTCCTTGTAAAGAATGGGACCCAAATTTACCTTCATTGTGTCTTCCAAATCCTGAAT ATTTGGCTCCTGAATACATACTTTCTGTGAGCTGTGAAACAGCCAGTGATATGTATTC TTTAGGAACTGTTATGTATGCTGTATTTAATAAAGGGAAACCTATATTTGAAGTCAAC AAGCAAGATATTTACAAGAGTTTCAGTAGGCAGTTGGATCAGTTGAGTCGTTTAGGAT CTAGTTCACTTACAAATATACCTGAGGAAGTTCGTGAACATGTAAAGCTACTGTTAAA TGTAACTCCGACTGTAAGACCAGATGCAGATCAAATGACAAAGATTCCCTTCTTTGAT GATGTTGGTGCAGTAACACTGCAATATTTTGATACCTTATTCCAAAGAGATAATCTTC AGAAATCACAGTTTTTCAAAGGACTGCCAAAGGTTCTACCAAAACTGCCCAAGCGTGT CATTGTGCAGAGAATTTTGCCTTGTTTGACTTCAGAATTTGTAAACCCTGACATGGTA CCTTTTGTTTTGCCCAATGTTCTACTTATTGCTGAGGAATGCACCAAAGAAGAATATG JTCAAATTAATTCTTCCTGAACTTGGCCCTGTGTTTAAGCAGCAGGAGCCAATCCAGAT ITTTGTTAATTTTCCTACAAAAAATGGATTTGCTACTAACCAAAACCCCTCCTGATGAG ATAAAGAACAGTGTTCTACCCATGGTTTACAGAGCACTAGAAGCTCCTTCCATTCAGA TCCAGGAGCTCTGTCTAAACATCATTCCAACCTTTGCAAATCTTATAGACTACCCATC CATGAAAAACGCTTTGATACCAAGAATTAAAAATGCTTGTCTACAAACATCTTCCCTT GCGGTTCGTGTAAATTCATTAGTGTGCTTAGGAAAGATTTTGGAATACTTGGATAAGT GGTTTGTACTTGATGATATCCTACCCTTCTTACAACAAATTCCATCCAAGGAACCTGC GGTCCTCATGGGAATTTTAGGTATTTACAAATGTACTTTTACTCATAAGAAGTTGGGA ATCACCAAAGAGCAGCTGGCCGGAAAAGTGTTGCCTCATCTTATTCCCCTGAGTATTG AAAACAATCTTAATCTTAATCAGTTCAATTCTTTCATTTCCGTCATAAAAGAAATGCT TAATAGATTGGAGTCTGAACATAAGACTAAACTGGAGCAACTTCATATAATGCAAGAA CAGCAGAAATCTTTGGATATAGGAAATCAAATGAATGTTTCTGAGGAGATGAAAGTTA CAAATATTGGGAATCAGCAAATTGACAAAGTTTTTAACAACATTGGAGCAGACCTTCT GACTGGCAGTGAGTCCGAAAATAAAGAGGACGGGTTACAGAATAAACATAAAAGAGCA TCACTTACACTTGAAGAAAAACAAAAATTAGCAAAAGAACAAGAGCAGGCACAGAAGC TGAAAAGCCAGCAGCCTCTTAAACCCCAAGTGCACACACCTGTTGCTACTGTTAAACA GACTAAGGACTTGACAGACACACTGATGGATAATATGTCATCCTTGACCAGCCTTTCT GTTAGTACCCCTAAATCTTCTGCTTCAAGTACTTTCACTTCTGTTCCTTCCATGGGCA TTGGTATGATGTTTTCTACACCAACTGATAATACAAAGAGAAATTTGACAAATGGCCT AAATGCCAATATGGGCTTTCAGACTTCAGGATTCAACATGCCCGTTAATACAAACCAG AACTTCTACAGTAGTCCAAGCACAGTTGGAGTGACCAAGATGACTCTGGGAACACCTC CCACTTTGCCAAACTTCAATGCTTTGAGTGTTCCTCCTGCTGGTGCAAAGCAGACCCA ACAAAGACCCACAGATATGTCTGCCCTTAATAATCTCTTTGGCCCTCAGAAACCCAAA GTTAGCATGAACCAGTTATCACAACAGAAACCAAATCAGTGGCTTAATCAGTTTGTAC CTCCTCAAGGTTCTCCAACTATGGGCAGTTCAGTAATGGGGACACAGATGAACGTGAT AGGACAATCTGCTTTTGGTATGCAGGGTAATCCTTTCTTTAACCCACAGAACTTTGCA CAGCCACCAACTACTATGACCAATAGCAGTTCAGCTAGCAATGATTTAAAAGATCTTT TTGGGTGAGGTGTCTTACTTCTATTTTGAAGGATTATTTCAGTTTCAATCATGGGTGA GCTGATTTACATCTTTATATAGTTGGCTTGGAGGAAG

Further analysis of the NOV58a protein yielded the following properties shown ii Table 58B.

Table 58B. Protein Sequence Properties NOV58a

PSort analysis: I 0.4564 probability located in mitochondrial matrix space; 0.3000 probability located ! in microbody (peroxisome); 0.3000 probability located in nucleus; 0.1507

I probability located in mitochondrial inner membrane

; SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV58a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 58C.

0

In a BLAST search of public sequence datbases, the NOV58a protein was found to have homology to the proteins shown in the BLASTP data in Table 58D.

PFam analysis predicts that the NOV58a protein contains the domains shown in the Table 58E.

Table 58E. Domain Analysis of NOV58a

Identities/

Pfam Domain NOV58a Match Region Similarities Expect Value for the Matched Region pkinase 159..327 44/203 (22%) 3e-07 1 16/203 (57%)

Example 59.

The NOV59 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 59A. Table 59 A. NOV59 Sequence Analysis

SEQ ID NO: 171 2933 bp

NOV59a, ACTCTATGTCTCCTCTCGTTGGATTGTGACACCGGGAGGTCAGGGAACTCCAGGACCT CG98021-01 DNA Sequence TGTTCTCTGCTGGATTCGCAGCAACCAGCACAGCACGTAGGGCGTAGTTGGTGCTGGA TGGATGTTTGTTGAATGAATGAATGATGAATGGCTGGCACCTTGTCTGCTCATCCCTA ACTCCTGTTCCTTCATCTGTGCAGCCCTAATCTTTGTTTCCTCATCTGTCCATCCCTT TATTTGTGCATCCTCATTCTTAGCCCCTTCACTGCCCTTCTCCATCTCTTCCTCCTTG TTCATTTGTCCCTGTTCTCTGTCCTCTACTCCACTCATGCCCATCTCTGTCCCCTTGA CTTACCCAGTCCCTGCTACTATCTCCATCCCTAATTTCTGCCCTCTTGTCTGTCTACT CCTAATTCCTTTTCCTTGTCCATCCCTAATACCTGTCACCTTGTCCTTCTTCCTCGAA TCTCCATCCCTAATCCATCTGCCCCTAATCTCTGTCCCCTTTGCCCATCCTTCCTTTT CTCGGTGTCTCTTTCCACCCTTATCTCCACACCTGCCCACCCTGCACTCCCATTCTGT TTCCCATCTGCACCCTTGCCCCATCCCTCCCACACACAGGACCAGACGGCCACCATGT CAGGAGACTACGAGGATGACCTCTGCCGGCGGGCACTCATCCTGGTCTCGGACCTCTG TGCGCGGGTCCGAGATGCTGACACCAACGACAGGTGCCAGGAGTTCAATGACCGAATC CGAGGCTATCCCCGGGGTCCAGATGCAGACATCTCCGTGAGCCTGCTGTCGGTCATCG TGACATTCTGTGGCATTGTCCTTCTGGGTGTCTCTCTCTTCGTGTCCTGGAAGTTGTG CTGGGTGCCCTGGCGGGACAAGGGAGGCTCGGCAGTGGGCGGTGGCCCCCTGCGCAAA GACCTAGGCCCTGGTGTCGGGCTGGCAGGCCTGGTAGGCGGAGGCGGGCACCACCTGG CGGCTGGCCTGGGTGGCCATCCTCTGCTGGGCGGCCCACACCACCATGCCCATGCCGC CCACCATCCACCCTTTGCTGAGCTGCTGGAGCCAGGCAGCCTGGGGGGTTCTGACACC CCTGAGCCCTCCTACTTGGACATGGACTCGTATCCAGAGGCTGCAGCAGCAGCAGTGG CCGCTGGGGTCAAACCGAGCCAAACATCCCCTGAGCTGCCCTCTGAGGGGGGAGCAGG CTCTGGGTTGCTCCTGCTGCCCCCCAGTGGTGGGGGCTTGCCCAGTGCCCAGTCACAT CAGCAGGTCACAAGCCTGGCACCCACTACCAGGTACCCAGCCCTGCCCCGACCCCTCA CCCAGCAGACTCTGACCTCCCAGCCGGACCCCAGCAGTGAGGAGCGCCCACCTGCCCT GCCCTTACCCCTGCCTGGAGGCGAGGAAAAAGCCAAACTCATTGGGCAGATTAAGCCA GAGCTGTACCAGGGGACTGGCCCTGGTGGCCGGCGGAGCGGTGGGGGCCCAGGCTCTG GAGAGGCAGGCACAGGGGCACCCTGTGGCCGTATCAGCTTCGCCCTGCGGTACCTCTA TGGCTCGGACCAGCTGGTGGTGAGGATCCTGCAGGCCCTGGACCTCCCTGCCAAGGAC TCCAACGGCTTCTCAGACCCCTACGTCAAGATCTACCTGCTGCCTGACCGCAAGAAAA AGTTTCAGACCAAGGTGCACAGGAAGACCCTGAACCCCGTCTTCAATGAGACGTTTCA ATTCTCGGTGCCCCTGGCCGAGCTGGCCCAACGCAAACTGCACTTCAGCGTCTATGAC TTTGACCGCTTCTCGCGGCACGACCTCATCGGCCAGGTGGTGCTGGACAACCTCCTGG AGCTGGCCGAGCAGCCCCCTGACCGCCCGCTCTGGAGGGACATCGTGGAGGGCGGCTC GGAAAAAGCAGATCTTGGGGAGCTCAACTTCTCACTCTGCTACCTCCCCACGGCCGGG CGCCTCACCGTGACCATCATCAAAGCCTCTAACCTCAAAGCGATGGACCTCACTGGCT TCTCAGACCCCTACGTGAAGGCCTCCCTGATCAGCGAGGGGCGGCGTCTGAAGAAGCG GAAAACCTCCATCAAGAAGAACACGCTGAACCCCACCTATAATGAGGCGCTGGTGTTC GACGTGGCCCCCGAGAGCGTGGAGAACGTGGGGCTCAGCATCGCCGTGGTGGACTACG ACTGCATCGGGCACAACGAGGTGATCGGCGTGTGCCGTGTGGGCCCCGACGCTGCCGA CCCGCACGGCCGCGAGCACTGGGCAGAGATGCTGGCCAATCCCCGCAAGCCCGTGGAG CACTGGCATCAGCTAGTGGAGGAAAAGACTGTGACCAGCTTCACAAAAGGCAGCAAAG GACTATCAGAGAAAGAGAACTCCGAGTGAGGGGTCTGGCCTAGGCCCGGGATCGGACC AGGCTCCCTCAGGACCCCATCCTTTCCTGCCCGGACCGTGAATTCATCTCCTTGAAGC CATAACGTCCGAGCTGCTGGTGCGGGGCAGCCCTGGCCCTAGGCTTCCTAACCCTGGA AGCGAGAGGATGAGAGGAGGCCGGCCCAGCTCCTTCTTTCAGGGTGGGGGTCATTCAG CCTCCACTGTGTCTGTCTTTTCTTCCCTGGGGCTCCCCCTCGAGGCGAGGGGCCATGC ATGTCTGGGGGACCCCTGCCCCCCAAAACCCTCTGTCTGTCTCTGTCTCTTTGCTGTT TGTCCAAGACTCAGTGTCCCGACCCTTGTTCTCGCCGTGAATGTCAATGGGCCAATCC TCTCTGTCCTTTCAGACACACACACACCTGTGTCCACCCCTTCTGTTCGCCACACCCT GCGTCTGGCCGGTCCCCCCACTGCTGCTGCTATCAACGCCAGAATAAACACACTCTGT GGGTCTCACTCCAAAAAAAAAAAAAAAAAAAGC

ORF Start: ATG at 635 ORF Stop: TGA at 2405

SEQ ID NO: 172 590 aa MW at 63303.0kD

NOV59a, MSGDYEDDLCRRALILVSDLCARλ/RDADTNDRCQEFNDRIRGYPRGPDADISVSLLSV CG98021-01 Protein Sequence IVTFCGIVLLGVSLFVS KLCWVP RDKGGSAVGGGPLRKDLGPGVGLAGLVGGGGHH LAAGLGGHPLLGGPHHHAHAAHHPPFAELLEPGSLGGSDTPEPSYLDMDSYPEAAAAA VAAGVKPSQTSPELPSEGGAGSGLLLLPPSGGGLPSAQSHQQVTSLAPTTRYPALPRP LTQQTLTSQPDPSSEERPPALPLPLPGGEEKAKLIGQIKPELYQGTGPGGRRSGGGPG SGEAGTGAPCGRISFALRYLYGSDQLWRILQALDLPAKDSNGFSDPYVKIYLLPDRK KKFQTKVHRKTLNPVFNETFQFSVPLAELAQRKLHFSVYDFDRFSRHDLIGQWLDNL LELAEQPPDRPLWRDIVEGGSEKADLGELNFSLCYLPTAGRLTVTIIKASNLKA DLT GFSDPYVKASLISEGRRLKKRKTSIKK TLNPTYNEALVFDVAPESVE VGLSIAVVD YDCIGH EVIGVCRVGPDAADPHGREH AEMLANPRKPVEH HQLVEEKTVTSFTKGS KGLSEKENSE Further analysis of the NOV59a protein yielded the following properties shown in Table 59B.

Table 59B. Protein Sequence Properties NOV59a

PSort analysis: 0.6000 probability located in endoplasmic reticulum (membrane); 0.4600 probability located in plasma membrane; 0.3128 probability located in microbody

(peroxisome); 0.3000 probability located in nucleus

SignalP analysis: Cleavage site between residues 28 and 29

A search of the NOV59a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 59C.

In a BLAST search of public sequence datbases, the NOV59a protein was found to have homology to the proteins shown in the BLASTP data in Table 59D.

PFam analysis predicts that the NOV59a protein contains the domains shown in the Table 59E.

Example 60.

The NOV60 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 60A. Table 60A. NOV60 Sequence Analysis

SEQ ID NO: 173 2133 bp

NOV60a, CGTTTACGGCATGTCATTCCTGGACACATGGCATGTTCCATGGCGTGTGGCGGTAGAG CG98030-01 DNA Sequence CTTGCAAGTATGAGAACCCAGCCCGCTGGAGTGAGCAGGAGCAAGCCATTAAGGGGGT TTACTCATCCTGGGTCACTGATAATATACTGGCCATGGCCCGCCCATCCTCTGAGCTC CTGGAGAAGTACCACATCATTGATCAGTTCCTCAGCCATGGCATAAAAACAATAATCA ACCTCCAGCGCCCTGGTGAGCATGCTAGCTGTGGGAACCCTCTGGAACAAGAAAGTGG CTTCACATACCTTCCTGAGGCTTTCATGGAGGCTGGCATTTACTTCTACAATTTCGGA TGGAAGGATTATGGTGTAGCGTCTCTTACTACTATCCTAGATATGGTGAAGGTGATGA CATTTGCCTTACAGGAAGGAAAAGTAGCTATCCATTGTCATGCAGGGCTTGGTCGAAC AGGTGTTTTAATAGCCTGTTACTTAGTTTTTGCAACGAGAATGACTGCTGACCAAGCA ATTATATTTGTGCGGGCAAAGCGACCCAATTCCATACAAACCAAGAGACAGCTCCTCT GTGTAAGGGAATTTACTCAGTTTCTAACTCCTCTCCGCAATATATTCTCTTGCTGTGA TCCCAAAGCACATGCTGTCACCTTACCTCAATATCTAATTCGCCAGCGTCATCTGCTT CATGGTTATGAGGCACGACTTCTGAAACACGTGCCAAAAATTATCCACCTAGTTTGCA AATTGCTGCTGGACTTAGCGGAGAACAGGCCAGTGATGATGAAGGATGTGTCCGAAGG ACCTGGTCTCTCTGCTGAAATAGAAAAGACAATGTCTGAGATGGTCACCATGCAGCTG GATAAAGAGTTACTGAGGCATGACAGTGATGTGTCCAACCCGCCTAACCCCACTGCAG TGGCAGCAGATTTTGACAATCGAGGCATGATTTTCTCCAATGAGCAACAGTTTGACCC TCTTTGGAAAAGGCGGAATGTTGAGTGCCTTCAACCCCTGACTCATCTGAAAAGGCGG CTCAGCTACAGTGACTCAGATTTAAAGAGGGCCGAGAACCTCCTGGAGCAAGGGGAGA CTCCACAGACAGTGCCTGCCCAGATCTTGGTTGGCCACAAGCCCAGGCAGCAGAAGCT CATAAGCCATTGTTACATCCCACAGTCTCCAGAACCAGACTTACACAAGGAAGCCTTG GTTCGCAGCACACTTTCTTTCTGGAGTCAGTCAAAGTTTGGAGGCCTGGAAGGACTCA AAGATAATGGGTCACCAATTTTCCATGGAAGGATCATTCCAAAGGAAGCACAGCAGAG TGGAGCTTTCTCTGCAGATGTTTCAGGCTCACACAGCCCTGGGGAGCCAGTTTCACCC AGCTTTGCAAATGTCCATAAGGATCCAAACCCTGCTCACCAGCAAGTGTCTCACTGTC AGTGTAAAACTCATGGTGTTGGGAGCCCTGGCTCTGTCAGGCAGAACAGCAGGACACC CCGAAGCCCTCTGGACTGTGGCTCCAGTCCCAAAGCACAGTTCTTGGTTGAACATGAA ACCCAGGACAGTAAAGATCTGTCTGAAGCAGCTTCACACTCTGCATTACAGTCTGAAT TGAGTGCTGAGGCAAGAAGAATACTGGCGGCCAAAGCCCTAGCAAATTTAAATGAATC TGTAGAAAAGGAGGAACTAAAAAGGAAGAAAGAGCTTAATTCCCGAGATGGAGCTTGG GAAAGAATATGTGGCGAGAGGGACCCTTTCATCCTATGCAGCTTGATGTGGTCTTGGG TGGAGCAACTGAAGGAGCCTGTAATCACCAAAGAGGATGTGGACATGTTGGTTGACAG GCGAGCAGATGCCGCAGAAGCACTTTTTTTATTAGAGAAGGGACAGCACCAGACTATT CTCTGCGTGTTGCACTGCATAGTGAACCTGCAGACAATTCCCGTGGATGTGGAGGAAG CTTTCCTTGCCCATGCCATTAAGGCATTCACTAAGGTTAATTTTGATTCTGAAAATGG ACCAACAGTTTACAACACCCTGAAGAAAATATTTAAGCACACGCTGGAAGAAAAAAGA AAAATGACAAAAGATGGCCCTAAGCCTGGCCTCTAGCTTTCACTC

ORF Start: ATG at 28 ORF Stop: TAG at 2122

SEQ ID NO: 174 698 aa MW at 78224.7kD

NOV60a, MACSMACGGRACKYENPARWSEQEQAIKGVYSSWVTDNILAMARPSSELLEKYHIIDQ CG98030-01 Protein Sequence FLSHGIKTIINLQRPGEHASCGNPLEQESGFTYLPEAFMEAGIYFYNFG DYGVASL TTILD^WKMTFA QEG VAIHCHAG GRTGV IACYLVFATRMTADQAIIF RAKRP NSIQTKRQLLCVREFTQFLTPLR IFSCCDPKAHAVTLPQYLIRQRHLLHGYEARLLK HVPKIIHLVCKLLLDLAENRPVMMKDVSEGPGLSAEIEKTMSEMVTMQLDKELLRHDS DVSNPPNPTAVAADFDNRGMIFΞNEQQFDPLWKRRNVECLQPLTHLKRRLSYSDSDLK RAENLLEQGETPQTVPAQILVGHKPRQQKLISHCYIPQSPEPDLHKEALVRSTLSFWS QSKFGGLEGLKDNGSPIFHGRIIPKEAQQSGAFSADVSGSHSPGEPVSPSFANVHKDP NPAHQQVSHCQCKTHGVGSPGSVRQNSRTPRSPLDCGSSPKAQFLVEHETQDSKDLSE AASHSALQSELSAEARRILAAKALANLNESVEKEELKRKKELNSRDGA ERICGERDP FILCΞLM SWVEQLKEPVITKEDVDMLVDRRADAAEALFLLEKGQHQTILCVLHCIVN LQTIPVnVEEAFIαAHAIKAFTKVNFDSENGPTλYNTLKKIFKHTLEE RKMTKDGPKP GL SEQ ID NO: 175 2147 bp

NOV60b, CGTTTACGGCATGTCATTCCTGGACACATGGCATGTTCCATGGCGTGTGGCGGTAGAG CG98030-02 DNA Sequence CTTGCAAGTATGAGAACCCAGCCCGCTGGAGTGAGCAGGAGCAAGCCATTAAGGGGGT TTACTCATCCTGGGTCACTGATAATATACTGGCCATGGCCCGCCCATCCTCTGAGCTC CTGGAGAAGTACCACATCATTGATCAGTTCCTCAGCCATGGCATAAAAACAATAATCA ACCTCCAGCGCCCTGGTGAGCATGCTAGCTGTGGGAACCCTCTGGAACAAGAAAGTGG CTTCACATACCTTCCTGAGGCTTTCATGGAGGCTGGCATTTACTTCTACAATTTCGGA TGGAAGGATTATGGTGTAGCGTCTCTTACTACTATCCTAGATATGGTGAAGGTGATGA CATTTGCCTTACAGGAAGGAAAAGTAGCTATCCATTGTCATGCAGGGCTTGGTCGAAC AGGTGTTTTAATAGCCTGTTACTTAGTTTTTGCAACGAGAATGACTGCTGACCAAGCA ATTATATTTGTGCGGGCAAAGCGACCCAATTCCATACAAACCAGAGGACAGCTCCTCT GTGTAAGGGAATTTACTCAGTTTCTAACTCCTCTCCGCAATATATTCTCTTGCTGTGA TCCCAAAGCACATGCTGTCACCTTACCTCAATATCTAATTCGCCAGCGTCATCTGCTT CATGGTTATGAGGCACGACTTCTGAAACACGTGCCAAAAATTATCCACCTAGTTTGCA AATTGCTGCTGGACTTAGCGGAGAACAGGCCAGTGATGATGAAGGATGTGTCCGAAGG ACCTGGTCTCTCTGCTGAAATAGAAAAGACAATGTCTGAGATGGTCACCATGCAGCTG GATAAAGAGTTACTGAGGCATGACAGTGATGTGTCCAACCCGCCTAACCCCACTGCAG TGGCAGCAGATTTTGACAATCGAGGCATGATTTTCTCCAATGAGCAACAGTTTGACCC TCTTTGGAAAAGGCGGAATGTTGAGTGCCTTCAACCCCTGACTCATCTGAAAAGGCGG CTCAGCTACAGTGACTCAGATTTAAAGAGGGCCGAGAACCTCCTGGAGCAAGGGGAGA CTCCACAGACAGTGCCTGCCCAGATCTTGGTTGGCCACAAGCCCAGGCAGCAGAAGCT CATAAGCCATTGTTACATCCCACAGTCTCCAGAACCAGACTTACACAAGGAAGCCTTG GTTCGCAGCACACTTTCTTTCTGGAGTCAGTCAAAGTTTGGAGGCCTGGAAGGACTCA AAGATAATGGGTCACCAATTTTCCATGGAAGGATCATTCCAAAGGAAGCACAGCAGAG TGGAGCTTTCTCTGCAGATGTTTCAGGCTCACACAGCCCTGGGGAGCCAGTTTCACCC AGCTTTGCAAATGTCCATAAGGATCCAAACCCTGCTCACCAGCAAGTGTCTCACTGTC AGTGTAAAACTCATGGTGTTGGGAGCCCTGGCTCTGTCAGGCAGAACAGCAGGACACC CCGAAGCCCTCTGGACTGTGGCTCCAGTCCCAAAGCACAGTTCTTGGTTGAACATGAA ACCCAGGACAGTAAAGATCTGTCTGAAGCAGCTTCACACTCTGCATTACAGTCTGAAT TGAGTGCTGAGGCAAGAAGAATACTGGCGGCCAAAGCCCTAGCAAATTTAAATGAATC TGTAGAAAAGGAGGAACTAAAAAGGAAGGTAGAAATGTGGCAGAAAGAGCTTAATTCC CGAGATGGAGCTTGGGAAAGAATATGTGGCGAGAGGGACCCTTTCATCCTATGCAGCT TGATGTGGTCTTGGGTGGAGCAACTGAAGGAGCCTGTAATCACCAAAGAGGATGTGGA CATGTTGGTTGACAGGCGAGCAGATGCCGCAGAAGCACTTTTTTTATTAGAGAAGGGA CAGCACCAGACTATTCTCTGCGTGTTGCACTGCATAGTGAACCTGCAGACAATTCCCG TGGATGTGGAGGAAGCTTTCCTTGCCCATGCCATTAAGGCATTCACTAAGGTTAGTTT TGATTCTGAAAATGGACCAACAGTTTACAACACCCTGAAGAAAATATTTAAGCACACG CTGGAAGAAAAAAGAAAAATGACAAAAGATGGCCCTAAGCCTGGCCTCTAGCTTTCAC T

ORF Start: ATG at 28 ORF Stop: TAG at 2137

SEQ ID NO: 176 703 aa MW at 78800.4kD

NOV60b, MACSMACGGRACKYENPAR SEQEQAIKGVYSSWVTDNILAMARPSSELLEKYHIIDQ CG98030-02 Protein Sequence FLSHGIKTIINLQRPGEHASCGNPLEQESGFTYLPEAFMEAGIYFY FGWKDYGVASL TTILDMVKVMTFALQEGKVAIHCHAGLGRTGVLIACYLVFATRMTADQAIIFVRAKRP NSIQTRGQLLCVREFTQFLTPLRNIFSCCDPKAHAVTLPQYLIRQRHLLHGYEARLLK HVPKIIHLVCKLLLDLAENRPVMMKDVSEGPGLSAEIEKTMSEMVTMQLDKELLRHDS DVSNPPNPTAVAADFDNRGMIFSNEQQFDPL KRRNVECLQPLTHLKRRLSYSDSDL RAENLLEQGETPQTVPAQILVGHKPRQQKLISHCYIPQSPEPDLHKEALVRSTLSF S QSKFGGLEGLKDNGSPIFHGRIIPKEAQQSGAFSADVSGSHSPGEPVSPSFANVHKDP NPAHQQVSHCQCKTHGVGSPGSVTsQNSRTPRSPLDCGSSPKAQFLVEHETQDSKDLSE AASHSALQSELSAEARRIIAAKALANLNESVEKEELKRKVEMWQKELNSRDGA ERIC GERDPFILCSLM SWVEQLKEPVITKEDVDMLVDRRADAAEALFLLEKGQHQTILCVL HCIVNLQTIPVDVEEAFLAHAIKAFTKVSFDSENGPTVYNTLKKIFKHTLEEKRK TK DGPKPGL

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 60B.

Further analysis of the NOV60a protein yielded the following properties shown in Table 60C.

Table 60C. Protein Sequence Properties NOV60a

PSort analysis: 0.9400 probability located in nucleus; 0.3000 probability located in microbody

(peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen) i SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV60a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 60D.

In a BLAST search of public sequence datbases, the NOVόOa protein was found to have homology to the proteins shown in the BLASTP data in Table 60E.

PFam analysis predicts that the NOV60a protein contains the domains shown in the Table 60F.

Example 61.

The NOV61 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 61 A. Table 61A. NOV61 Sequence Analysis

SEQ ID NO: 177 4172 bp

NOV61a, ATGGCGGCGGCGGGAGCCCTGGAACGGAGCTTCGTGGAGCTAAGCGGAGCTGAGCGCG -01 DNA Sequence AAAGGCCGAGGCACTTTCGGGAATTCACAGTCTGCAGCATTGGGACTGCAAATGCCGT GGCTGGCGCCGTAAAATACAGTGAAAGCGCGGGAGGCTTTTACTACGTGGAGAGTGGC AAGTTGTTCTCCGTAACCAGAAACAGGTTCATTCATTGGAAGACCTCTGGAGATACAT TGGAGCTGATGGAGGAGTCACTGGACATAAATCTGTTGAATAATGCCATTCGCCTAAA ATTCCAAAATTGCAGTGTTTTACCTGGAGGGGTTTATGTCTCTGAGACTCAGAATCGT GTGATAATCTTGATGTTAACCAATCAAACAGTGCACAGGTTACTTTTACCACACCCCT CCCGGATGTATAGGAGTGAGTTGGTAGTTGACAGTCAGATGCAGTCAATATTCACTGA CATTGGAAAAGTTGATTTCACAGATCCTTGCAACTATCAGTTAATTCCAGCAGTACCT GGAATATCTCCTAATTCCACCGCCTCTACAGCCTGGCTCAGCAGTGATGGGGAGGCCC TGTTTGCCTTACCATGTGCTTCTGGGGGAATCTTTGTTCTTAAGCTACCTCCTTATGA CATACCTGGTATGGTGTCAGTCGTGGAACTGAAACAGAGTTCAGTAATGCAACGATTG CTTACAGGCTGGATGCCAACAGCTATCAGGGGTGACCAGTCGCCTTCAGATCGTCCCC TCAGTCTTGCTGTTCATTGTGTGGAGCATGATGCCTTCATCTTTGCTTTGTGTCAGGA TCATAAACTACGAATGTGGTCTTACAAGGAGCAAATGTGCCTAATGGTAGCTGACATG CTGGAGTATGTCCCTGTGAAGAAAGACCTTCGGCTTACTGCTGGAACTGGACACAAAT TACGGCTTGCTTATTCCCCCACCATGGGACTCTACCTGGGGATATACATGCATGCACC AAAACGAGGACAGTTCTGCATTTTCCAGTTGGTGAGCACTGAGAGTAATCGCTATAGT CTCGATCATATTTCTTCACTGTTCACTTCTCAGGAGACACTGATTGACTTTGCCTTAA CTTCCACGGATATCTGGGCCCTGTGGCATGATGCTGAGAACCAAACAGTAGTGAAATA CATCAACTTTGAACATAATGTTGCAGGTCAGTGGAATCCAGTTTTTATGCAGCCTCTG CCAGAGGAAGAGATTGTCATCAGAGATGATCAAGACCCCAGAGAGATGTATCTGCAAA GTCTTTTTACACCAGGACAATTCACAAATGAAGCTTTATGTAAGGCTTTACAGATTTT CTGCCGAGGAACTGAGAGGAATTTGGATCTTTCCTGGAGTGAACTGAAGAAAGAAGTT ACTTTAGCTGTTGAAAATGAGCTTCAAGGAAGTGTAACAGAGTATGAATTCTCCCAGG AGGAGTTTCGAAATTTACAACAAGAATTCTGGTGCAAGTTCTATGCCTGTTGTCTTCA GTATCAAGAAGCCCTCTCTCACCCTCTTGCCCTACATTTGAATCCACACACAAACATG GTGTGCCTGCTGAAAAAAGGGTACCTGTCTTTCCTTATTCCCTCATCCTTAGTGGATC ATTTGTATCTCCTGCCTTATGAGAACCTTTTGACAGAAGATGAGACAACCATATCTGA TGATGTGGATATCGCTCGGGATGTCATATGTCTTATAAAATGCCTCCGGCTGATTGAA GAGTCAGTAACTGTGGATATGTCAGTTATAATGGAAATGAGTTGTTATAACCTACAGT CTCCGGAAAAGGCTGCAGAGCAGATTCTGGAAGATATGATCACTATTGATGTAGAAAA TGTGATGGAGGATATTTGTAGTAAACTGCAAGAGATTAGGAACCCAATCCATGCAATT GGACTACTTATACGGGAAATGGATTATGAAACAGAAGTGGAAATGGAAAAGGGATTCA ATCCAGCTCAGCCTTTGAATATTCGAATGAATCTTACCCAGCTCTATGGTAGTAACAC AGCAGGGTATATTGTGTGCAGAGGGGTGCATAAAATCGCCAGTACTCGTTTCCTGATC TGCAGAGATCTTTTGATCTTACAGCAGCTGTTAATGAGGCTTGGAGATGCTGTGATTT GGGGAACTGGTCAGCTCTTTCAAGCTCAGCAAGACCTACTACATCGAACAGCTCCCCT ACTCTTATCTTATTACCTCATTAAATGGGGAAGTGAGTGCTTGGCAACTGATGTTCCA CTTGACACACTGGAGTCTAATCTCCAACACTTATCAGTACTGGAATTAACAGACTCTG GTGCTTTAATGGCAAATAGGTTTGTATCTAGTCCTCAGACTATTGTGGAGTTATTCTT CCAAGAAGTTGCAAGAAAACACATTATATCTCACCTCTTCTCTCAGCCAAAGGCACCT CTGAGCCAAACTGGATTGAATTGGCCTGAAATGATTACTGCAATTACCAGTTATTTAT TGCAGCTTTTATGGCCTAGCAATCCTGGTTGTCTCTTTCTAGAATGTTTGATGGGAAA TTGCCAATATGTACAATTGCAGGATTATATTCAACTGCTACATCCCTGGTGTCAAGTC AATGTTGGTTCCTGTCGATTTATGCTGGGAAGGTGTTACCTAGTTACAGGAGAAGGAC AGAAGGCTCTGGAATGTTTTTGTCAGGCAGCATCTGAAGTAGGCAAAGAGGAATTCTT GGATCGCTTGATTCGCTCAGAGGATGGGGAGATCGTGTCTACCCCCAGGCTGCAGTAT TATGACAAGGTTTTACGACTACTAGATGTCATTGGTTTGCCTGAACTGGTTATTCAGT TGGCTACATCAGCCATAACTGAAGCAAGTGATGACTGGAAAAGTCAGGCTACTCTAAG GACATGTATTTTCAAACATCATTTGGATTTGGGTCACAATAGCCAAGCATATGAAGCC TTAACCCAAATTCCTGATTCCAGCAGGCAATTAGATTGTTTACGGCAGTTGGTGGTAG TTCTTTGTGAACGCTCACAGCTACAGGATCTTGTAGAGTTTCCCTATGTGAATCTGCA TAATGAGGTTGTGGGAATAATTGAGTCACGTGCTAGAGCTGTGGACCTTATGACTCAC AATTACTATGAACTTCTGTATGCCTTTCACATCTATCGCCACAATTACCGCAAGGCTG GCACAGTGATGTTTGAGTATGGAATGCGGCTTGGCAGAGAAGTTCGAACTCTCCGGGG ACTTGAGAAACAAGGCAACTGTTATCTGGCTGCTCTCAATTGTTTACGACTTATTCGT CCAGAATATGCGTGGATTGTGCAGCCAGTGTCTGGTGCAGTGTATGATCGCCCTGGAG CATCCCCTAAGAGGAATCATGATGGAGAATGCACAGCTGCCCCCACAAATCGACAAAT TGAAATCCTGGAACTGGAAGATCTGGAGAAAGAGTGTTCCTTGGCTCGCATCCGCCTC ACTTTGGCTCAGCATGATCCATCAGCGGTTGCAGTTGCTGGAAGTTCATCAGCAGAGG AAATGGTCACTCTCTTGGTTCAGGCGGGCCTCTTTGACACTGCCATATCACTCTGTCA GACTTTTAAGCTTCCCTTAACGCCAGTCTTTGAAGGGCTTGCCTTCAAATGCATCAAA TTGCAATTTGGAGGAGAGGCAGCACAAGCAGAAGCCTGGGCCTGGCTAGCAGCCAATC AGCTCTCATCTGTCATCACTACTAAGGAGTCTAGTGCTACAGATGAAGCATGGCGACT ATTATCCACTTACCTGGAGAGGTACAAAGTCCAGAATAACTTGTATCACCACTGTGTA ATCAACΛAGCTCTTGTCTCATGGAGTGCCTCTGCCTAATTGGCTTATAAACAGTTACA AGAAGGTTGATGCTGCTGAATTGCTTCGTTTATACTTAAACTATGACCTTTTAGAAGA AGCTGTGGATTTMTGTC-AGAATATGTGGATGCrGTATTGGGAAAAGGACATCAATAC TTCGGAATTGAGGTAGGC-ATATAC^AATGGTCCCCaATTGGGAGAGACAGTGCCAACA GTf^O-ACATCGCACTGTCCCAGAAAATACTTGACAAATTGGAGGACTACCAGCAAAA AGTTGATAAGGCAACACGGGATTTATTATATCGTCGGACCTTGTGATTTGGATT

ORF Start: ATG at 1 ORF Stop: TGA at 4162

SEQ ID NO: 178 1387 aa MW at l57181.6kD

NOVόla, MAAAGALERSFVELSGAERERPRHFREFTVCSIGTANAVAGAVKYSESAGGFYYVESG CG98061-01 Protein Sequence KLFSVTRNRFIH KTSGDTLELMEESLDINLLNNAIRLKFQNCSVLPGGVYVΞETQNR VIILMLTNQTVHRLLLPHPSRMYRSELWDSQMQSIFTDIGKVDFTDPCNYQLIPAVP s GISPNSTAΞTAWLSSDGEALFALPCAΞGGIFVLKLPPYDIPGiVSWEL QSSV QRL LTG MPTAIRGDQSPSDRPLSLAVHCVEHDAFIFALCQDHKLRM SYKEQMCLMVADM LEYVPVKKDLRLTAGTGHKLRLAYSPTMGLYLGIYMHAP RGQFCIFQLVSTESNRYS LDHISSLFTSQETLIDFALTSTDI ALWHDAENQTWKYINFEHNVAGQW PVFMQPL PEEEIVIRDDQDPREMYLQSLFTPGQFTNEALCKALQIFCRGTERNLDLSWSELKKEV TLAVENELQGSVTEYEFSQEEFR LQQEFWCKFYACCLQYQEALSHPLALHLNPHTNM VCLLKKGYLSFLIPSSLVDHLYLLPYENLLTEDETTISDDVDIARDVICLIKCLRLIE ESVTVDMSVIME SCYNLQSPEKAAEQILEDMITIDVENVMEDICSKLQEIRNPIHAI GLLIREMDYETEVEMEKGFNPAQPLNIRMNLTQLYGSNTAGYIVCRGVH IASTRFLI CRDLLILQQLLMRLGDAVIWGTGQLFQAQQDLLHRTAPLLLSYYLIKWGSECLATDVP LDTLESNLQHLSVLELTDSGALMANRFVSSPQTIVELFFQEVARKHIISHLFSQPKAP LSQTGLNWPEMITAITSYLLQLLWPSNPGCLFLECLMGNCQYVQLQDYIQLLHPWCQV VGSCRFMLGRCYLVTGEGQ ALECFCQAASEVGKEEFLDRLIRSEDGEIVSTPRLQY YD VLRLLDVIGLPELVIQLATSAITEASDD KSQATLRTCIFKHHLDLGHNSQAYEA LTQIPDSSRQLDCLRQLVWLCERSQLQDLVEFPYV LHNEWGIIESRARAVDLMTH NYYELLYAFHIYRHNYRKAGTVMFEYGMRLGREVRTLRGLEKQGNCYLAALNCLRLIR PEYAWIVQPVSGAVYDRPGASPKRNHDGECTAAPTNRQIEILELEDLEKECSLARIRL TLAQHDPSAVAVAGSSSAEEMVTLLVQAGLFDTAISLCQTFKLPLTPVFEGLAFKCIK LQFGGEAAQAEAWAWLAA QLSSVITTKESSATDEA RLLSTYLERYKVQNNLYHHCV INKLLSHGVPLPN LINSYKKVDAAELLRLYLNYDLLEEAVDLVSEYVDAVLGKGHQY FGIEVGIYKWSPIGRDSANSHNIALSQKILDKLEDYQQKVDKATRDLLYRRTL

SEQ ID NO: 179 5264 bp

NOV61b, GCTCTTCTGGATTCCTCGCTGCCCACCCTCATTCTCCCGGTGGAAGCCTCGCAACGAA CG98061-02 DNA Sequence GGGCCGGAGCCGCCTTTCTGCTCCCGGAATGCTTCACCTGTCCGCAGCTCCGCCCGCC CCACCCCCGGAAGTGACGGCGACCGCGCGGCCTGCCTTTGTTCCGTTGGGCGTCGCGG CGACGGCGGGAAGATGGCGGCGGCGGGAGCCCTGGAACGGAGCTTCGTGGAGCTAAGC

GGAGCTGAGCGCGAAAGGCCGAGGCACTTTCGGGAATTCACAGTCTGCAGCATTGGGA CTGCAAATGCCGTGGCTGGCGCCGTAAAATACAGTGAAAGCGCGGGAGGCTTTTACTA CGTGGAGAGTGGCAAGTTGTTCTCCGTAACCAGAAACAGGTTCATTCATTGGAAGACC TCTGGAGATACATTGGAGCTGATGGAGGAGTCACTGGACATAAATCTGTTGAATAATG CCATTCGCCTAAAATTCCAAAATTGCAGTGTTTTACCTGGAGGGGTTTATGTCTCTGA GACTCAGAATCGTGTGATAATCTTGATGTTAACCAATCAAACAGTGCACAGGTTACTT TTACCACACCCCTCCCGGATGTATAGGAGTGAGTTGGTAGTTGACAGTCAGATGCAGT CAATATTCACTGACATTGGAAAAGTTGATTTCACAGATCCTTGCAACTATCAGTTAAT TCCAGCAGTACCTGGAATATCTCCTAATTCCACCGCCTCTACAGCCTGGCTCAGCAGT GATGGGGAGGCCCTGTTTGCCTTACCATGTGCTTCTGGGGGAATCTTTGTTCTTAAGC TACCTCCTTATGACATACCTGGTATGGTGTCAGTCGTGGAACTGAAACAGAGTTCAGT AATGCAACGATTGCTTACAGGCTGGATGCCAACAGCTATCAGGGGTGACCAGTCGCCT TCAGATCGTCCCCTCAGTCTTGCTGTTCATTGTGTGGAGCATGATGCCTTCATCTTTG CTTTGTGTCAGGATCATAAACTACGAATGTGGTCTTACAAGGAGCAAATGTGCCTAAT GGTAGCTGACATGCTGGAGTATGTCCCTGTGAAGAAAGACCTTCGGCTTACTGCTGGA ACTGGACACAAATTACGGCTTGCTTATTCCCCCACCATGGGACTCTACCTGGGGATAT ACATGCATGCACCAAAACGAGGACAGTTCTGCATTTTCCAGTTGGTGAGCACTGAGAG TAATCGCTATAGTCTCGATCATATTTCTTCACTGTTCACTTCTCAGGAGACACTGATT GACTTTGCCTTAACTTCCACGGATATCTGGGCCCTGTGGCATGATGCTGAGAACCAAA CAGTAGTGAAATACATCAACTTTGAACATAATGTTGCAGGTCAGTGGAATCCAGTTTT TATGCAGCCTCTGCCAGAGGAAGAGATTGTCATCAGAGATGATCAAGACCCCAGAGAG ATGTATCTGCAAAGTCTTTTTACACCAGGACAATTCACAAATGAAGCTTTATGTAAGG CTTTACAGATTTTCTGCCGAGGAACTGAGAGGAATTTGGATCTTTCCTGGAGTGAACT GAAGAAAGAAGTTACTTTAGCTGTTGAAAATGAGCTTCAAGGAAGTGTAACAGAGTAT GAATTCTCCCAGGAGGAGTTTCGAAATTTACAACAAGAATTCTGGTGCAAGTTCTATG CCTGTTGTCTTCAGTATCAAGAAGCCCTCTCTCACCCTCTTGCCCTACATTTGAATCC ACACACAAACATGGTGTGCCTGCTGAAAAAAGGGTACCTGTCTTTCCTTATTCCCTCA TCCTTAGTGGATCATTTGTATCTCCTGCCTTATGAGAACCTTTTGACAGAAGATGAGA CAACCATATCTGATGATGTGGATATCGCTCGGGATGTCATATGTCTTATAAAATGCCT CCGGCTGATTGAAGAGTCAGTAACTGTGGATATGTCAGTTATAATGGAAATGAGTTGT TATAACCTACAGTCTCCGGAAAAGGCTGCAGAGCAGATTCTGGAAGATATGATCACTA TTGATGTAGAAAATGTGATGGAGGATATTTGTAGTAAACTGCAAGAGATTAGGAACCC AATCCATGCAATTGGACTACTTATACGGGAAATGGATTATGAAACAGAAGTGGAAATG GAAAAGGGATTCAATCCAGCTCAGCCTTTGAATATTCGAATGAATCTTACCCAGCTCT ATGGTAGTAACAC-AGCAGGGTATATTGTGTGCAGAGGGGTGCATAAAATCGCCAGTAC TCGTTTCCTGATCTGCAGAGATCTTTTGATCTTACAGCAGCTGTTAATGAGGCTTGGA GATGCTGTGATTTGGGGAACTGGTCAGCTCTTTO.AGCTCA.GαΛGACCTACTACATC GAACAGCTCCCCTACTCTTATCTTATTACCTCATTAAATGGGGAAGTGAGTGCTTGGC AACTGATGTTCCACTTGACACACTGGAGTCTAATCTCCAACACTTATCAGTACTGGAA TTAACAGACTCTGGTGCTTTAATGGCAAATAGGTTTGTATCTAGTCCTCAGACTATTG TGGAGTTATTCTTCCAAGAAGTTGCAAGAAAACACATTATATCTCACCTCTTCTCTCA GCCAAAGGCACCTCTGAGCCAAACTGGATTGAATTGGCCTGAAATGATTACTGCAATT ACCAGTTATTTATTGCAGCTTTTATGGCCTAGCAATCCTGGTTGTCTCTTTCTAGAAT GTTTGATGGGAAATTGCCAATATGTACAATTGCAGGATTATATTCAACTGCTACATCC CTGGTGTCAAGTCAATGTTGGTTCCTGTCGATTTATGCTGGGAAGGTGTTACCTAGTT ACAGGAGAAGGACAGAAGGCTCTGGAATGTTTTTGTCAGGCAGCATCTGAAGTAGGCA AAGAGGAATTCTTGGATCGCTTGATTCGCTCAGAGGATGGGGAGATCGTGTCTACCCC CAGGCTGCAGTATTATGACAAGGTTTTACGACTACTAGATGTCATTGGTTTGCCTGAA CTGGTTATTCAGTTGGCTACATCAGCCATAACTGAAGCAAGTGATGACTGGAAAAGTC AGGCTACTCTAAGGACATGTATTTTCAAACATCATTTGGATTTGGGTCACAATAGCCA AGCATATGAAGCCTTAACCCAAATTCCTGATTCCAGCAGGCAATTAGATTGTTTACGG CAGTTGGTGGTAGTTCTTTGTGAACGCTCACAGCTACAGGATCTTGTAGAGTTTCCCT ATGTGAATCTGCATAATGAGGTTGTGGGAATAATTGAGTCACGTGCTAGAGCTGTGGA CCTTATGACTCACAATTACTATGAACTTCTGTATGCCTTTCACATCTATCGCCACAAT TACCGCAAGGCTGGCACAGTGATGTTTGAGTATGGAATGCGGCTTGGCAGAGAAGTTC GAACTCTCCGGGGACTTGAGAAACAAGGCAACTGTTATCTGGCTGCTCTCAATTGTTT ACGACTTATTCGTCCAGAATATGCGTGGATTGTGCAGCCAGTGTCTGGTGCAGTGTAT GATCGCCCTGGAGCATCCCCTAAGAGGAATCATGATGGAGAATGCACAGCTGCCCCCA CAAATCGACAAATTGAAATCCTGGAACTGGAAGATCTGGAGAAAGAGTGTTCCTTGGC TCGCATCCGCCTCACTTTGGCTCAGCATGATCCATCAGCGGTTGCAGTTGCTGGAAGT TCATCAGCAGAGGAAATGGTCACTCTCTTGGTTCAGGCGGGCCTCTTTGACACTGCCA TATCACTCTGTCAGACTTTTAAGCTTCCCTTAACGCCAGTCTTTGAAGGGCTTGCCTT CAAATGCATCAAATTGCAATTTGGAGGAGAGGCAGCACAAGCAGAAGCCTGGGCCTGG CTAGCAGCCAATCAGCTCTCATCTGTCATCACTACTAAGGAGTCTAGTGCTACAGATG AAGCATGGCGACTATTATCCACTTACCTGGAGAGGTACAAAGTCCAGAATAACTTGTA TCACCACTGTGTAATCAACAAGCTCTTGTCTCATGGAGTGCCTCTGCCTAATTGGCTT ATAAACAGTTACAAGAAGGTTGATGCTGCTGAATTGCTTCGTTTATACTTAAACTATG ACCTTTTAGAAGAAGCTGTGGATTTGGTGTCAGAATATGTGGATGCTGTATTGGGAAA AGGACATCAATACTTCGGAATTGAGTTTCCACTGTCCGCAACAGCCCCAATGGTGTGG CTTCCATACTCCTCTATTGATCAGCTTCTCCAAGCTCTGGGAGAGAACAGTGCCAACA GTCACAACATCGCACTGTCCCAGAAAATACTTGACAAATTGGAGGACTACCAGCAAAA AGTTGATAAGGCAACACGGGATTTATTATATCGTCGGACCTTGTGATTTGGATTGTCA

CCTAGCCTTTGTAACCGCTTGGTGCCTCTTAGGACTTAAGACTACCCTACAGGAACCC TGTACTCAAGGCCGATTTTTGTAACTGTAAATGATGTGTACAACATTCAAGTCTGCAT TCTGCACAAGATAGGAGGGCGGAAGAGTCAGAGGACCCTGTGCTTGCTGGTGGTGCTA ACACAATTTCTGGTGTTCAACCTTGGTCTCAAATAGCTGCTTTTGTATATGATTCACG AGCTTTTTTAGAGTTTATATTTTTTTAAACTACCGAAGACATTCATTATCTGCAAATT AAGACTCACCTTCACTTTCCAAAATAGCTGAGGGTTGTTGGCTTGTTGTAGCTGACCA CCAAAAGCAGTCACTGCAAATCTTTTAATTCTTCCCTATCACCTTTTGTATTTTAATG CAATTATTTTGGTCCAGAACTGACCTGTATTTTCTGTATTGTACACAAAAGCTAATAA TTTTGTGTACTTTTTATTTATTTTGGAGGTTTTATATGATCTTCAATTGAGTATTAAA TAATTTGCCTAGATTAAGCCTAAAATGATGACCAGCTAATTAAAGAAGATATTTTGAA TCTGGTTCTGAGCTAAAGTTGAGTAAATTCTTAGCTAAGAAAAAATTGGAAATCCATC ATCTATATTAGCAACAGATTCTCAGAGTAAATTGTTAACTTCTATGATTTATGATAAT CAAGCTGGACTTGATCATACAAGTTAGTCTCATAATGTATTGGACCAAAATGTAAACT TCATTGGTCAGATTTAGAAGCATTCATGCTCACAAGTTTTGGGAAAGTGAAAAATAAT AAAATCATCTTGGATTTTATTCTGTATATTAAAATTTATCTTTT

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 6 IB.

Table 61B. Comparison of NOVόla against NOVόlb.

NOVόla Residues/ j Identities/

Protein Sequence

Match Residues Similarities for the Matched Region

NOVόlb 1..1387 1308/1402 (93%) 1..1402 1312/1402 (93%)

Further analysis of the NOVόla protein yielded the following properties shown in Table 61 C.

Table 61C. Protein Sequence Properties NOVόla

PSort analysis: 0.4500 probability located in cytoplasm; 0.3000 probability located in microbody (peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP analysis: No Known Signal Sequence Predicted A search of the NOVόla protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 6 ID.

In a BLAST search of public sequence datbases, the NOVόla protein was found to have homology to the proteins shown in the BLASTP data in Table 6 IE.

PFam analysis predicts that the NOVόla protein contains the domains shown in the Table 6 IF.

Table 61F. Domain Analysis of NOVόla

Identities/

Pfam Domain NOVόla Match Region Similarities Expect Value for the Matched Region

No Significant Matches Found

Example 62.

The NOV62 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 62A. Table 62A. NOV62 Sequence Analysis

SEQ ID NO: 181 5544 bp

NOV62a, GCGGGACTCAAGAGTAGCCTTCCTCGAGGACCTGCCTTTCCCATTTGCTGCCTGAAGT -01 DNA Sequence TAATGTTTCTTGCTGGCCAAATCAGGGACATGCCGGCATTAGCGGGATGAGTGGGTGT TCCGGCAGGGATGTGGTCATTGACGGCCAGTGAGGGCGAGAGTACCACGGCCCACTTC

TTCCTTGGAGCTGGAGATGAGGGGCTGGGCACCCGTGGAATAGGCATGAGGCCAGAAG AGAGTGACAGCGAGCTCCTTGAGGATGAGGAGGATGAAGTGCCTCCTGAACCTCAGAT CATTGTTGGCATCTGTGCCATGACCAAGAAATCCAAGTCCAAGCCAATGACTCAAATC CTAGAGCGACTCTGCAGATTTGACTACCTGACTGTTGTCATTCTGGGAGAAGATGTAA TCCTTAATGAACCTGTGGAAAACTGGCCATCCTGCCACTGCCTCATCTCTTTCCACTC CAAAGGCTTTCCTCTGGACAAAGCTGTTGCTTACTCCAAGCTTCGAAACCCCTTTCTT ATCAATGATCTGGCCATGCAGTATTACATCCAAGATAGGAGGGAGGTGTACCGGATCC TGCAGGAAGAGGGTATTGATCTGCCTCGATATGCTGTGCTCAACCGTGATCCTGCCCG GCCTGAGGAATGCAACCTGATAGAAGGTGAAGACCAAGTAGAGGTCAATGGAGCTGTC TTTCCCAAGCCCTTTGTGGAGAAGCCAGTGAGTGCAGAAGACCACAATGTTTACATCT ACTACCCCAGCTCAGCTGGAGGAGGAAGCCAGCGTCTCTTTCGTAAGATTGGCAGCCG AAGCAGTGTTTACTCTCCTGAGAGCAGCGTCCGAAAGACGGGGTCGTACATCTATGAG GAGTTTATGCCAACAGATGGCACAGATGTCAAGGTGTATACAGTGGGGCCAGATTATG CCCATGCTGAAGCTAGAAAATCTCCAGCTTTGGATGGGAAGGTTGAACGAGACAGTGA GGGGAAAGAGATTCGATATCCAGTCATGCTGACTGCCATGGAAAAGCTGGTGGCCAGG AAAGTCTGCGTAGCTTTCAAGCAAACAGTTTGTGGATTTGACCTTCTTCGTGCCAATG GTCATTCCTTTGTGTGTGATGTCAATGGCTTTAGTTTTGTCAAGAACTCGATGAAATA CTACGATGACTGTGCCAAGATTCTGGGGAACACCATAATGCGGGAGCTTGCCCCACAG TTCCAGATTCCATGGTCCATCCCCACGGAGGCTGAGGACATTCCCATTGTTCCCACCA CATCTGGCACTATGATGGAACTTCGTTGTGTCATTGCAATTATTCGTCATGGGGATCG TACTCCCAAGCAGAAGATGAAGATGGAAGTGAAACACCCAAGGTTTTTTGCTCTGTTT GAAAAACATGGTGGCTACAAGACAGGGAAATTAAAACTCAAGCGACCTGAGCAGCTCC AGGAGGTGCTGGATATCACAAGGCTGTTGTTGGCTGAACTGGAGAAAGAACCAGGTGG TGAGATCGAGGAGAAGACTGGAAAACTAGAGCAGCTGAAGTCTGTACTGGAGATGTAT GGTCACTTCTCAGGTATAAACCGGAAGGTACAATTGACTTACTACCCTCATGGAGTAA AAGCTTCTAATGAGGGGCAAGATCCACAGAGGGAAACTCTGGCCCCATCTCTGTTGCT GGTACTGAAGTGGGGTGGAGAACTGACTCCTGCTGGCCGTGTTCAGGCTGAGGAGCTG GGGCGAGCTTTTCGCTGCATGTACCCTGGAGGACAGGGTGACTATGCTGGCTTCCCTG GTTGTGGGCTGCTTCGTCTCCATAGCACTTTCCGCCACGATCTCAAGATCTATGCCTC TGATGAGGGTCGTGTTCAGATGACTGCTGCTGCCTTCGCCAAGGGCCTTCTGGCTCTA GAAGGGGAGCTGACACCCATTTTGGTGCAAATGGTGAAGAGTGCCAACATGAATGGGC TACTGGACAGCGATGGGGATTCCTTGAGCAGCTGCCAGCACCGGGTGAAGGCTCGGCT GCACCATATTCTACAGCAGGATGCACCCTTTGGCCCTGAGGACTACGATCAGCTGGCT CCCACCAGAAGTACTTCCCTGCTCAACTCCATGACTATCATCCAGAATCCTGTGAAGG TCTGTGATCAGGTATTTGCCCTGATCGAAAACCTCACCCACCAGATCCGGGAACGAAT GCAGGACCCCAGGTCTGTAGACCTGCAGCTCTACCACAGTGAGACACTAGAGCTAATG CTACAGCGTTGGAGCAAGCTGGAGCGTGACTTTCGACAGAAGAGTGGGCGCTATGATA TCAGTAAGATCCCTGACATCTATGACTGTGTCAAGTATGATGTGCAGCACAATGGGAG TCTGGGACTTCAAGGCACAGCAGAGTTGCTCCGTCTCTCTAAGGCACTGGCTGATGTG GTCATTCCCCAGGAGTACGGGATCAGTCGGGAGGAGAAACTGGAAATTGCTGTGGGCT TCTGTCTTCCACTGTTGCGGAAGATACTACTTGACCTGCAGAGAACCCACGAGGATGA GTCTGTCAACAAGCTGCATCCCCTGTACTCCCGAGGCGTGCTCTCCCCAGGTCGCCAC GTTCGAACGCGTCTCTATTTCACCAGTGAGAGCCATGTCCACTCCCTGCTCAGTGTCT TCCGTTATGGAGGACTTCTTGATGAGACCCAGGATGCACAATGGCAGCGAGCTTTGGA TTATCTTAGTGCCATCTCAGAGCTTAACTACATGACCCAGATTGTCATCATGCTTTAT GAGGACAACACACAGGATCCCTTATCAGAGGAACGGTTCCATGTGGAGCTACACTTCA GCCCCGGAGTGAAAGGTGTTGAGGAAGAAGGCAGTGCCCCGGCTGGCTGTGGATTCCG TCCAGCCTCTTCTGAGAATGAGGAGATGAAAACCAACCAAGGCAGTATGGAGAACCTG TGTCCAGGAAAGGCATCAGATGAACCAGACCGGGCATTGCAGACTTCACCCCAGCCTC CTGAGGGCCCTGGCCTTCCGAGGAGATCACCCCTCATTCGTAACCGAAAAGCTGGTTC CATGGAGGTACTTTCTGAGACTTCATCCTCGAGGCCTGGTGGCTACCGGCTCTTTTCA TCTTCACGGCCACCCACAGAAATGAAGCAGAGTGGCCTAGGGTTTGAAGGGTGTTCCA TGGTGCCTACCATCTACCCTCTGGAAACACTGCATAATGCCCTTTCCCTACGTCAAGT GAGTGAATTCTTGAGTAGAGTCTGCCAGCGCCACACTGATGCCCAGGCACAGGCATCT GCAGCCCTCTTTGATTCCATGCACAGCAGCCAGGCCTCAGATAACCCATTTTCTCCAC CACGTACTCTTCATTCACCTCCCCTGCAACTCCAGCAGCGCTCTGAGAAGCCCCCTTG GTTAGAGACAAGGTTTTGCCATGTTGGCCAGGCTGGTTTAGAGCTCCTGACCTCAAGT GATCTGCCTGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCACCC AGCCAGACAGCAGTGGCCCTTCTAGCACTGTGTCCAGTGCTGGTCCTTCTTCCCCTAC TACAGTAGATGGTAACTCCCAATTTGGCTTCAGTGATCAACCCTCCCTAAATTCACAC GTGGCTGAAGAACATCAAGGCCTTGGGCTGCTCCAGGAGACCCCTGGGAGTGGAGCAC AAGAGCTCTCCATAGAAGGGGAGCAAGAGCTTTTTGAACCAAATCAGTCCCCACAGGT GCC1ACCTATGGAAACC-AGCCΛGCC-ATACGAGGAGGTCAGCCAGCCATGTCAGGAGGTC CCTGAC-ATCAGCCAGCClATGCCAGGACATTTC^GAGGCGCT GCCAGCCATGTCAGA

Further analysis of the NOV62a protein yielded the following properties shown in Table 62B. Table 62B. Protein Sequence Properties NOV62a

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV62a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 62C.

In a BLAST search of public sequence datbases, the NOV62a protein was found to have homology to the proteins shown in the BLASTP data in Table 62D.

PFam analysis predicts that the NOV62a protein contains the domains shown in the Table 62E.

Example 63.

The NOV63 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 63 A.

Further analysis of the NOV63a protein yielded the following properties shown in Table 63B.

Table 63B. Protein Sequence Properties NOV63a

! PSort analysis: 0.6400 probability located in microbody (peroxisome); 0.4500 probability located in cytoplasm; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV63a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 63 C.

In a BLAST search of public sequence datbases, the NOV63a protein was found to have homology to the proteins shown in the BLASTP data in Table 63D.

PFam analysis predicts that the NOV63a protein contains the domains shown in the Table 63E.

Example 64.

The NOV64 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 64A. Table 64A. NOV64 Sequence Analysis

SEQ ID NO: 185 271 1 bp

NOV64a, CCTAGGCAACCCCGCTAAACAAGATGGCGACCTCCGAGAGGGCTCTCCTGAGGACCAG CG98164-01 DNA Sequence AGCTGCCTCTCTCCTGAGAGGCTTGGGCAGATCCCGAACTGGAGCCCGATCGTTACAG TTTCGCGCAGAAAAAGAGCGTCAGCCTTGCTGGTCTTTTCCCATGGGGCAGAAGACGA AAGGCAGCTCTAACATAGCCTCCTCCTACCTGCTCCAGCAGCTCATGCACCGCTATCA GGAGCTGGACTCGGACGGAGATGAGGACCACGGCGAGGGCGAGGCGGGATCCGAGGAG TCCTCAGAGTCCGAAATGCTGAATTTGGAGGAGGAATTTGATGGGGTCCTGAGAGAGG AGGCTGTGGCCAAAGCACTCCATCACTTGGGGCGCTCAGGCTCTGGGACTGAGCAAGT CTACCTCAATCTAACTTTATCAGGTTGTAATTTAATTGATGTTAGCATTCTCTGTGGA TATGTTCATCTACAGAAGTTGGATCTTTCAGCGAATAAAATTGAAGATTTATCTTGTG TGAGTTGTATGCCTTATCTCCTAGAACTTAATGCTTCTCAAAATAATTTGACTACGTT CTTCAATTTCAAGCCACCCAAAAACCTCAAGAAGGCGGATTTTTCCCACAACCAAATT TCTGAAATTTGTGATTTGTCAGCGTATCATGCTCTCACTAAACTAATTTTGGATGGCA ATGAGATAGAAGAAATCAGTGGACTAGAGATGTGCAACAACCTAATTCACCTTAGTTT GGCCAACAATAAGATCACGACAATTAATGGCTTAAACAAGTTACCAATCAAAATACTT TGTCTGAGCAATAACCAGATTGAGATGATCACAGGTTTGGAGGATCTGAAAGCCCTGC AGAACCTGGATCTGTCCCACAATCAGATAAGCAGCCTCCAAGGCTTAGAGAATCATGA CCTCCTGGAAGTGATCAACCTGGAGGATAATAAGATTGCTGAGCTGAGAGAAATAGAA TACATTAAAAATTTACCCATCCTTCGAGTTCTCAATCTTCTAGAAAATCCAATTCAGG AAAAGTCTGAATATTGGTTCTTCGTAATTTTTATGCTTCTGCGATTAACAGAATTAGA TCAGAAGAAGATTAAAGTGGAAGAAAAGGTTTCAGCAGTGAATAAATATGATCCTCCC CCTGAAGTGGTTGCAGCTCAAGACCACCTGACCCATGTTGTCAACAGCGTGATGCAGC CGCAGAGGATCTTTGACAGCACTCTTCCCAGCCTGGATGCCCCTTATCCCATGCTGAT ACTAGCTGGTCCTGAAGCTTGTGGGAAACGAGAGCTTGCCCATCGCCTCTGCAGACAG TTTAGCACTTACTTCAGATATGGGGCCTGTCATACCACAAGACCACCTTACTTTGGAG AAGGGGATCGAGTTGATTATCATTTTATCTCTCAAGACGTTTTTGATGAAATGGTGAA CATGGGGAAATTCATTCTAACATTTAGTTATGGTAATCACAAGTATGGATTAAATAGG GACACCGTAGAAGGTATCGCAAGAGATGGTTTGGCAAGCTGTATTCATATGGAAATAG MGGTGTMGAAGTTTGAAATATTCCTATTTTGAGCCTCGTTATATCCTGGTGGTGCC CATGAACAAGGAAAAATATGAGGGATATTTGCGGAGAAAAGGATTATTCAGTCGTGCA GAAATTGAATTTGCTGTCTCCAGAGTGGACCTTTATATTAAAATTAATCAGAATTTTC CGGGATATTTTGATGAGGTAATCAATGCAGATGATCTGGATGTTGCCTACCAAAAACT GAGTCAGCTCATTAGAGAATACCTTGGATTGACTGAGGAACCTGCCAAGAGTTTGGCT ACAACTGCAGATGTTAAGACATCCCACCTGAAACCTGAAGCGCATCCTACAAAGTATA TTTCTTCGAATATGGGTGATTTCCTGCATTCTACAGACAGAAACTACCTCATTAAATT TTGGGCCAAACTTTCAGCCAAAAAAACACCAGCGGAAAGAGATTCTATACACAGACAG CATGAGGCAGCCCGGCAAGCTCTAATGGGAAGGATACGCCCTGATCACACACTCCTAT TTCAAAGGGGTCCAGTACCAGCACCTCTCACCAGTGGTCTACACTATTATACAACTTT AGAAGAACTCTGGAAAAGTTTTGATCTTTGTGAAGACTATTTTAAACCTCCATTTGGA CCATATCCTGAAAAGAGTGGGAAGGATTCCTTGGTTTCCATGAAATGTTCATTGTTTC GGTTCTGTCCGTGGTCAAAAGAATTGCCTTTCCAGCCTCCGGAGGGGAGCATTTCTTC ACACCTAGGATCAGGAGCCAGTGACAGTGAGACCGAAGAGACCCGGAAAGCACTACCT ATACAATCATTTTCACATGAAAAAGAGTCTCACCAACACAGACAACACTCGGTCCCAG TCATCAGTCGCCCAGGTTCCAACGTCAAACCCACCCTCCCTCCAATCCCTCAGGGCCG CAGGTAGACTAGCACTTGATGTCTGATCCTAACATGGAAAACCTGCTCTGCTGATGTC GAATTCCTTGCCTTACCTGGCCATGGGTCCAGCTGTTTCTCACTCAACCCATTACCCA CGGAAGAATGTTCTACCTGCCTTAATTCTATCAGCCAGTTTCTCTTGTGATTCTTTGG CTGGTGTCTTTTAGTTTTTTAATTAAAAAATTGTTTCTTAAAA

ORF Start: ATG at 24 ORF Stop: TAG at 2499

SEQ ID NO: 186 825 aa MW at 93626.3kD

NOV64a, MATSERALLRTRAASLLRGLGRSRTGARSLQFRAEKERQPCWSFPMGQKTKGSSNIAS CG98164-01 Protein Sequence SYLLQQLMHRYQELDSDGDEDHGEGEAGSEESSESEMLNLEEEFDGVLREEAVAKALH HLGRSGSGTEQVYL LTLSGCNLIDVSILCGYVHLQKLDLSANKIEDLSCVSCMPYLL El-NASQlSiWLTTFFNFKPPKNLKKADFSH QISEICDLSAYHALTKLILDGNEIEEISG LEMQJNLIHLSLANNKITTINGLNKLPIKILCLSN QIEMITGLEDLKALQNLDLSHN QISSLQGLENHDLLEVINLEDNKIAELREIEYIKNLPILRVLNLLENPIQEKSEY FF VIFMLLRLTELDQKKIKVEEKVSAVNKYDPPPEWAAQDHLTHWNSVMQPQRIFDST LPSLDAPYPMLILAGPEACGKRELAHRLCRQFSTYFRYGACHTTRPPYFGEGDRVDYH FISQDVFDEMVN GKFILTFSYGNHKYGLNRDTVEGIARDGLASCIHMEIEGVRSLKY SYFEPRYILWPMNKEKYEGYLRRKGLFSRAEIEFAVSRVDLYIKINQNFPGYFDEVI NADDLDVAYQKLSQLIREYLGLTEEPAKSLATTADVKTSHLKPEAHPTKYISSNMGDF LHSTDRNYLIKF AKLSAKKTPAERDSIHRQHEAARQALMGRIRPDHTLLFQRGPVPA PLTSGLHYYTTLEELWKSFDLCEDYFKPPFGPYPEKSGKDSLVSMKCSLFRFCPWSKE LPFQPPEGSISSHLGSGASDSETEETRKALPIQSFΞHEKESHQHRQHSVPVISRPGSN VKPTLPPIPQGRR SEQ ID NO: 187 2550 bp

NOV64b, AAGATGGCGACCTCCGAGAGGGCTCTCCTGAGGACCAGAGCTGCCTCTCTCCTGAGAG CG98164-02 DNA Sequence GCTTGGGCAGATCCCGAACTGGAGCCCGATCGTTACAGTTTCGCGCAGAAAAAGAGCG TCAGCCTTGCTGGTCTTTTCCCATGGGGCAGAAGACGAAAGGCAGCTCTAACATAGCC TCCTCCTACCTGCTCCAGCAGCTCATGCACCGCTATCAGGAGCTGGACTCGGACGGAG ATGAGGACCAGGGCGAGGGCGAGGCGGGATCCGAGGAGTCCTCAGAGTCCGAAATGCT GAATTTGGAGGAGGAATTTGATGGGGTCCTGAGAGAGGAGGCTGTGGCCAAAGCACTC CATCACTTGGGGCGCTCAGGCTCTGGGACTGAGCAAGTCTACCTCAATCTAACTTTAT CAGGTTGTAATTTAATTGATGTTAGCATTCTCTGTGGATATGTTCATCTACAGAAGTT GGATCTTTCAGCGAATAAAATTGAAGATTTATCTTGTGTGAGTTGTATGCCTTATCTC CTAGAACTTAATGCTTCTCAAAATAATTTGACTACGTTCTTCAATTTCAAGCCACCCA AAAACCTCAAGAAGGCGGATTTTTCCCACAACCAAATTTCTGAAATTTGTGATTTGTC AGCGTATCATGCTCTCACTAAACTAATTTTGGATGGCAATGAGATAGAAGAAATCAGT GGACTAGAGATGTGCAACAACCTAATTCACCTTAGTTTGGCCAACAATAAGATCACGA CAATTAATGGCTTAAACAAGTTACCAATCAAAATACTTTGTCTGAGCAATAACCAGAT TGAGATGATCACAGGTTTGGAGGATCTGAAAGCCCTGCAGAACCTGGATCTGTCCCAC AATCAGATAAGCAGCCTCCAAGGCTTAGAGAATCATGACCTCCTGGAAGTGATCAACC TGGAGGATAATAAGATTGCTGAGCTGAGAGAAATAGAATACATTAAAAATTTACCCAT CCTTCGAGTTCTCAATCTTCTAGAAAATCCAATTCAGGAAAAGTCTGAATATTGGTTC TTCGTAATTTTTATGCTTCTGCGATTAACAGAATTAGATCAGAAGAAGATTAAAGTGG AAGAAAAGGTTTCAGCAGTGAATAAATATGATCCTCCCCCTGAAGTGGTTGCAGCTCA AGACCACCTGACCCATGTTGTCAACAGCGTGATGCAGCCGCAGAGGATCTTTGACAGC ACTCTTCCCAGCCTGGATGCTCCTTATCCCATGCTGATACTAGCTGGTCCTGAAGCTT GTGGGAAACGAGAGCTTGCCCATCGCCTCTGCAGACAGTTTAGCACTTACTTCAGATA TGGGGCCTGTCATACCACAAGACCACCTTACTTTGGAGAAGGGGATCGAGTTGATTAT CATTTTATCTCTCAAGACGTTTTTGATGAAATGGTGAACATGGGGAAATTCATTCTAA CATTTAGTTATGGTAATCACAAGTATGGATTAAATAGGGACACCGTAGAAGGTATCGC AAGAGATGGTTTGGCAAGCTGTATTCATATGGAAATAGAAGGTGTAAGAAGTTTGAAA TATTCCTATTTTGAGCCTCGTTATATCCTGGTGGTGCCCATGAACAAGGAAAAATATG AGGGATATTTGCGGAGAAAAGGATTATTCAGTCGTGCAGAAATTGAATTTGCTGTCTC CAGAGTGGACCTTTATATTAAAATTAATCAGAATTTTCCGGGATATTTTGATGAGGTA ATCAATGCAGATGATCTGGATGTTGCCTACCAAAAACTGAGTCAGCTCATTAGAGAAT ACCTTGGATTGACTGAGGAACCTGCCAAGAGTTTGGCTACAACTGCAGATGTTAAGAC ATCCCACCTGAAACCTGAAGCGCATCCTACAAAGTATATTTCTTCGAATATGGGTGAT TTCCTGCATTCTACAGACATAAACTACCTCATTAAATTTTGGGCCAAACTTTCAGCCA AAAAAACACCAGCGGAAAGAGATTCTATACACAGACAGCACGAGGCAGCCCGGCAAGC TCTAATGGGAAGGATACGCCCTGATCACACACTCCTATTTCAAAGGGGTCCAGTACCA GCACCTCTCACCAGTGGTCTACACTATTATACAACTTTAGAAGAACTCTGGAAAAGTT TTGATCTTTGTGAAGACTATTTTAAACCTCCATTTGGACCATATCCTGAAAAGAGTGG GAAGGATTCCTTGGTTTCCATGAAATGTTCATTGTTTCGGTTCTGTCCGTGGTCAAAA GAATTGCCTTTCCAGCCTCCGGAGGGGAGCATTTCTTCACACCTAGGATCAGGAGCCA GTGACAGTGAGACCGAAGAGACCCGGAAAGCACTACCTATACAATCATTTTCACATGA AAAAGAGTCTCACCAACACAGACAACACTCGGTCCCAGTCATCAGTCGCCCAGGTTCC AACGTCAAACCCACCCTCCCTCCAATCCCTCGGGGCCGCAGGTAGACTAGCACTTGAT GTCTGATCCTAACATGGAAAACCTGCTCTGCTGATGTCGAATTCCTTGCCTTACCT

ORF Start: ATG at 4 ORF Stop: TAG at 2479

SEQ ID NO: 188 825 aa MW at 93602.3kD

NOV64b, MATSERALLRTRAASLLRGLGRSRTGARSLQFRAEKERQPC SFPMGQKTKGSSNIAS CG98164-02 Protein Sequence SYLLQQLMHRYQELDSDGDEDQGEGEAGSEESSESEMLNLEEEFDGVLREEAVAKALH HLGRSGSGTEQVYLNLTLSGCNLIDVSILCGYVHLQKLDLSANKIEDLSCVSCMPYLL ELNASQNNLTTFFNFKPPKNLKKADFSHNQISEICDLSAYHALTKLILDGNEIEEISG LEMCN LIHLSLANNKITTINGLNKLPIKILCLSNNQIEMITGLEDLKALQNLDLSHN QISSLQGLENHDLLEVINLEDNKIAELREIEYIKNLPILRVLNLLENPIQEKSEYWFF VIFMLLRLTELDQKKI VEEKVSAVNKYDPPPEWAAQDHLTHWNSVMQPQRIFDST LPSLDAPYPMLILAGPEACGKRELAHRLCRQFSTYFRYGACHTTRPPYFGEGDRVDYH FISQDVFDEtvrVNMGKFILTFSYGNHKYGLNRDTVEGIARDGLASCIHMEIEGVRSLKY SYFEPRYILWPMNKEKYEGYLRRKGLFSRAEIEFAVSRVDLYIKINQNFPGYFDEVI NADDLDVAYQKLSQLIREYLGLTEEPAKSLATTADVKTSHLKPEAHPTKYISSNMGDF LHSTDINYLIKFWAKLSAKKTPAERDSIHRQHEAARQAL GRIRPDHTLLFQRGPVPA PLTSGLHYYTTLEEL KSFDLCEDYFKPPFGPYPEKSGKDSLVSMKCSLFRFCPWSKE LPFQPPEGSISSHLGSGASDSETEETRKALPIQSFSHEKESHQHRQHSVPVISRPGSN VKPTLPPIPRGRR

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 64B.

Further analysis of the NOV64a protein yielded the following properties shown in Table 64C.

Table 64C. Protein Sequence Properties NOV64a

PSort analysis: 0.9074 probability located in mitochondrial matrix space; 0.6000 probability located in mitochondrial inner membrane; 0.6000 probability located in mitochondrial intermembrane space; 0.6000 probability located in mitochondrial outer membrane

, SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV64a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 64D.

In a BLAST search of public sequence datbases, the NOV64a protein was found to have homology to the proteins shown in the BLASTP data in Table 64E.

PFam analysis predicts that the NOV64a protein contains the domains shown in the Table 64F.

Example 65.

The NOV65 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 65 A.

Further analysis of the NOV65a protein yielded the following properties shown in Table 65B.

Table 65B. Protein Sequence Properties NOV65a

SignalP analysis: Cleavage site between residues 65 and 66

A search of the NOV65a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 65 C.

In a BLAST search of public sequence datbases, the NOV65a protein was found to have homology to the proteins shown in the BLASTP data in Table 65D.

PFam analysis predicts that the NOV65a protein contains the domains shown in the Table 65E.

Table 65E. Domain Analysis of NOV65a

Identities/

Pfam Domain NOV65a Match Region Similarities Expect Value for the Matched Reeion

Example 66.

The NO V66 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 66A.

Further analysis of the NOVόόa protein yielded the following properties shown in Table 66B.

Table 66B. Protein Sequence Properties NOVόόa

PSort analysis: 0.4500 probability located in cytoplasm; 0.3719 probability located in microbody

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOVόόa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 66C.

In a BLAST search of public sequence datbases, the NOVόόa protein was found to have homology to the proteins shown in the BLASTP data in Table 66D.

PFam analysis predicts that the NOVόόa protein contains the domains shown in the Table 66E.

Example 67.

The NOV67 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 67A.

Further analysis of the NOV67a protein yielded the following properties shown in Table 67B.

Table 67B. Protein Sequence Properties NOV67a

PSort analysis: 0.4741 probability located in microbody (peroxisome); 0.4500 probability located in cytoplasm; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP analysis: No Known Signal Sequence Predicted A search of the NOV67a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 67C.

In a BLAST search of public sequence datbases, the NOV67a protein was found to have homology to the proteins shown in the BLASTP data in Table 67D.

PFam analysis predicts that the NOV67a protein contains the domains shown in the Table 67E.

Example 68.

The NOV68 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 68 A. Table 68A. NOV68 Sequence Analysis

SEQ ID NO: 195 5474 bp

NOV68a, TGATCATAAACAATACTTTTGGAGCTGGATTAATATTAAGTCACTTGAGAGATATAGA -01 DNA Sequence AAATACCATGTTCGTGGTCAACTTTGATTATTTTAGCCGGGTTCATCTGGTTTGCACA TTGAGACCGTAATACTTCAGGTTCTAATTGTGTCCAGAAGGCTATGTGTTAACATTCA TAGCAAACTGGTTACCTTTATTTCCTGAAAGTTAAATTTTGAAAGAAAGGGATACCAA GTGAGAAAGCAACCTTCAGTTAAACAAAGGGGTACATCAAGTTTGATACTCTTGGATT AAAAATCAGGTGACAATTGGAACATGGAGGAGAAATTCATGATTATAGAAACCATGAA GCCAATCTTTTTTACAACAAAGCTGCTTGTTTTTTTCTTAATCATGTAGTGGCTGCTA TCAGGCCAGTTCTGGAACTTCACTGAGTCCCTCTGCTCTTCTGAATCAGCTCTTGATT GGTGGTGACTTCTCGGAAGTTCTTATCCCTACCCTCCACCTTCTGCTCCAGGGTGGCA CGACTCAAACCTGCCCTACGGCCCATTAGCTCCATTCCATGAAGTTCCTATCCAGTAC CAGGCACGTTTCTTCTGCGTCTGTCTGGCTCGCGTGTTTCTTTTTGCCTGTGTCCCGC CGGGTCAGGCTCTCCCCGTCTCTCAGACTTTCCCGTCCCCGTGTCCTCCGCGGCCGTC TCTCTCCAACTCTCTCCCCCTCTCAGCCACTTCCTGTCTCCAGTATGTCCCTGGCGCG GCCCGGCTGGCCGTCTGCGCACCCTCTCTCCCCTCGGCTCTTTCCTAGGAAAGCTGAG CCTCATAGCTTCCGGGAGAAGGTTTTCCGGAAGAAACCTCCAGTCTGTGCAGTATGTA AGGTGACCATCGATGGGACAGGCGTTTCGTGCAGAGTCTGCAAGGTGGCGACGCACAG AAAATGTGAAGCAAAGGTGACTTCAGCCTGTCAGGCCTTGCCTCCCGTGGAGTTGCGG CGAAACACGGCCCCAGTCAGGCGCATAGAGCACCTGGGATCCACCAAATCTCTGAACC ACTCAAAGCAGCGCAGCACTCTGCCCAGGAGCTTCAGCCTGGACCCGCTCATGGAGCG GCGCTGGGACTTAGACCTCACCTACGTGACGGAGCGCATCTTGGCCGCCGCCTTCCCC GCGCGGCCCGATGAACAGCGGCACCGGGGCCACCTGCGCGAGCTGGCCCATGTGCTGC AATCCAAGCACCGGGACAAGTACCTGCTCTTCAACCTTTCAGAGAAAAGGCATGACCT GACCCGCTTAAACCCCAAGGTTCAAGACTTCGGCTGGCCTGAGCTGCATGCTCCACCC CTGGACAAGCTGTGCTCCATCTGCAAAGCCATGGAGACATGGCTCAGTGCTGACCCAC AGCACGTGGTCGTACTATACTGCAAGGGAAACAAGGGCAAGCTTGGGGTCATCGTTTC TGCCTACATGCACTACAGCAAGATCTCTGCAGGGGCGGACCAGGCACTGGCCACTCTT ACCATGCGGAAATTCTGCGAGGACAAGGTGGCCACAGAACTGCAGCCCTCCCAGCGTC GATATATCAGCTACTTCAGTGGGCTGCTATCTGGCTCCATCAGAATGAACAGCAGCCC TCTCTTCCTGCACTATGTGCTCATCCCCATGCTGCCAGCCTTTGAACCTGGCACAGGC TTCCAGCCCTTCCTTAAAATCTACCAGTCCATGCAGCTTGTCTACACATCTGGAGTCT ATCACATTGCAGGCCCTGGTCCCCAGCAGCTTTGCATCAGCCTGGAGCCAGCCCTCCT CCTCAAAGGCGATGTCATGGTAACATGTTATCACAAGGGTGGCCGGGGCACAGACCGG ACCCTCGTGTTCCGAGTCCAGTTCCACACCTGCACCATCCACGGACCACAGCTCACTT TCCCCAAGGACCAGCTTGACGAGGCCTGGACTGATGAGAGGTTCCCCTTCCAAGCCTC CGTGGAGTTTGTCTTCTCCTCCAGCCCCGAGAAGATCAAAGGCAGCACTCCACGGAAC GACCCCTCGGTCTCTGTCGACTACAACACCACTGAGCCAGCCGTGCGCTGGGACTCCT ATGAGAACTTCAACCAGCACCACGAGGACAGTGTGGATGGCTCCTTGACCCACACCCG GGGTCCCCTGGATGGCAGTCCTTATGCCCAGGTGCAGCGGCCTCCCCGGCAGACCCCC CCGGCACCCTCTCCAGAGCCTCCACCACCCCCCATGCTCTCTGTCAGCAGCGACTCAG GCCATTCCTCCACGCTGACCACAGAGCCGGCTGCTGAGTCCCCTGGCCGGCCGCCCCC TACAGCTGCTGAACGGCAGGAGCTGGATCGCCTCCTAGGAGGCTGCGGAGTGGCCAGT GGGGGCCGGGGAGCTGGGCGCGAGACGGCCATCCTAGATGACGAAGAGCAGCCCACTG TGGGCGGAGGCCCCCACCTCGGAGTGTATCCAGGCCATAGGCCTGGCCTCAGCCGCCA CTGCTCCTGCCGCCAGGGCTACCGGGAGCCCTGCGGGGTTCCCAATGGGGGCTACTAC CGGCCAGAGGGAACCCTGGAGAGGAGGCGACTGGCCTACGGGGGCTATGAGGGATCCC CCCAGGGCTACGCCGAGGCCTCGATGGAGAAGAGGCGCCTCTGCCGATCGCTGTCAGA GGGGCTATACCCCTACCCACCTGAGATGGGGAAACCAGCCACTGGGGACTTTGGCTAC CGCGCCCCAGGCTACCGGGAGGTGGTCATCCTGGAGGACCCTGGGCTGCCTGCCCTAT ACCCATGCCCAGCCTGCGAGGAGAAGCTGGCGCTGCCTACAGCAGCCTTGTATGGACT GCGGCTGGAGAGGGAGGCTGGAGAAGGGTGGGCAAGTGAGGCTGGCAAGCCTCTCCTG CACCCAGTGCGGCCTGGGCACCCGCTGCCTCTGCTCTTGCCTGCCTGTGGGCATCACC ATGCCCCGATGCCTGACTACAGCTGCCTGAAGCCACCCAAGGCAGGCGAGGAAGGGCA CGAGGGCTGCTCCTACACCATGTGCCCCGAAGGCAGGTATGGGCATCCAGGGTACCCT GCCCTGGTGACATACAGCTATGGAGGAGCAGTTCCCAGTTACTGCCCAGCATATGGCC GTGTGCCTCATAGCTGTGGCTCTCCAGGAGAGGGCAGAGGGTATCCCAGCCCTGGTGC CCACTCCCCACGGGCTGGCTCCATTTCCCCGGGCAGCCCGCCCTATCCACAATCTAGG AAGCTGAGCTACGAGATCCCTACGGAGGAGGGAGGGGACAGGTACCCATTGCCTGGGC ACCTGGCCTCAGCAGGACCTTTGGCATCTGCAGAGTCGCTGGAGCCGGTGTCCTGGAG GGAGGGCCCCAGTGGGCACAGCACACTGCCTCGGTCTCCCCGAGATGCCCCATGCAGT GCTTCGTCAGAGTTGTCTGGTCCCTCCACGCCCCTGCACACCAGCAGTCCAGTCCAGG GCAAGGAAAGCACCCGGCGACAGGACACCAGGTCCCCCACCTCAGCGCCCACTCAGAG ACTGAGTCCTGGCGAGGCCTTGCCCCCTGTTTCCCAGGCAGGCACCGGAAAGGCCCCT GAGCTGCCGTCGGGAAGTGGGCCTGAGCCTCTGGCCCCTAGCCCAGTCTCTCCGACCT TCCCTCCCAGCTCGCCCAGTGACTGGCCTCAGGAAAGGAGTCCAGGGGGCCACTCAGA TGGCGCCAGTCCTCGGAGCCCTGTGCCCACCACACTTCCTGGCCTCCGCCACGCCCCC TGGCAAGGCCCTCGAGGCCCCCCCGACAGCCCAGATGGGTCTCCCCTCACTCCTGTGC CTTCCCAGATGCCCTGGCTTGTGGCCAGCCCAGAGCCGCCTCAGAGCTCACCTACACC

Further analysis of the NOV68a protein yielded the following properties shown in Table 68B.

A search of the NOV68a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 68C.

In a BLAST search of public sequence datbases, the NOV68a protein was found to have homology to the proteins shown in the BLASTP data in Table 68D.

PFam analysis predicts that the NOV68a protein contains the domains shown in the Table 68E.

Example 69.

The NOV69 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 69A.

Further analysis of the NOV69a protein yielded the following properties shown in Table 69B.

Table 69B. Protein Sequence Properties NOV69a

PSort analysis: 0.6000 probability located in nucleus; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen); 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV69a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 69C.

In a BLAST search of public sequence datbases, the NOV69a protein was found to have homology to the proteins shown in the BLASTP data in Table 69D.

PFam analysis predicts that the NOV69a protein contains the domains shown in the Table 69E.

Example 70.

The NOV70 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 70A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 70B.

Table 70B. Comparison of NOV70a against NOV70b.

NOV70a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV70b 1..163 161/163 (98%) 1..163 161/163 (98%)

Further analysis of the NOV70a protein yielded the following properties shown in Table 70C. Table 70C. Protein Sequence Properties NOV70a

PSort analysis: 0.6000 probability located in plasma membrane; 0.5689 probability located in microbody (peroxisome); 0.4500 probability located in cytoplasm; 0.1000 probability located in mitochondrial matrix space

SignalP analysis: No Known Signal Sequence Predicted

A search of the NOV70a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 70D.

In a BLAST search of public sequence datbases, the NOV70a protein was found to have homology to the proteins shown in the BLASTP data in Table 70E.

PFam analysis predicts that the NOV70a protein contains the domains shown in the Table 70F.

Table 70F. Domain Analysis of NOV70a

Identities/

Pfam Domain NOV70a Match Region Similarities Expect Value for the Matched Region pro_ιsomerase 7..163 108/179 (60%) 3.7e-87 140/179 (78%)

Example B: Sequencing Methodology and Identification of NOVX Clones

1. GeneCalling™ Technology: This is a proprietary method of performing differential gene expression profiling between two or more samples developed at CuraGen and described by Shimkets, et al., "Gene expression analysis by transcript profiling coupled to a gene database query" Nature Biotechnology 17:198-803 (1999). cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then digested with up to as many as 120 pairs of restriction enzymes and pairs of linker-adaptors specific for each pair of restriction enzymes were ligated to the appropriate end. The restriction digestion generates a mixture of unique cDNA gene fragments. Limited PCR amplification is performed with primers homologous to the linker adapter sequence where one primer is biotinylated and the other is fluorescently labeled. The doubly labeled material is isolated and the fluorescently labeled single strand is resolved by capillary gel electrophoresis. A computer algorithm compares the electropherograms from an experimental and control group for each of the restriction digestions. This and additional sequence-derived information is used to predict the identity of each differentially expressed gene fragment using a variety of genetic databases. The identity of the gene fragment is confirmed by additional, gene-specific competitive PCR or by isolation and sequencing of the gene fragment.

2. SeqCalling™ Technology: cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then sequenced using CuraGen's proprietary SeqCalling technology. Sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations.

3. PathCalling™ Technology:

The NOVX nucleic acid sequences are derived by laboratory screening of cDNA library by the two-hybrid approach. cDNA fragments covering either the full length of the DNA sequence, or part of the sequence, or both, are sequenced. In silico prediction was based on sequences available in CuraGen Corporation's proprietary sequence databases or in the public human sequence databases, and provided either the full length DNA sequence, or some portion thereof.

The laboratory screening was performed using the methods summarized below:

cDNA libraries were derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then directionally cloned into the appropriate two-hybrid vector (Gal4-activation domain (Gal4-AD) fusion). Such cDNA libraries as well as commercially available cDNA libraries from Clontech (Palo Alto, CA) were then transferred from E.coli into a CuraGen Corporation proprietary yeast strain (disclosed in U. S. Patents 6,057,101 and 6,083,693, incorporated herein by reference in their entireties).

Gal4-binding domain (Gal4-BD) fusions of a CuraGen Corportion proprietary library of human sequences was used to screen multiple Gal4-AD fusion cDNA libraries resulting in the selection of yeast hybrid diploids in each of which the Gal4-AD fusion contains an individual cDNA. Each sample was amplified using the polymerase chain reaction (PCR) using non-specific primers at the cDNA insert boundaries. Such PCR product was sequenced; sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations.

Physical clone: the cDNA fragment derived by the screening procedure, covering the entire open reading frame is, as a recombinant DNA, cloned into pACT2 plasmid (Clontech) used to make the cDNA library. The recombinant plasmid is inserted into the host and selected by the yeast hybrid diploid generated during the screening procedure by the mating of both CuraGen Corporation proprietary yeast strains N106' and YULH (U. S. Patents 6,057,101 and 6,083,693).

4. RACE: Techniques based on the polymerase chain reaction such as rapid amplification of cDNA ends (RACE), were used to isolate or complete the predicted sequence of the cDNA of the invention. Usually multiple clones were sequenced from one or more human samples to derive the sequences for fragments. Various human tissue samples from different donors were used for the RACE reaction. The sequences derived from these procedures were included in the SeqCalling Assembly process described in preceding paragraphs.

5. Exon Linking: The NOVX target sequences identified in the present invention were subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case of the reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) of the DNA or protein sequence of the target sequence, or by translated homology of the predicted exons to closely related human sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The PCR product derived from exon linking was cloned into the pCR2.1 vector from Invitrogen. The resulting bacterial clone has an insert covering the entire open reading frame cloned into the pCR2.1 vector. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component of the assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported herein.

6. Physical Clone:

Exons were predicted by homology and the intron/exon boundaries were determined using standard genetic rules. Exons were further selected and refined by means of similarity determination using multiple BLAST (for example, tBlastN, BlastX, and BlastN) searches, and, in some instances, GeneScan and Grail. Expressed sequences from both public and proprietary databases were also added when available to further define and complete the gene sequence. The DNA sequence was then manually corrected for apparent inconsistencies thereby obtaining the sequences encoding the full-length protein.

The PCR product derived by exon linking, covering the entire open reading frame, was cloned into the pCR2.1 vector from Invitrogen to provide clones used for expression and screening purposes.

Example C: Quantitative expression analysis of clones in various cells and tissues

The quantitative expression of various clones was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell lines and tissues using real time quantitative PCR (RTQ PCR). RTQ PCR was performed on an Applied Biosystems ABI PRISM® 7700 or an ABI PRISM® 7900 HT Sequence 03/010327

Detection System. Various collections of samples are assembled on the plates, and referred to as Panel 1 (containing normal tissues and cancer cell lines), Panel 2 (containing samples derived from tissues from normal and cancer sources), Panel 3 (containing cancer cell lines), Panel 4 (containing cells and cell lines from normal tissues and cells related to inflammatory conditions), Panel 5D/5I (containing human tissues and cell lines with an emphasis on metabolic diseases), AI_comprehensive_panel (containing normal tissue and samples from autoimmune diseases), Panel CNSD.01 (containing central nervous system samples from normal and diseased brains) and CNS_neurodegeneration_panel (containing samples from normal and Alzheimer's diseased brains). RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s: 18s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span ofa single exon. First, the RNA samples were normalized to reference nucleic acids such as constitutively expressed genes (for example, β-actin and GAPDH). Normalized RNA (5 ul) was converted to cDNA and analyzed by RTQ-PCR using One Step RT-PCR Master Mix Reagents (Applied Biosystems; Catalog No. 4309169) and gene-specific primers according to the manufacturer's instructions.

In other cases, non-normalized RNA samples were converted to single strand cDNA (sscDNA) using Superscript II (Invitrogen Corporation; Catalog No. 18064-147) and random hexamers according to the manufacturer's instructions. Reactions containing up to 10 μg of total RNA were performed in a volume of 20 μl and incubated for 60 minutes at 42°C. This reaction can be scaled up to 50 μg of total RNA in a final volume of 100 μl. sscDNA samples are then normalized to reference nucleic acids as described previously, using IX TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions.

Probes and primers were designed for each assay according to Applied Biosystems Primer Express Software package (version I for Apple Computer's Macintosh Power PC) or a similar algorithm using the target sequence as input. Default settings were used for reaction conditions and the following parameters were set before selecting primers: primer concentration = 250 nM, primer melting temperature (Tm) range = 58°-60°C, primer optimal Tm = 59°C, maximum primer difference = 2°C, probe does not have 5'G, probe Tm must be 10°C greater than primer Tm, amplicon size 75bp to lOObp. The probes and primers selected (see below) were synthesized by Synthegen (Houston, TX, USA). Probes were double purified by HPLC to remove uncoupled dye and evaluated by mass spectroscopy to verify coupling of reporter and quencher dyes to the 5' and 3' ends of the probe, respectively. Their final concentrations were: forward and reverse primers, 900nM each, and probe, 200nM.

PCR conditions: When working with RNA samples, normalized RNA from each tissue and each cell line was spotted in each well of either a 96 well or a 384- well PCR plate (Applied Biosystems). PCR cocktails included either a single gene specific probe and primers set, or two multiplexed probe and primers sets (a set specific for the target clone and another gene-specific set multiplexed with the target probe). PCR reactions were set up using TaqMan® One-Step RT-PCR Master Mix (Applied Biosystems, Catalog No. 4313803) following manufacturer's instructions. Reverse transcription was performed at 48°C for 30 minutes followed by amplification/PCR cycles as follows: 95°C 10 min, then 40 cycles of 95°C for 15 seconds, 60°C for 1 minute. Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression is then obtained by taking the reciprocal of this RNA difference and multiplying by 100.

When working with sscDNA samples, normalized sscDNA was used as described previously for RNA samples. PCR reactions containing one or two sets of probe and primers were set up as described previously, using IX TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification was performed as follows: 95°C 10 min, then 40 cycles of 95°C for 15 seconds, 60°C for 1 minute. Results were analyzed and processed as described previously.

Panels 1, 1.1, 1.2, and 1.3D The plates for Panels 1 , 1.1 , 1.2 and 1.3D include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in these panels are broken into 2 classes: samples derived from cultured cell lines , „„„„ 03/010327

and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in these panels are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on these panels are comprised of samples derived from all major organ systems from single adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose.

In the results for Panels 1 , 1.1, 1.2 and 1.3D, the following abbreviations are used: ca. = carcinoma,

* = established from metastasis, met = metastasis, s cell var = small cell variant, non-s = non-sm = non-small, squam = squamous, pi. eff = pi effusion = pleural effusion, glio = glioma, astro = astrocytoma, and neuro = neuroblastoma.

General_screening_panel_vl.4 and General_screening_panel_vl.5

The plates for Panels 1.4 and 1.5 include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in Panels 1.4 and 1.5 are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in Panel 1.4 are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on Panels 1.4 and 1.5 are comprised of pools of samples derived from all major organ systems from 2 to 5 different adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus. stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. Abbreviations are as described for Panels 1, 1.1, 1.2, and 1.3D.

Panels 2D and 2.2 The plates for Panels 2D and 2.2 generally include 2 control wells and 94 test samples composed of RNA or cDNA isolated from human tissue procured by surgeons working in close cooperation with the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative (NDRI). The tissues are derived from human malignancies and in cases where indicated many malignant tissues have "matched margins" obtained from noncancerous tissue just adjacent to the tumor. These are termed normal adjacent tissues and are denoted "NAT" in the results below. The tumor tissue and the "matched margins" are evaluated by two independent pathologists (the surgical pathologists and again by a pathologist at NDRI or CHTN). This analysis provides a gross histopathological assessment of tumor differentiation grade. Moreover, most samples-include the original surgical pathology report that provides information regarding the clinical stage of the patient. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated "NAT", for normal adjacent tissue, in Table RR). In addition, RNA and cDNA samples were obtained from various human tissues derived from autopsies performed on elderly people or sudden death victims (accidents, etc.). These tissues were ascertained to be free of disease and were purchased from various commercial sources such as Clontech (Palo Alto, CA), Research Genetics, and Invitrogen.

Panel 3D

The plates of Panel 3D are comprised of 94 cDNA samples and two control samples. Specifically, 92 of these samples are derived from cultured human cancer cell lines, 2 samples of human primary cerebellar tissue and 2 controls. The human cell lines 3/010327

are generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: Squamous cell carcinoma of the tongue, breast cancer, prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon, lung and CNS cancer cell lines. In addition, there are two independent samples of cerebellum. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. The cell lines in panel 3D and 1.3D are of the most common cell lines used in the scientific literature.

Panels 4D, 4R, and 4.1D Panel 4 includes samples on a 96 well plate (2 control wells, 94 test samples) composed of RNA (Panel 4R) or cDNA (Panels 4D/4.1D) isolated from various human cell lines or tissues related to inflammatory conditions. Total RNA from control normal tissues such as colon and lung (Stratagene, La Jolla, CA) and thymus and kidney (Clontech) was employed. Total RNA from liver tissue from cirrhosis patients and kidney from lupus patients was obtained from BioChain (Biochain Institute, Inc., Hayward, CA). Intestinal tissue for RNA preparation from patients diagnosed as having Crohn's disease and ulcerative colitis was obtained from the National Disease Research Interchange (NDRI) (Philadelphia, PA).

Astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, human umbilical vein endothelial cells were all purchased from Clonetics (Walkersville, MD) and grown in the media supplied for these cell types by Clonetics. These primary cell types were activated with various cytokines or combinations of cytokines for 6 and/or 12- 14 hours, as indicated. The following cytokines were used; IL-1 beta at approximately 1- 5ng/ml, TNF alpha at approximately 5-lOng/ml, IFN gamma at approximately 20- 50ng/ml, IL-4 at approximately 5-10ng/ml, IL-9 at approximately 5-10ng/ml, IL-13 at approximately 5-10ng/ml. Endothelial cells were sometimes starved for various times by culture in the basal media from Clonetics with 0.1 % serum. Mononuclear cells were prepared from blood of employees at CuraGen

Corporation, using Ficoll. LAK cells were prepared from these cells by culture in DMEM 5% FCS (Hyclone), 1 OOμM non essential amino acids (Gibco/Life Technologies, 03/010327

Rockville, MD), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO^"5M (Gibco), and lOmM Hepes (Gibco) and Interleukin 2 for 4-6 days. Cells were then either activated with 10-20ng/ml PMA and l-2μg/ml ionomycin, IL-12 at 5-10ng/ml, IFN gamma at 20- 50ng/ml and IL-18 at 5-10ng/ml for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10°M (Gibco), and lOmM Hepes (Gibco) with PHA (phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5μg/ml. Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from two donors, isolating the mononuclear cells using Ficoll and mixing the isolated mononuclear cells 1 :1 at a final concentration of approximately 2xl0⁶cells/ml in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol (5.5x10^"DM) (Gibco), and lOmM Hepes (Gibco). The MLR was cultured and samples taken at various time points ranging from 1 - 7 days for RNA preparation. Monocytes were isolated from mononuclear cells using CD 14 Miltenyi Beads, +ve

VS selection columns and a Vario Magnet according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone, Logan, UT), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO^"5M (Gibco), and lOmM Hepes (Gibco), 50ng/ml GMCSF and 5ng/ml IL-4 for 5-7 days. Macrophages were prepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0°M (Gibco), lOmM Hepes (Gibco) and 10% AB Human Serum or MCSF at approximately 50ng/ml. Monocytes, macrophages and dendritic cells were stimulated for 6 and 12-14 hours with lipopolysaccharide (LPS) at lOOng/ml. Dendritic cells were also stimulated with anti- CD40 monoclonal antibody (Pharmingen) at lOμg/ml for 6 and 12-14 hours.

CD4 lymphocytes, CD8 lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection columns and a Vario Magnet according to the manufacturer's instructions. CD45RA and CD45RO CD4 lymphocytes were isolated by depleting "mononuclear cells of CD8, CD56, CD14 and CD19 cells using CD8, CD56, CD14 and CD19 Miltenyi beads and positive selection. CD45RO beads were then used to isolate the CD45RO CD4 lymphocytes with the remaining cells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8 lymphocytes were placed in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"5M (Gibco), and lOmM Hepes (Gibco) and plated at 10⁶cells/ml onto Falcon 6 well tissue culture plates that had been coated overnight with 0.5μg/ml anti-CD28 (Pharmingen) and 3ug/ml anti- CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA preparation. To prepare chronically activated CD8 lymphocytes, we activated the isolated CD8 lymphocytes for 4 days on anti-CD28 and anti-CD3 coated plates and then harvested the cells and expanded them in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), and 1 OmM Hepes (Gibco) and IL-2. The expanded CD8 cells were then activated again with plate bound anti-CD3 and anti-CD28 for 4 days and expanded as before. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culture. The isolated NK cells were cultured in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^_:,M (Gibco), and lOmM Hepes (Gibco) and IL-2 for 4-6 days before RNA was prepared.

To obtain B cells, tonsils were procured from NDRI. The tonsil was cut up with sterile dissecting scissors and then passed through a sieve. Tonsil cells were then spun down and resupended at 10⁶cells/ml in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"5M (Gibco), and lOmM Hepes (Gibco). To activate the cells, we used PWM at 5μg/ml or anti-CD40 (Pharmingen) at approximately lOμg/ml and IL-4 at 5-10ng/ml. Cells were harvested for RNA preparation at 24,48 and 72 hours. To prepare the primary and secondary Thl/Th2 and Trl cells, six-well Falcon plates were coated overnight with lOμg/ml anti-CD28 (Pharmingen) and 2μg/ml OKT3 (ATCC), and then washed twice with PBS. Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, MD) were cultured at 10⁵-10⁶cells/ml in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"5M (Gibco), 1 OmM Hepes (Gibco) and IL-2 (4ng/ml). IL-12 (5ng/ml) and anti-IL4 (lμg/ml) were used to direct to Thl, while IL-4 (5ng/ml) and anti-IFN gamma (lμg/ml) were used to direct to Th2 and IL-10 at 5ng/ml was used to direct to Trl. After 4-5 days, the activated Thl, Th2 and Trl lymphocytes were washed once in DMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^" ⁵M (Gibco), lOmM Hepes (Gibco) and IL-2 (lng/ml). Following this, the activated Thl, Th2 and Trl lymphocytes were re-stimulated for 5 days with anti-CD28/OKT3 and cytokines as described above, but with the addition of anti-CD95L (lμg/ml) to prevent apoptosis. After 4-5 days, the Thl, Th2 and Trl lymphocytes were washed and then expanded again with IL-2 for 4-7 days. Activated Thl and Th2 lymphocytes were maintained in this way for a maximum of three cycles. RNA was prepared from primary and secondary Thl , Th2 and Trl after 6 and 24 hours following the second and third activations with plate bound anti-CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures in Interleukin 2.

The following leukocyte cells lines were obtained from the ATCC: Ramos, EOL-1, KU-812. EOL cells were further differentiated by culture in O.lmM dbcAMP at 5xl0^Dcells/ml for 8 days, changing the media every 3 days and adjusting the cell concentration to SxlO^cells/ml. For the culture of these cells, we used DMEM or RPMI (as recommended by the ATCC), with the addition of 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^" ⁵M (Gibco), lOmM Hepes (Gibco). RNA was either prepared from resting cells or cells activated with PMA at lOng/ml and ionomycin at lμg/ml for 6 and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumor line NCI-H292 were also obtained from the ATCC. Both were cultured in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO^"5M (Gibco), and lOmM Hepes (Gibco). CCD1106 cells were activated for 6 and 14 hours with approximately 5 ng/ml TNF alpha and lng/ml IL-1 beta, while NCI-H292 cells were activated for 6 and 14 hours with the following cytokines: 5ng/ml IL-4, 5ng/ml IL-9, 5ng/ml IL-13 and 25ng/ml IFN gamma.

For these cell lines and blood cells, RNA was prepared by lysing approximately 10⁷cells/ml using Trizol (Gibco BRL). Briefly, 1/10 volume of bromochloropropane (Molecular Research Corporation) was added to the RNA sample, vortexed and after 10 minutes at room temperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor. The aqueous phase was removed and placed in a 15ml Falcon Tube. An equal volume of isopropanol was added and left at -20°C overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34 rotor and washed in 70% ethanol. The pellet was redissolved in 300μl of RNAse-free water and 35μl buffer (Promega) 5μl DTT, 7μl RNAsin and 8μl DNAse were added. The tube was incubated at 37°C for 30 minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re- precipitated with 1/10 volume of 3M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down and placed in RNAse free water. RNA was stored at -80°C.

AI_comprehensive panel_vl.O

The plates for AI_comprehensive panel_vl .0 include two control wells and 89 test samples comprised of cDNA isolated from surgical and postmortem human tissues obtained from the Backus Hospital and Clinomics (Frederick, MD). Total RNA was extracted from tissue samples from the Backus Hospital in the Facility at CuraGen. Total RNA from other tissues was obtained from Clinomics.

Joint tissues including synovial fluid, synovium, bone and cartilage were obtained from patients undergoing total knee or hip replacement surgery at the Backus Hospital. Tissue samples were immediately snap frozen in liquid nitrogen to ensure that isolated RNA was of optimal quality and not degraded. Additional samples of osteoarthritis and rheumatoid arthritis joint tissues were obtained from Clinomics. Normal control tissues were supplied by Clinomics and were obtained during autopsy of trauma victims. Surgical specimens of psoriatic tissues and adjacent matched tissues were provided as total RNA by Clinomics. Two male and two female patients were selected between the ages of 25 and 47. None of the patients were taking prescription drugs at the time samples were isolated.

Surgical specimens of diseased colon from patients with ulcerative colitis and Crohns disease and adjacent matched tissues were obtained from Clinomics. Bowel tissue from three female and three male Crohn's patients between the ages of 41-69 were used. Two patients were not on prescription medication while the others were taking dexamethasone, phenobarbital, or tylenol. Ulcerative colitis tissue was from three male and four female patients. Four of the patients were taking lebvid and two were on phenobarbital.

Total RNA from post mortem lung tissue from trauma victims with no disease or with emphysema, asthma or COPD was purchased from Clinomics. Emphysema patients ranged in age from 40-70 and all were smokers, this age range was chosen to focus on patients with cigarette-linked emphysema and to avoid those patients with alpha-lanti- trypsin deficiencies. Asthma patients ranged in age from 36-75, and excluded smokers to prevent those patients that could also have COPD. COPD patients ranged in age from 35- 80 and included both smokers and non-smokers. Most patients were taking corticosteroids, and bronchodilators.

In the labels employed to identify tissues in the AI_comprehensive panel_vl.O panel, the following abbreviations are used:

Al = Autoimmunity Syn = Synovial

Normal = No apparent disease

Rep22 /Rep20 = individual patients

RA = Rheumatoid arthritis

Backus = From Backus Hospital OA = Osteoarthritis

(SS) (BA) (MF) = Individual patients

Adj = Adjacent tissue

Match control = adjacent tissues

-M = Male -F = Female

COPD = Chronic obstructive pulmonary disease

Panels 5D and 51

The plates for Panel 5D and 51 include two control wells and a variety of cDNAs isolated from human tissues and cell lines with an emphasis on metabolic diseases.

Metabolic tissues were obtained from patients enrolled in the Gestational Diabetes study. Cells were obtained during different stages in the differentiation of adipocytes from human mesenchymal stem cells. Human pancreatic islets were also obtained.

In the Gestational Diabetes study subjects are young (18 - 40 years), otherwise healthy women with and without gestational diabetes undergoing routine (elective) Caesarean section. After delivery of the infant, when the surgical incisions were being repaired/closed, the obstetrician removed a small sample (<1 cc) of the exposed metabolic tissues during the closure of each surgical level. The biopsy material was rinsed in sterile saline, blotted and fast frozen within 5 minutes from the time of removal. The tissue was then flash frozen in liquid nitrogen and stored, individually, in sterile screw-top tubes and kept on dry ice for shipment to or to be picked up by CuraGen. The metabolic tissues of interest include uterine wall (smooth muscle), visceral adipose, skeletal muscle (rectus) and subcutaneous adipose. Patient descriptions are as follows:

Patient 2: Diabetic Hispanic, overweight, not on insulin Patient 7-9: Nondiabetic Caucasian and obese (BMI>30) Patient 10: Diabetic Hispanic, overweight, on insulin

Patient 11 : Nondiabetic African American and overweight Patient 12: Diabetic Hispanic on insulin

Adipocyte differentiation was induced in donor progenitor cells obtained from Osirus (a division of Clonetics/BioWhittaker) in triplicate, except for Donor 3U which had only two replicates. Scientists at Clonetics isolated, grew and differentiated human mesenchymal stem cells (HuMSCs) for CuraGen based on the published protocol found in

Mark F. Pittenger, et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells

Science Apr 2 1999: 143-147. Clonetics provided Trizol lysates or frozen pellets suitable for mRNA isolation and ds cDNA production. A general description of each donor is as follows:

Donor 2 and 3 U: Mesenchymal Stem cells, Undifferentiated Adipose Donor 2 and 3 AM: Adipose, AdiposeMidway Differentiated Donor 2 and 3 AD: Adipose, Adipose Differentiated Human cell lines were generally obtained from ATCC (American Type Culture

Collection), NCI or the German tumor cell bank and fall into the following tissue groups: kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver

HepG2 cancer cells, heart primary stromal cells, and adrenal cortical adenoma cells. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. All samples were processed at CuraGen to produce single stranded cDNA.

Panel 51 contains all samples previously described with the addition of pancreatic islets from a 58 year old female patient obtained from the Diabetes Research Institute at the University of Miami School of Medicine. Islet tissue was processed to total RNA at an outside source and delivered to CuraGen for addition to panel 51.

In the labels employed to identify tissues in the 5D and 51 panels, the following abbreviations are used:

GO Adipose = Greater Omentum Adipose SK = Skeletal Muscle UT = Uterus

PL = Placenta AD = Adipose Differentiated AM = Adipose Midway Differentiated U = Undifferentiated Stem Cells

Panel CNSD.01 The plates for Panel CNSD.01 include two control wells and 94 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80°C in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

Disease diagnoses are taken from patient records. The panel contains two brains from each of the following diagnoses: Alzheimer's disease, Parkinson's disease, Huntington's disease, Progressive Supernuclear Palsy, Depression, and "Normal controls". Within each of these brains, the following regions are represented: cingulate gyrus, temporal pole, globus palladus, substantia nigra, Brodman Area 4 (primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9 (prefrontal cortex), and Brodman area 17 (occipital cortex). Not all brain regions are represented in all cases; e.g., Huntington's disease is characterized in part by neurodegeneration in the globus palladus, thus this region is impossible to obtain from confirmed Huntington's cases. Likewise Parkinson's disease is characterized by degeneration of the substantia nigra making this region more difficult to obtain. Normal control brains were examined for neuropathology and found to be free of any pathology consistent with neurodegeneration.

In the labels employed to identify tissues in the CNS panel, the following abbreviations are used: PSP = Progressive supranuclear palsy

Sub Nigra = Substantia nigra

Glob Palladus= Globus palladus

Temp Pole = Temporal pole

Cing Gyr = Cingulate gyrus BA 4 = Brodman Area 4

Panel CNS Neurodegeneration Vl.O

The plates for Panel CNS_Neurodegeneration_V1.0 include two control wells and 47 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean Hospital) and the Human Brain and Spinal Fluid Resource Center (VA Greater Los Angeles Healthcare System). Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80°C in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

Disease diagnoses are taken from patient records. The panel contains six brains from Alzheimer's disease (AD) patients, and eight brains from "Normal controls" who showed no evidence of dementia prior to death. The eight normal control brains are divided into two categories: Controls with no dementia and no Alzheimer's like pathology (Controls) and controls with no dementia but evidence of severe Alzheimer's like pathology, (specifically senile plaque load rated as level 3 on a scale of 0-3; 0 = no evidence of plaques, 3 = severe AD senile plaque load). Within each of these brains, the following regions are represented: hippocampus, temporal cortex (Brodman Area 21), parietal cortex (Brodman area 7), and occipital cortex (Brodman area 17). These regions were chosen to encompass all levels of neurodegeneration in AD. The hippocampus is a region of early and severe neuronal loss in AD; the temporal cortex is known to show neurodegeneration in AD after the hippocampus; the parietal cortex shows moderate neuronal death in the late stages of the disease; the occipital cortex is spared in AD and therefore acts as a "control" region within AD patients. Not all brain regions are represented in all cases.

In the labels employed to identify tissues in the CNS_Neurodegeneration_V1.0 panel, the following abbreviations are used:

AD = Alzheimer's disease brain; patient was demented and showed AD-like pathology upon autopsy Control = Control brains; patient not demented, showing no neuropathology

Control (Path) = Control brains; pateint not demented but showing sever AD-like pathology

SupTemporal Ctx = Superior Temporal Cortex

Inf Temporal Ctx = Inferior Temporal Cortex

The quantitative expression of various clones was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell lines and tissues using real time quantitative PCR (RTQ PCR). RTQ PCR was performed on an Applied Biosystems ABI PRISM® 7700 or an ABI PRISM® 7900 HT Sequence Detection System. Various collections of samples are assembled on the plates, and referred to as Panel 1 (containing normal tissues and cancer cell lines), Panel 2 (containing samples derived from tissues from normal and cancer sources), Panel 3 (containing cancer cell lines), Panel 4 (containing cells and cell lines from normal tissues and cells related to inflammatory conditions), Panel 5D/5I (containing human tissues and cell lines with an emphasis on metabolic diseases), AI_comprehensive_panel (containing normal tissue and samples from autoinflammatory diseases), Panel CNSD.01 (containing samples from normal and diseased brains) and CNS_neurodegeneration_panel (containing samples from normal and Alzheimer's diseased brains). RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2:1 to 2.5: 1 28s: 18s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon. First, the RNA samples were normalized to reference nucleic acids such as constitutively expressed genes (for example, β-actin and GAPDH). Normalized RNA (5 ul) was converted to cDNA and analyzed by RTQ-PCR using One Step RT-PCR Master Mix Reagents (Applied Biosystems; Catalog No. 4309169) and gene-specific primers according to the manufacturer's instructions.

PCR conditions: When working with RNA samples, normalized RNA from each tissue and each cell line was spotted in each well of either a 96 well or a 384-well PCR plate (Applied Biosystems). PCR cocktails included either a single gene specific probe and primers set, or two multiplexed probe and primers sets (a set specific for the target clone and another gene-specific set multiplexed with the target probe). PCR reactions were set up using TaqMan® One-Step RT-PCR Master Mix (Applied Biosystems, Catalog No. 4313803) following manufacturer's instructions. Reverse transcription was performed at 48°C for 30 minutes followed by amplification/PCR cycles as follows: 95°C 10 min, then 40 cycles of 95°C for 15 seconds, 60°C for 1 minute. Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression is then obtained by taking the reciprocal of this RNA difference and multiplying by 100.

When working with sscDNA samples, normalized sscDNA was used as described previously for RNA samples. PCR reactions containing one or two sets of probe and primers were set up as described previously, using IX TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification was performed as follows: 95°C 10 min, then 40 cycles of 95°C for 15 seconds, 60°C for 1 minute. Results were analyzed and processed as described previously. Panels 1, 1.1, 1.2, and 1.3D The plates for Panels 1, 1.1, 1.2 and 1.3D include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in these panels are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in these panels are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on these panels are comprised of samples derived from all major organ systems from single adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus. stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose.

In the results for Panels 1. 1.1, 1.2 and 1.3D, the following abbreviations are used: ca. = carcinoma,

General_screening_panel_vl.4 and General_screening_panel_vl.5

The plates for Panels 1.4 and 1.5 include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in Panels 1.4 and 1.5 are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in Panels 1.4 and 1.5 are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on Panels 1.4 and 1.5 are comprised of pools of samples derived from all major organ systems from 2 to 5 different adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. Abbreviations are as described for Panels 1, 1.1, 1.2, and 1.3D. Panels 2D, 2.2, 2.3 and 2.4

The plates for Panels 2D, 2.2, 2.3 and 2.4 generally include 2 control wells and 94 test samples composed of RNA or cDNA isolated from human tissue procured by surgeons working in close cooperation with the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative (NDRI) or from Ardais or Clinomics). The tissues are derived from human malignancies and in cases where indicated many malignant tissues have "matched margins" obtained from noncancerous tissue just adjacent to the tumor. These are termed normal adjacent tissues and are denoted "NAT" in the results below. The tumor tissue and the "matched margins" are evaluated by two independent pathologists (the surgical pathologists and again by a pathologist at NDRI/ CHTN/Ardais/Clinomics). Unmatched RNA samples from tissues without malignancy (normal tissues) were also obtained from Ardais or Clinomics. This analysis provides a gross histopathological assessment of tumor differentiation grade. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical stage of the patient. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated "NAT", for normal adjacent tissue, in Table RR). In addition, RNA and cDNA samples were obtained from various human tissues derived from autopsies performed on elderly people or sudden death victims (accidents, etc.). These tissues were ascertained to be free of disease and were purchased from various commercial sources such as Clontech (Palo Alto, CA), Research Genetics, and Invitrogen. 03/010327

HASS Panel v 1.0

The HASS panel v 1.0 plates are comprised of 93 cDNA samples and two controls. Specifically, 81 of these samples are derived from cultured human cancer cell lines that had been subjected to serum starvation, acidosis and anoxia for different time periods as well as controls for these treatments, 3 samples of human primary cells, 9 samples of malignant brain cancer (4 medulloblastomas and 5 glioblastomas) and 2 controls. The human cancer cell lines are obtained from ATCC (American Type Culture Collection) and fall into the following tissue groups: breast cancer, prostate cancer, bladder carcinomas, pancreatic cancers and CNS cancer cell lines. These cancer cells are all cultured under standard recommended conditions. The treatments used (serum starvation, acidosis and anoxia) have been previously published in the scientific literature. The primary human cells were obtained from Clonetics (Walkersville, MD) and were grown in the media and conditions recommended by Clonetics. The malignant brain cancer samples are obtained as part ofa collaboration (Henry Ford Cancer Center) and are evaluated by a pathologist prior to CuraGen receiving the samples . RNA was prepared from these samples using the standard procedures. The genomic and chemistry control wells have been described previously.

Panel 3D

The plates of Panel 3D are comprised of 94 cDNA samples and two control samples. Specifically, 92 of these samples are derived from cultured human cancer cell lines, 2 samples of human primary cerebellar tissue and 2 controls. The human cell lines are generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: Squamous cell carcinoma of the tongue, breast cancer, prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon, lung and CNS cancer cell lines. In addition, there are two independent samples of cerebellum. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. The cell lines in panel 3D and 1.3D are of the most common cell lines used in the scientific literature. Panels 4D, 4R, and 4. ID

Panel 4 includes samples on a 96 well plate (2 control wells, 94 test samples) composed of RNA (Panel 4R) or cDNA (Panels 4D/4.1D) isolated from various human cell lines or tissues related to inflammatory conditions. Total RNA from control normal tissues such as colon and lung (Stratagene, La Jolla, CA) and thymus and kidney (Clontech) was employed. Total RNA from liver tissue from cirrhosis patients and kidney from lupus patients was obtained from BioChain (Biochain Institute, Inc., Hayward, CA). Intestinal tissue for RNA preparation from patients diagnosed as having Crohn's disease and ulcerative colitis was obtained from the National Disease Research Interchange (NDRI) (Philadelphia, PA).

Astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, human umbilical vein endothelial cells were all purchased from Clonetics (Walkersville, MD) and grown in the media supplied for these cell types by Clonetics. These primary cell types were activated with various cytokines or combinations of cytokines for 6 and/or 12- 14 hours, as indicated. The following cytokines were used; IL-1 beta at approximately 1- 5ng/ml, TNF alpha at approximately 5-10ng/ml, IFN gamma at approximately 20-

50ng/ml, IL-4 at approximately 5-10ng/ml, IL-9 at approximately 5-10ng/ml, IL-13 at approximately 5-10ng/ml. Endothelial cells were sometimes starved for various times by culture in the basal media from Clonetics with 0.1% serum.

Mononuclear cells were prepared from blood of employees at CuraGen Corporation, using Ficoll. LAK cells were prepared from these cells by culture in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco/Life Technologies, Rockville, MD), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"5M (Gibco), and lOmM Hepes (Gibco) and Interleukin 2 for 4-6 days. Cells were then either activated with 10-20ng/ml PMA and l-2μg/ml ionomycin, IL-12 at 5-10ng/ml, IFN gamma at 20- 50ng/ml and IL-18 at 5-1 Ong/ml for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), and lOmM Hepes (Gibco) with PHA (phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5μg/ml. Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from two donors, isolating the mononuclear cells using Ficoll and mixing the isolated mononuclear cells 1 :1 at a final concentration of approximately 2xl0⁶cells/ml in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol (5.5x10^"5M) (Gibco), and lOmM Hepes (Gibco). The MLR was cultured and samples taken at various time points ranging from 1- 7 days for RNA preparation.

Monocytes were isolated from mononuclear cells using CD 14 Miltenyi Beads, +ve VS selection columns and a Vario Magnet according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone, Logan, UT), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO^"sM (Gibco), and lOmM Hepes (Gibco), 50ng/ml GMCSF and 5ng/ml IL-4 for 5-7 days. Macrophages were prepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10°M (Gibco), lOmM Hepes (Gibco) and 10% AB Human Serum or MCSF at approximately 50ng/ml. Monocytes, macrophages and dendritic cells were stimulated for 6 and 12-14 hours with lipopolysaccharide (LPS) at lOOng/ml. Dendritic cells were also stimulated with anti- CD40 monoclonal antibody (Pharmingen) at lOμg/ml for 6 and 12-14 hours.

CD4 lymphocytes, CD8 lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection columns and a Vario Magnet according to the manufacturer's instructions. CD45RA and CD45RO CD4 lymphocytes were isolated by depleting mononuclear cells of CD8, CD56, CD14 and CD19 cells using CD8, CD56, CD14 and CD19 Miltenyi beads and positive selection. CD45RO beads were then used to isolate the CD45RO CD4 lymphocytes with the remaining cells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8 lymphocytes were placed in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"5M (Gibco), and lOmM Hepes (Gibco) and plated at 10⁶cells/ml onto Falcon 6 well tissue culture plates that had been coated overnight with 0.5μg/ml anti-CD28 (Pharmingen) and 3ug/ml anti- CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA preparation. To prepare chronically activated CD8 lymphocytes, we activated the isolated CD8 lymphocytes for 4 days on anti-CD28 and anti-CD3 coated plates and then harvested the cells and expanded them in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"5M (Gibco), and lOmM Hepes (Gibco) and IL-2. The expanded CD8 cells were then activated again with plate bound anti-CD3 and anti-CD28 for 4 days and expanded as before. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culture. The isolated NK cells were cultured in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"5M (Gibco), and lOmM Hepes (Gibco) and IL-2 for 4-6 days before RNA was prepared.

To obtain B cells, tonsils were procured from NDRI. The tonsil was cut up with sterile dissecting scissors and then passed through a sieve. Tonsil cells were then spun down and resupended at 10⁶cells/ml in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x1 O^M (Gibco), and lOmM Hepes (Gibco). To activate the cells, we used PWM at 5μg/ml or anti-CD40 (Pharmingen) at approximately lOμg/ml and IL-4 at 5-10ng/ml. Cells were harvested for RNA preparation at 24,48 and 72 hours.

To prepare the primary and secondary Thl/Th2 and Trl cells, six-well Falcon plates were coated overnight with lOμg/ml anti-CD28 (Pharmingen) and 2μg/ml OKT3 (ATCC), and then washed twice with PBS. Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, MD) were cultured at 10 0⁶cells/ml in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"5M (Gibco), lOmM Hepes (Gibco) and IL-2 (4ng/ml). IL-12 (5ng/ml) and anti-IL4 (lμg/ml) were used to direct to Thl, while IL-4 (5ng/ml) and anti-IFN gamma (lμg/ml) were used to direct to Th2 and IL-10 at 5ng/ml was used to direct to Trl. After 4-5 days, the activated Thl, Th2 and Trl lymphocytes were washed once in DMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^" ⁵M (Gibco), 1 OmM Hepes (Gibco) and IL-2 ( 1 ng/ml). Following this, the activated Thl , Th2 and Trl lymphocytes were re-stimulated for 5 days with anti-CD28/OKT3 and cytokines as described above, but with the addition of anti-CD95L (1 μg/ml) to prevent apoptosis. After 4-5 days, the Thl, Th2 and Trl lymphocytes were washed and then expanded again with IL-2 for 4-7 days. Activated Thl and Th2 lymphocytes were maintained in this way for a maximum of three cycles. RNA was prepared from primary and secondary Thl, Th2 and Trl after 6 and 24 hours following the second and third activations with plate bound anti-CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures in Interleukin 2.

The following leukocyte cells lines were obtained from the ATCC: Ramos, EOL-1, KU-812. EOL cells were further differentiated by culture in O.lmM dbcAMP at 5xl0^:,cells/ml for 8 days, changing the media every 3 days and adjusting the cell concentration to 5xl0³cells/ml. For the culture of these cells, we used DMEM or RPMI (as recommended by the ATCC), with the addition of 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^" ⁵M (Gibco), lOmM Hepes (Gibco). RNA was either prepared from resting cells or cells activated with PMA at 1 Ong/ml and ionomycin at 1 μg/ml for 6 and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumor line NCI-H292 were also obtained from the ATCC. Both were cultured in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"^ (Gibco), and lOmM Hepes (Gibco). CCD1106 cells were activated for 6 and 14 hours with approximately 5 ng/ml TNF alpha and lng/ml IL-1 beta, while NCI-H292 cells were activated for 6 and 14 hours with the following cytokines: 5ng/ml IL-4, 5ng/ml IL-9, 5ng/ml IL-13 and 25ng/ml IFN gamma.

For these cell lines and blood cells, RNA was prepared by lysing approximately 10⁷cells/ml using Trizol (Gibco BRL). Briefly, 1/10 volume of bromochloropropane (Molecular Research Corporation) was added to the RNA sample, vortexed and after 10 minutes at room temperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor. The aqueous phase was removed and placed in a 15ml Falcon Tube. An equal volume of isopropanol was added and left at -20°C overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34 rotor and washed in 70% ethanol. The pellet was redissolved in 300μl of RNAse-free water and 35μl buffer (Promega) 5μl DTT, 7μl RNAsin and 8μl DNAse were added. The tube was incubated at 37°C for 30 minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re- precipitated with 1/10 volume of 3M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down and placed in RNAse free water. RNA was stored at -80°C. AI_comprehensi ve panel_v 1.0

Total RNA from post mortem lung tissue from trauma victims with no disease or with emphysema, asthma or COPD was purchased from Clinomics. Emphysema patients ranged in age from 40-70 and all were smokers, this age range was chosen to focus on patients with cigarette-linked emphysema and to avoid those patients with alpha- lanti- trypsin deficiencies. Asthma patients ranged in age from 36-75, and excluded smokers to prevent those patients that could also have COPD. COPD patients ranged in age from 35- 80 and included both smokers and non-smokers. Most patients were taking corticosteroids, and bronchodilators.

In the labels employed to identify tissues in the AI_comprehensive panel_vl.O panel, the following abbreviations are used: Al = Autoimmunity Syn = Synovial Normal = No apparent disease Rep22 /Rep20 = individual patients RA = Rheumatoid arthritis Backus = From Backus Hospital OA = Osteoarthritis

(SS) (BA) (MF) = Individual patients Adj = Adjacent tissue Match control = adjacent tissues -M = Male -F = Female

COPD = Chronic obstructive pulmonary disease Panels 5D and 51

The plates for Panel 5D and 51 include two control wells and a variety of cDNAs isolated from human tissues and cell lines with an emphasis on metabolic diseases. Metabolic tissues were obtained from patients enrolled in the Gestational Diabetes study. Cells were obtained during different stages in the differentiation of adipocytes from human mesenchymal stem cells. Human pancreatic islets were also obtained.

In the Gestational Diabetes study subjects are young (18 - 40 years), otherwise healthy women with and without gestational diabetes undergoing routine (elective) Caesarean section. After delivery of the infant, when the surgical incisions were being repaired/closed, the obstetrician removed a small sample (<1 cc) of the exposed metabolic tissues during the closure of each surgical level. The biopsy material was rinsed in sterile saline, blotted and fast frozen within 5 minutes from the time of removal. The tissue was then flash frozen in liquid nitrogen and stored, individually, in sterile screw-top tubes and kept on dry ice for shipment to or to be picked up by CuraGen. The metabolic tissues of interest include uterine wall (smooth muscle), visceral adipose, skeletal muscle (rectus) and subcutaneous adipose. Patient descriptions are as follows: Patient 2: Diabetic Hispanic, overweight, not on insulin Patient 7-9: Nondiabetic Caucasian and obese (BMI>30) Patient 10: Diabetic Hispanic, overweight, on insulin

Patient 11 : Nondiabetic African American and overweight Patient 12: Diabetic Hispanic on insulin Adiocyte differentiation was induced in donor progenitor cells obtained from Osirus (a division of Clonetics/BioWhittaker) in triplicate, except for Donor 3U which had only two replicates. Scientists at Clonetics isolated, grew and differentiated human mesenchymal stem cells (HuMSCs) for CuraGen based on the published protocol found in Mark F. Pittenger, et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells Science Apr 2 1999: 143-147. Clonetics provided Trizol lysates or frozen pellets suitable for mRNA isolation and ds cDN A production. A general description of each donor is as follows: Donor 2 and 3 U: Mesenchymal Stem cells, Undifferentiated Adipose

Donor 2 and 3 AM: Adipose, AdiposeMidway Differentiated

Donor 2 and 3 AD: Adipose, Adipose Differentiated

Human cell lines were generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver HepG2 cancer cells, heart primary stromal cells, and adrenal cortical adenoma cells. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. All samples were processed at CuraGen to produce single stranded cDNA.

Panel 51 contains all samples previously described with the addition of pancreatic islets from a 58 year old female patient obtained from the Diabetes Research Institute at the University of Miami School of Medicine. Islet tissue was processed to total RNA at an outside source and delivered to CuraGen for addition to panel 51. In the labels employed to identify tissues in the 5D and 51 panels, the following abbreviations are used:

GO Adipose = Greater Omentum Adipose SK = Skeletal Muscle UT = Uterus PL = Placenta

AD = Adipose Differentiated

AM = Adipose Midway Differentiated U = Undifferentiated Stem Cells

Panel CNSD.01

The plates for Panel CNSD.01 include two control wells and 94 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80°C in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

Disease diagnoses are taken from patient records. The panel contains two brains from each of the following diagnoses: Alzheimer's disease, Parkinson's disease,

Huntington's disease, Progressive Supernuclear Palsy, Depression, and "Normal controls". Within each of these brains, the following regions are represented: cingulate gyrus, temporal pole, globus palladus, substantia nigra, Brodman Area 4 (primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9 (prefrontal cortex), and Brodman area 17 (occipital cortex). Not all brain regions are represented in all cases; e.g., Huntington's disease is characterized in part by neurodegeneration in the globus palladus, thus this region is impossible to obtain from confirmed Huntington's cases. Likewise Parkinson's disease is characterized by degeneration of the substantia nigra making this region more difficult to obtain. Normal control brains were examined for neuropathology and found to be free of any pathology consistent with neurodegeneration.

In the labels employed to identify tissues in the CNS panel, the following abbreviations are used:

PSP = Progressive supranuclear palsy

Sub Nigra = Substantia nigra Glob Palladus= Globus palladus

Temp Pole = Temporal pole

Cing Gyr = Cingulate gyrus

BA 4 = Brodman Area 4

Panel CNSJ feurodegeneration Vl .O The plates for Panel CNS_Neurodegeneration_Vl .0 include two control wells and

47 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean Hospital) and the Human Brain and Spinal Fluid Resource Center (VA Greater Los Angeles Healthcare System). Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80°C in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

In the labels employed to identify tissues in the CNS_Neurodegeneration_Vl .0 panel, the following abbreviations are used:

SupTemporal Ctx = Superior Temporal Cortex

Inf Temporal Ctx = Inferior Temporal Cortex

A. CG100126-01: Keratin Associated Protein Expression of gene CGI 00126-01 was assessed using the primer-probe set Ag4163, described in Table AA. Results of the RTQ-PCR runs are shown in Tables AB, AC and AD.

Table AA. Probe Name Ag4163

Table AB. General_screeningjpanel_vl.4

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Table AC. Panel 4.1D

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Table AD. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4163 Results from one experiment with the CGI 00126-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screening_panel_vl.4 Summary: Ag4163 Highest expression of the CG 100126-01 gene is detected in Melanoma LOXIM VI and a colon cancer HCT- 1 16 cell lines (CTs=33.8). In addition, significant expression of this gene is also detected in a breast cancer T47D cell line. Therefore, expression of this gene can be used to distinguish these samples from other samples used in this panel and also as diagnostic marker for melanoma, colon and breast cancer. Furthermore, therapeutic modulation of this gene product can be useful in the treatment of these cancers.

Panel 4.1D Summary: Ag4163 Highest expression of the CG100126-01 gene is detected in kidney (CT=29). Moderate expression of this gene is also seen in lung, thymus and microvascular dermal endothelial cells. Therefore, expression of this gene can be used to distinguish these samples from other samples in this panel. In addition, therapeutic modulation of this gene can be useful in the treatment of autoimmune and inflammatory diseases that affect lung and kidney.

General oncology screening panel_v_2.4 Summary: Ag4163 Highest expression of the CGI 00126-01 gene is detected exclusively in melanoma sample(CT=29.8). Therefore, expression of this gene may be used as a diagnostic marker for detection of melanoma and therapeutic modulation of this gene product may be beneficial in the treatment of melanoma.

B. CG100146-01: UDP-GIucuronosyl Transferase Expression of gene CG100146-01 was assessed using the primer-probe set Ag4165, described in Table BA. Results of the RTQ-PCR runs are shown in Tables BB and BC.

Table BA. Probe Name Ag4165

Table BB. General_screening_panel_yl.4

Table BC. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4165 Expression of the CGI 00146-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General_screening_panel_vl.4 Summary: Ag4165 Highest expression of the CG100146-01 gene is detected exclusively in small intestine (Ct=32.7). In addition, low expression of this gene is also detected in liver. Thus, expression of this gene can be used to distinguish these samples from other samples used in this panel. Furthermore, therapeutic modulation of this gene product could be useful in the treatment of small intestine and liver related disorders. The CGI 00146-01 gene codes for UDP- glucuronosyltransferase. UDP-Glucuronosyltransferases (UGTs) are glycoproteins, which catalyze the confugation ofa broad variety of lipophilic aglycon substrates with glucuronic acid using UDP-glucuronic acid (UDP-GlcUA) as the sugar donor. The major function of glucuronidation is to change hydrophobic compounds into hydrophilic derivatives, a process which facilitates their detoxification and excretion (Radominska- Pandya et al., 2001, Curr Drug Metab 2(3):283-98, PMID: 11513331). Mutations in the UGT1 Al gene, one of the gene belonging to UGT family, are implicated in type I and type II Crigler-Najjar syndromes and the more common mild hyperbilirubinemia known as Gilbert syndrome (Kadakol et al., 2000, Hum. Mutat. 16: 297-306, PubMed ID:11013440). Thus, the CGI 00146-01 gene may also play a role in pathogenesis of Crigler-Najjar syndromes and Gilbert syndrome and therapeutic modulation of this gene could be beneficial in the treatment of these diseases.

Panel 4.1D Summary: Ag4165 Results from one experiment with the CG100146-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run. General oncology screening pan el_v_2.4 Summary: Ag4165 Highest expression of the CGI 00146-01 gene is detected in colon sample (CT=27.8). Expression of this gene is exclusive to colon samples, with lower expression in cancer samples compared to adjacent normal tissue. Therefore, this gene may play a role as tumor suppressor and therapeutic modulation to increase the activity of the gene product may be beneficial in the treatment of colon cancer. C. CG100179-01: Cyclophilin Like

Expression of gene CGI 00179-01 was assessed using the primer-probe set Ag4166, described in Table CA. Results of the RTQ-PCR runs are shown in Tables CB, CC, CD and CE.

Table CA. Probe Name Ag4166

Table CB. CNS neurodegeneration vl.O

Table CC. General_screening_panel_vl.4

Table CD. Panel 4.1D

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Table CE. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4166 This panel confirms the expression of the CGI 00179-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4166 Highest expression of the CGI 00179-01 gene is detected in the breast cancer T47D cell line (CT=26). High expression of this gene is seen in cluster of breast, ovarian, pancreatic, CNS, colon, gastric, renal, lung cancer cell lines and melanoma cell lines. Thus, therapeutic modulation of this gene could be beneficial in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4166 Highest expression of the CG100179-01 gene is detected in anti-CD95 CHI 1 treated secondary Thl/Th2/Trl cells (CT=28.5). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

General oncology screening panel_v_2.4 Summary: Ag4166 Highest expression of the CGI 00179-01 gene is detected in kidney cancer (CT=28.5), with significant expression also seen in melanoma, colon, lung, bladder, prostate and kidney cancers. In addition, expression of this gene is higher in the cancers than in the normal adjacent tissue. Therefore, expression of this gene could be as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.

D. CG100212-01 and CG100212-02: Novel Gene Belonging to Zinc-Containing Alcohol Dehydrogenase Superfamily

Expression of gene CGI 00212-01 and full length physical clone CGI 00212-02 was assessed using the primer-probe set Ag4167, described in Table DA. Results of the RTQ-PCR runs are shown in Tables DB, DC, DD and DE. Please note that CGI 00212-02 represents a full-length physical clone of the CGI 00212-01 gene, validating the prediction of the gene sequence.

Table DA. Probe Name Ag4167

Table DB. CNS neurodegeneration vl.O

Table DC. General_screeningjpanel_vl.4

Table DD. Panel 4.1D

Table DE. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4167 This panel confirms the expression of the CGI 00212-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4167 Highest expression of the CGI 00212-01 gene is detected in a breast cancer T47D cell line (CT=26). High expression of this gene is seen in cluster of breast, ovarian, colon, gastric, renal, lung, pancreatic, CNS, hepatic, prostate cancer cell lines and melanoma cell lines. Thus, therapeutic modulation of this gene product could be beneficial in the treatment of these cancers. Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Panel 4.1D Summary: Ag4167 Highest expression of the CG100212-01 gene is detected in IL-9 treated NCI-H292 cell line (CT=31). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

General oncology screening panel_v_2.4 Summary: Ag4167 Highest expression of the CGI 00212-01 gene is detected in kidney cancer (CT=28.9), with significant expression also seen in metastatic melanoma, colon, lung, bladder, prostate and kidney cancers. In addition, expression of this gene is higher in the cancers than in the normal adjacent tissue. Therefore, expression of this gene could be as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers. E. CG100222-01: NADP-Dependent Leukotriene B4

Expression of gene CGI 00222-01 was assessed using the primer-probe set Ag4169, described in Table EA. Results of the RTQ-PCR runs are shown in Tables EB and EC.

Table EA. Probe Name Ag4169

Table EB. General_screeningjpanel_vl.4

Table EC. Panel 4.1D

CNS_neurodegeneration_vl.O Summary: Ag4169 Expression of the CG100222-01 gene is low/undetectable (CTs > 34.5) across all of the samples on this panel (data not shown).

General_screening_panel_vl.4 Summary: Ag4169 Highest expression of the CGI 00222-01 gene is detected in ovarian cancer SK-OV-3 cell line (CT=28). In addition, low but significant expression of this gene is seen in CNS cancer, colon cancer, lung cancer, ovarian cancer and melanoma cell lines. Thus, expression of this gene could be used as diagnostic marker in detection of these cancers. Therapeutic modulation of this gene product through the use of antibodies or small molecule drugs, may be beneficial in the treatment of these cancers, [mpattu, 25-Mar-02]

Panel 4.1D Summary: Ag4169 Highest expression of the CG100222-01 gene is detected in Kidney (CT=29). Thus, expression of this gene can be used to distinguish the kidney sample from other samples used in this panel. In addition, low but significant expression of this gene is also seen in lung and thymus. Therefore, therapeutic modulation of this gene can be beneficial in the autoimmune and inflammatory diseases that affect lung and kidney.

Panel 5 Islet Summary: Ag4169 Expression of the CGI 00222-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag4169 Results from one experiment with the CGI 00222-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

F. CG100266-01 and CG100266-02: Cyclophilin A Like Gene

Expression of gene CGI 00266-01 and full length clone CGI 00266-02 was assessed using the primer-probe set Ag4174. described in Table FA. Results of the RTQ- PCR runs are shown in Tables FB. FC and FD.

Table FA. Probe Name Ag4174

Start SEQ ID

Primers Sequences [Length Position No

Forward 5 ' -gggagaaatttgatgacaagaa-3 ' 22 371 218

Probe TET-5 ' -cttcatcctaaagcacgcaggtcctg-3 ' -TAMRA; 26 393 219

Reverse 5 ' -actgtttgtgttgggtccagta-3 ' 1 22 438 220

Table FB. General_screening_panel_vl.4

03/010327

Table FC. Panel 4.1D

Rel. Exp.(%) JRel. Exp.(%) iTissue Name Ag4174, Run Tissue Name |Ag4174, Run 173507624 173507624 jSecondarv Thl act iO.O iHUVEC IL-1 beta !0.0 iSecondary Th2 act jO.O iHUVEC IFN gamma Io.o

Secondary Trl act JO.O HUVEC TNF alpha + IFN gamma 0.0 [Secondary T l rest (0.0 HUVEC TNF alpha + IL4 0.0

Table FD. General oncology screening panel_v_2.4

o on cancer 2 ;0.0 I Adenocarcinoma of the prostate 1 4.2

Colon cancer 3 jo.o Adenocarcinoma of the prostate 2 (0.0

Colon cancer NAT

^■0.0 Adenocarcinoma of the prostate 3 '5.6 J

CNS_neurodegeneration_vl.O Summary: Ag4174 Results from one experiment with the CGI 00266-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screening_panel_vl.4 Summary: Λg4174 Highest expression of the CGI 00266-01 gene is seen in a lung cancer cell line (CT=30.2). Significant levels of expression are also seen in fetal lung tissue, which is more proliferative than the adult counterpart. Thus, expression of this gene, a cyclophilin A homog. could be used to differentiate between fetal lung and adult lung and as a marker of lung cancer. This is in agreement with published reports that a novel cyclophilin like molecule is co-expressed in small cell lung cancer cell lines (Kim JO. Oncogene 1998 Aug 27; 17(8): 1019-26).

Furthermore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of lung cancer.

Low but significant levels of expression are also seen in the amygdala, hippocampus and whole and fetal brain. Cyclophilin A has been implicated in neuronal differentiation and human embryonic brain cells (Nahreini P, Cell Mol Neurobiol 2001 Feb;21(l):65-79). Based on the expression of this cyclophilin homolog in the CNS, modualation of the expression of this gene may be useful in the treatment of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy. Panel 4. ID Summary: Ag4174 Expression of the CG100266-01 gene is restricted to normal kidney, lung and thymus (CTs=30-34). This pattern of expression suggests that this gene product may be involved in the normal homeostasis of these tissues. Therapeutic modulation of the expression or function of this gene may be useful in maintaining or restoring function to these organs during inflammation. General oncology screening panel_v_2.4 Summary: Ag4174 Expression of the

CG100266-01 gene is restricted to a melanoma (CT=33.8). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker to detect the presence of melanoma. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of melanoma. G. CG100456-01: CoA Transferase-Like

Expression of gene CGI 00456-01 was assessed using the primer-probe set Ag4179, described in Table GA. Results of the RTQ-PCR runs are shown in Tables GB, GC and GD.

Table GA. Probe Name Ag4179

Table GB. General_screening_panel_vl.4

Renal ca. UO-31 13.9 jPancreas Pool 10.7

Table GC. Panel 4.1D

03/01032

HUVEC starved 53.2

Table GD. General oncology screening panel_v_2.4

General_screening panel_vl.4 Summary: Ag4179 Highest expression of the CGI 00456-01 gene is detected in a breast cancer BT 549 cell line (CT=24). High expression of this gene is seen in cluster of breast, ovarian, colon, gastric, renal, lung, pancreatic, CNS, hepatic, prostate cancer cell lines and melanoma cell lines. Thus, therapeutic modulation of this gene product could be beneficial in the treatment of these cancers.

In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus. cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1 D Summary: Ag4179 Highest expression of the CG100456-01 gene is detected in ionomycin treated Ramos B cells (CT=28). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in

General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. General oncology screening panel_v_2.4 Summary: Ag4179 Highest expression of the CGI 00456-01 gene is detected in malignant colon cancer (CT=26), with significant expression also seen in metastatic melanoma, colon, lung, bladder, prostate and kidney cancers. In addition, expression of this gene is higher in the cancers than in the normal adjacent tissue. Therefore, expression of this gene could be as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.

H. CG100466-01: Adenine Nucleotide Translocator 2 (ANT 2) (ADP/ATP Translocase 2)

Expression of gene CGI 00466-01 was assessed using the primer-probe set Ag4177. described in Table HA. Results of the RTQ-PCR runs are shown in Tables HB, HC and HD.

Table HA. Probe Name Ag4177

Start SEQ ID jPrimers Sequences Length

Position No iForward 5 ' - tgtgggtaaagctgaagctg- 3 ^■ 20 452 I 224

^!Probe TET- 5 ' -aggcctctgtgactgcctggttaaga-3 ' -TAMRA, 26 485 I 225 iReverse 5 ' -ttggtacaggcccttaatcc-3 ' 20 526 226

Control 3

115.1 ^•Control (Path) 2 Parietal Ctx 32.8 [Temporal Ctx

Control (Path)

!44.8 Temporal Ctx Control (Path) 3 Parietal Ctx ^!5.0

Control (Path) 2

42.9 Control (Path) 4 Parietal Ctx ;48.3 Temporal Ctx

Table HC. General_screening_panel_vl.4

Kidney Pool Adrenal Gland

Fetal Kidney ;4.5 [Pituitary gland Pool 10.8

JRenal ca. 786-0 J17.8 [Salivary Gland |4.0 jRenal ca. A498 J6.5 jThyroid (female) 1-2.1

Renal ca. ACHN il4.5 Pancreatic ca. CAPAN2 129.3

_;Renal ca. UO-31 11 1.9 (Pancreas Pool [4.8

Table HD. Panel 4.1D

CNS_neurodegeneration_vl.O Summary: Ag4177 This panel confirms the expression of the CG100466-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4177 Highest expression of the CGI 00466-01 gene is detected in a gastric cancer KATO III cell line (CT=22). High expression of this gene is seen in cluster of breast, ovarian, colon, gastric, renal, lung, pancreatic, CNS, hepatic, prostate cancer cell lines and melanoma cell lines. Thus, therapeutic modulation of this gene product could be beneficial in the treatment of these cancers.

The CGI 00466-01 gene codes for adenine nucleotide translocator (ANT 2) homologue. Dysfunctioning of the ANT2 have been shown to to induce myopathies in mouse and in humans (Fiore et al., 2001, Clin Chim Acta 311(2): 125-35, PMID: 11566172). ANT has a role in mtDNA maintenance and mutation in ANT has been implicated in autosomal dominant progressive external ophthalmoplegia and other mitochondrial diseases (Kaukonen et al., 2000, Science 289(5480):782-5, PMID: 10926541). Mice deficient in the heart muscle specific isoform of the ANT1 exhibit many of the hallmarks of human oxidative phosphorylation (OXPHOS) disease, including a dramatic proliferation of skeletal muscle mitochondria (Murdoch et al., 1999. J Biol Chem 274(20): 14429-33, PMID: 10318868). Therefore, therapeutic modulation of the ANT protein encoded by the CGI 00466-01 gene through the use of small molecule drug could be useful in the treatment mitochondria related diseases including autosomal dominant progressive external ophthalmoplegia and cancers. In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Panel 4. ID Summary: Ag4167 Highest expression of the CGI 00466-01 gene is detected in IL-9 treated NCI-H292 cell line (CT=25). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. General oncology screening panel_v_2.4 Summary: Ag4177 Results from one experiment with the CGI 00466-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run. 0

I. CG100609-01: Glutathione S-Transferase

Expression of gene CGI 00609-01 was assessed using the primer-probe set Ag4182, described in Table IA. Results of the RTQ-PCR runs are shown in Tables IB, IC and ID.

Table IA. Probe IN fame Ag4182

Start SEQ ID

Primers Sequences Length ] Position No

Forward 5 ' -ctctacatggacctgctgtca-3 ' 21 j 73 227

Probe TET- 5 ' -ccgtgccgtctacatcttctcgaag-3 ' -TAMRA 25 ! 102 228

Reverse 5 ' -agttgaactggatgtcatgctt-3 ' 22 i 127 229

Table IB. CNS_neurodegeneration_vl.O

Table IC. General_screening_panel_vl.4

Table ID. Panel 4.1D

CNS_neurodegeneration_vl.O Summary: Ag4182 This panel confirms the expression of the CGI 00609-01 gene at very low levels in the brain in an independent group of individuals. This gene is found to be upregulated in' the temporal cortex of Alzheimer's disease patients. Therefore, therapeutic modulation of the expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease.

General_screening_panel_vl.4 Summary: Ag4182 Highest expression of the CGI 00609-01 gene is detected in testis (CT=29). Thus, expression of this gene can be used to distinguish testis from other samples in this panel. In addition, therapeutic modulation of this gene can be useful in the treatment of testis related diseases such as fertility and hypogonadism.

Low levels of expression of this gene is also associated with a CNS cancer, colon cancer, lung cancer, and an ovarian cancer cell lines. Therefore, therapeutic modulation of this gene can be beneficial in the treatments of these cancers. Panel 4.1D Summary: Ag4182 Highest expression of the CG100609-01 gene is detected exclusively in kidney (CT=30.6). In addition low expression of this gene is also seen in thymus. Thus, expression of this gene can be used to distinguish these two samples from other samples in this panel. Furthermore, small molecule therapies designed with the protein encoded for by this gene could modulate kidney function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney, including lupus and glomerulonephritis

Panel CNS_1 Summary: Ag4182 Expression of the CGI 00609-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag4182 Expression of the CGI 00609-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

J. CG100710-01: AAA (ATPase Associated with Various Activities) Expression of gene CGI 00710-01 was assessed using the primer-probe set Ag4249, described in Table JA.

Table JA. Probe Name Ag4249

Probe TET-5 ' -tgccagccctgagcaagtgcc-3 ' -TAMRA! 21 235

Reverse j5 ' -ctgcagagcacagcactca-3 ' [ 19 262 -? T>

CNS neurodegeneration vl.O Summary: Ag4249 Expression of the CG100710-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel

(data not shown).

General_screening_panel_vl.4 Summary: Ag4249 Expression of the

CG100710-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel

(data not shown). Panel 4.1D Summary: Ag4249 Expression of the CG100710-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag4249 Expression of the

CGI 00710-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel

(data not shown).

K. CG100730-01: Exoribonuclease

Expression of gene CGI 00730-01 was assessed using the primer-probe set

Ag4187, described in Table KA. Results of the RTQ-PCR runs are shown in Tables KB,

KC, KD and KE. Table KA. Probe Name Ag4187

Table KB. CNS_neurodegeneration_vl.O

Table KC. General_screening_panel_vl.4

Table KD. Panel 4.1D

{Dendritic cells

;8.: !anti-CD40 (Neutrophils TNFa+LPS 4.3

Monoc\ -tes rest 19.2 Neutrophils rest |7.4

MonocNtes LPS 2/7 ^{" " "} Colon jo.o

Macrophages rest =8.5 Lung ^"J3.7

Macrophages LPS (0.0 Thymus |l7.9

HUVEC none lθ.8 Kidney jioo.o

HUVEC starved 1.0 1

Table KE. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4187 Results from one experiment with the CGI 00730-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screeningjpanel__vl.4 Summary: Ag4187 Highest expression of the CG100730-01 gene is detected in CNS cancer SNB-75 cell line (CT=32). In addition high expression of this gene is seen in pancreatic cancer, CNS cancer, renal, lung, breast and ovarian cancer cell line. Therefore, therapeutic modulation of this gene through the use of small molecule drugs can be useful in the treatment of these cancers.

In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, and cerebral cortex. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Panel 4.1D Summary: Ag4187 Highest expression of the CG100730-01 gene is detected in kidney (CT=32.7). Thus, expression of this gene can be used to distinguish kidney samples from other samples in this panel. Furthermore, small molecule therapies designed with the protein encoded for by this gene could modulate kidney function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney, including lupus and glomerulonephritis.

In addition, low expression of this gene is seen in resting primary Thl and Trl cells, activated CD45RO CD4 lymphocyte, 3 day Two Way MLR, eosinophils. monocytes, macrophages, dendritic cells, ionomycin treated basophils and thymus. Therefore, therapeutic modulation of this gene may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus. psoriasis, rheumatoid arthritis, and osteoarthritis. General oncology screening panel_v_2.4 Summary: Ag4187 Highest expression of the CG100730-01 gene is detected in lung cancer sample (CT=33.7). with significant expression also seen in metastatic melanoma, lung, prostate and kidney cancers. In addition, expression of this gene is higher in the cancers than in the normal adjacent tissue. Therefore, expression of this gene could be as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.

L. CG100819-01: Polynucleotide Phosphorylase

Expression of gene CGI 00819-01 was assessed using the primer-probe set Ag4195, described in Table LA. Results of the RTQ-PCR runs are shown in Tables LB, LC and LD.

Table LA. Probe Name Ag4195

Table LB. General_screening_panel_vl.4

Placenta iθ.6 jColon cancer tissue

(Uterus Pool jColon ca. SW1 1 16 .3.0

hl/Th2/Tι _anti- ;s.ι ,CCD 1106 (Keratinocytes) none |24.0 CD95CH11

CCDl 106 (Keratinocytes)

LAK cells rest 12.. 124.5 TNFalpha + IL-1 beta

Table LD. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4195 Results from one experiment with the CGI 00819-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screening_panel__vl.4 Summary: Ag4195 Highest expression of the CGI 00819-01 gene is detected in a gastric cancer NCI-N87 cell line (CT=25.3). High expression of this gene is seen in cluster of CNS cancer, colon, gastric, renal, lung, breast, ovarian, pancreatic, prostate, squamous cell carcinoma cell lines and melanoma. Therefore, therapeutic modulation of this gene could be beneficial in the treatment of these cancers. Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. Interestingly, expression of this gene is higher in fetal lung and liver (CTs=29) as compared to the corresponding adult tissues (CTs=32-33). Therefore, expression of this gene could be useful in distinguishing the fetal lung and liver from the corresponding adult tissues.

Panel 4.1D Summary: Ag4195 Highest expression of the CG100819-01 gene is detected in activated secondary Th2 cells (CT=27). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte. and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

General oncology screening panel_v_2.4 Summary: Ag4195 Highest expression of the CG100819-01 gene is detected in lung cancer (CT=28.7), with significant expression also seen in metastatic melanoma, colon, lung, prostate and kidney cancers. In addition, expression of this gene is higher in the cancers than in the normal adjacent tissue. Therefore, expression of this gene could be as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.

M. CG100872-01: Protein-Arginine Deiminase

Expression of gene CGI 00872-01 was assessed using the primer-probe sets Ag4197 and Ag4299, described in Tables MA and MB. Results of the RTQ-PCR runs are shown in Table MC. Table MA. Probe Name Ag4197

Table MB. Probe Name Ag4299

Table MC. Panel 4.1D jRel. j |ReI. Rel.

;Exp.(%) jRel. Exp.(%) ;Exp.(%) Exp.(%) Tissue Name g4197, g4299, Run Tissue Name g4197, Ag4299.

^■Run j l 83712613 jRun Run

1174255682 I T 74255682 1183712613

•Secondary Th 1 act 0.0 0.0 HUVEC IL-l beta 0.0 jO.O

^Secondary Th2 act O.O {0.0 JHUVEC IFN gamma 0.0 jo.o iHUVEC TNF alpha \

Secondary Trl act 0.5 29. 1 0.0 0.0 \+ IFN gamma

Secondary Th 1 _;HUVEC TNF alpha

,0.0 0.0 ^■0.0

^•rest ^!+ IL4 i

(Secondary Th2

0.0 0.0 'HUVEC IL-1 1 ,0.0 ;o.o

.Macrophages LPS .O 0.0 Thynuis 10.8 Ό.O

IHUVEC none 0.0 Ό.O iKidney 100.0 ^ΓI 00.0 JHUVEC starved 0.0 0.0

CNS_neurodegeneration_vl.O Summary: Ag4197/Ag4299 Expression of the CGI 00872-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General_screening_panel_vl.4 Summary: Ag4197 Expression of the CGI 00872-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 4.1D Summary: Ag4197/Ag4299 Low expression of the CG100872-01 gene is seen in kidney (CTs=32-36). Therefore, expression of this gene can be used to distinguish this sample from other samples used in this panel. In addition, therapeutic modulation of this gene can be useful in the treatment of autoimmune and inflammatory diseases that affect the kidney including lupus and glomerulonephritis.

General oncology screening panel_v_2.4 Summary: Ag4197 Expression of the CGI 00872-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

N. CG100980-01: Protein-Arginine Deiminase Type III Expression of gene CGI 00980-01 was assessed using the primer-probe set Ag4200, described in Table NA. Results of the RTQ-PCR runs are shown in Tables NB and NC.

Table NA. Probe Name Ag4200

Table NB. General_screening_panel_vl.4

Table NC. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4200 Expression of the CGI 00980-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General_screening__panel_vl.4 Summary: Ag4200 Highest expression of the CG100980-01 gene is detected in renal cancer ACHN cell line (CT=23.6). Significant expression of this gene is seen exclusively in cluster of CNS, pancreatic, colon, renal, lung, breast, ovarian, squamous cell carcinoma and prostate cancers cell lines. Therefore, expression of this gene can be used as diagnostic marker for these cancers and therapeutic modulation through the use of small molecule target could be useful in the treatments of these cancers.

Panel 4.1D Summary: Ag4200 Expression of the CGI 00980-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 5 Islet Summary: Ag4200 Expression of the CG100980-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag4200 Highest expression of the CGI 00980-01 gene is detected in bladder cancer (CT=28.7), with low but significant expression of this gene in squamous cell carcinoma, colon and prostate cancers. In addition, expression of this gene is higher in the cancers than in the normal adjacent tissue. Therefore, expression of this gene may be useful as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.

O. CG56763-01: GPCR

Expression of gene CG56763-01 was assessed using the primer-probe set Ag3012, described in Table OA. Results of the RTQ-PCR runs are shown in Tables OB and OC.

Table OA. Probe Name Ag3012

Table OB. Panel 1.3D

Salivary gland 2.8 Renal ca. UO-31 0.0

Pituitary gland 0.0 Renal ca. TK-10 0.0

Brain (fetal) 0.0 Liver 0.0

Brain (whole) 0.0 Liver (fetal) 0.0 jLiver ca. (hepatoblast)

Brain (amygdala) 12.6 0.0 ;HepG2

Brain (cerebellum) 0.0 iLung O.O iBrain (hippocampus) 5.5 Lung (fetal) .O jBrain (substantia nigra) 3.0 , Lung ca. (small cell) LX-1 ι l .4 iLung ca. (small cell) NCI-

Brain (thalamus) 3.1 0.0 IH69

'Lung ca. (s.cell var.) SHP-

Cerebral Cortex 0.0 12.4 ι77 iLung ca. (large cell)NCI-

Spinal cord 00.0 H460 ;o.o

Table OC. Panel 4D

ILAK cells 92 IL-9 18.9 jPMA/ionomycin io.o NCI-H2

INK Cells IL-2 rest o.o 0.0

CNS_neurodegeneration_vl.O Summary: Ag3012 Expression of this gene is low/undetectable (CTs > 34.5) across all of the samples on this panel (data not shown).

Panel 1.3D Summary: Ag3012 This gene is expressed at low levels in the samples derived from spinal cord (CT = 32.1) and testis (CT=33.6). Thus, the expression of this gene could be used to distinguish these samples from the other samples in the panel. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of CNS disorders, fertility and hypogonadism.

Panel 4D Summary: Ag3012 This gene is expressed at low levels in a sample derived from liver cirrhosis (CT = 33.4). In addition, expression of this gene is not detected in normal liver in Panel 1.3D, suggesting that its expression is unique to liver cirrhosis. This gene encodes a putative GPCR; therefore, antibodies or small molecule therapeutics could reduce or inhibit fibrosis that occurs in liver cirrhosis. This gene is also expressed at low levels in the lung and colon.

General oncology screening panel_v_2.4 Summary: Ag3012 Expression of this gene is low/undetectable (CTs > 34.5) across all of the samples on this panel (data not shown).

P. CG56777-01: Prostaglandin-F Synthase 1

Expression of gene CG56777-01 was assessed using the primer-probe set Ag3017, described in Table PA.

Table PA. Probe Name Ag3017

CNS_neurodegeneration_vl.O Summary: Ag3017 Results from one experiment with the CG56777-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 1.3D Summary: Ag3017 Expression of the CG56777-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 4D Summary: Ag3017 Expression of the CG56777-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag3017 Expression of the CG56777-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Q. CG56941-01: >ptnr:SPTREMBL-ACC:O60523 Ribonuclease H Type II

Expression of gene CG56941-01 was assessed using the primer-probe set Ag3096. described in Table QA. Results of the RTQ-PCR runs arc shown in Tables QB, QC. QD and QE.

Table QA. Probe Name Ag3096

Table QB. CNS_neurodegeneration_vl.O

Brain (substantia

0.0 Lung ca. (small cell) LX-1 ;0.3 nigra)

Lung ca. (small cell) NCI- iBrain (thalamus) 0.3 iθ.1 H69^"

Tung ca. (s.cell var.) SHP-

Cerebral Cortex 1.4

77

:o. Lung ca. (large cell)NCI-

ISpinal cord .0.4 H460

Lung ca. (non-sm. cell) glio/astro U87-MG iθ.5 11.2 A549 glio/astro U-1 18- Lung ca. (non-s.cell) NC1- O. l 0.3 MG .H23^{^~} jastrocytoma Lung ca. (non-s.cell) HOP-

0.2 0.1 1SW1783 62 ineuro*; met SK-N- Lung ca. (non-s.cl) NCI- _n .,

^■4.1 !AS H522 astrocytoma SF-539 . l Lung ca. (squam.) SW 900 ,0.1

Table QE. General oncology screening panel_v_2.4

Tissue Name

jColon cancer

CNS_neurodegeneration_vl.O Summary: Ag3096 This panel confirms the expression of the CG56941-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

Panel 1.3D Summary: Ag3096 Highest expression of the CG56941-01 gene is detected in brain (cerebellum) (CT=27.7). In addition, high to moderate expression of this gene is also detected in fetal brain and other regions of central nervous systems, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Low levels of expression of this gene is also seen in a ovarian cancer, two lung cancer, liver cancer, a colon cancer and a CNS cancer cell line. Therefore, therapeutic modulation of this gene could be useful in the treatment of these cancers.

Panel 4.1D Summary: Ag3096 Highest expression of the CG56941-01 gene is detected in microvascular dermal endothelial cells (CT=34.4). In addition, low levels of expression of this gene is also seen in dendritic cells, and two way MLR. Therefore, therapeutic modulation of this gene could be useful in the treatment of autoimmune and inflammatory diseases that involve these cells, such as lupus erythematosus, asthma, emphysema, Crohn's disease, ulcerative colitis, rheumatoid arthritis, osteoarthritis, and psoriasis. General oncology screening panel_v_2.4 Summary: Ag3096 Highest expression of the CG56941-01 gene is detected in lung cancer (CT=34.3). Expression of this gene is higher in the cancer sample than in the corresponding adjacent control sample (CT=39.6). Thus, expression of this gene may be useful as diagnostic marker for detection of lung cancer and therapeutic modulation of this gene may be useful in the treatment of this cancer.

R. CG57109-01 and CG57109-02 and CG57109-03 and CG57109-04 and CG57109-05 and CG57109-06: Doublecortin/CAMKinase

Expression of gene CG57109-01 , variants CG57109-02, CG57109-03, CG57109- 04, CG57109-06 and full length physical clone CG57109-05 was assessed using the primer-probe sets Agl 137, Agl 150, Agl860, Ag31 12 and Ag4281 , described in Tables RA, RB, RC, RD and RE. Results of the RTQ-PCR runs are shown in Tables RF, RG, RH, Rl, RJ, RK, RL, RM and RN. Please note that the variants CG57109-03, CG57109-04, CG57109-06 correspond to the probe and primer sets Agl50 and Ag3112 only. CG57109- 05 represents a full-length physical clone of the CG57109-01 gene, validating the prediction of the gene sequence.

Table RA. Probe Name Agl 137

1 T Start SEQ ID

Primers jSequences iLength

1 4 1 Position No

Forward 5 ' -gacatggtggacagtgagatct-3 ' J 22 1338 257

Probe ιTET-5 ' -cctctctcaccccaacatcgtgaaat-3 ' -TAMRA 26 j 1373 258

Reverse J5 ' -tctgtttcgtagacttcatgca-3 ' 22 1399 259

Table RB. Probe Name Agl 150

Start 1 SEQ ID

Primers Sequences Length Position j No

Forward 5 ' -gaaattggctgattttggactt-3 ' 22 1634 260

Probe TET-5 ' -cctatatttactgtgtgtgggacccca-3 ' -TAMRA 27 1674 ]^~~261

Reverse 5 ' -agaatttcgggagctacgtaag-3 ' 22 1702 1 262

Table RC. Probe Name Agl860

Table RD. Probe Name Ag3112

Table RE. Probe Name Ag4281

Table RF. Al comprehensive panel vl.O

Table RH. General_screening_panel_vl.4

Table RJ. Panel 2.2

Tissue Name Rel. Exp.(%) Tissue Name Rel. Exp.(%)

Kidney Ca, Nuclear

0.0 Gastric Cancer 064005 48.0 grade 3 (OD04348)

Table RK. Panel 3D

Secondary Th2 rest 0.0 iHUVEC IL-11 0.0

0

Table RM. Panel 4D

03/010327

Table RN. Panel CNS 1

|Rei. Exp.(%)Agl860, Rel. Exp.(%)Agl860,

Tissue Name Tissue Name IRun 171634856 Run 171634856

03/010327

AI_comprehensive panel_vl.0 Summary: Agl 860 Highest expression of the CG57109-01 transcript in this panel is seen in synovium from an OA patient (CT=33.7). Overall, this gene is expressed in OA tissue but not in normal joint tissue and is expressed in pulmonary tissue from patients with atopic asthma but not in normal lung tissue. Please see panel 4D for discussion of utility of this gene in inflammation.

CNS_neurodegeneration_vl.O Summary: Agl 860/Ag31 12/Ag4281 Three experiments with two different probe and primer sets produce results that are in very good agreement. This panel does not show differential expression of the CG57109-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system. One experiment with Ag6051 , which is specific to CG57109-06 only, is in general agreement with the results above. Highest expression in this panel was in the temporal cortex of an Alzheimer's patient (CT=34.6).

General_scrcening_panel_vl.4 Summary: Ag4281 Highest expression of the CG57109-01 gene appears to be in the fetal brain (CI 29.5). Overall, expression of this gene appears to be highly brain-specific in this panel, with moderate levels of expression in the amygdala, hippocampus, thalamus and spinal cord and low but significant levels in the cerebral cortex and the substantia nigra. This gene encodes a novel doublecortin/CAM kinase like protein. Other members of this family have been implicated in the calcium- signaling pathway that controls neuronal migration in the developing brain. In addition, CAM kinase has been shown to play a crucial role in hippocampal LTP from studies in transgenic and knock-out mice, and may also play a role in memory formation in the mature nervous system as well as the developing brain. CAM kinases have also been shown to phosporylate tau, an integral component of the neuro fibrillary tangles seen in Alzheimer's, in a manner which shifts tau electrophorytic motility to that seen in the AD brain. Furthermore, tau from AD brains shows aberrent phosphorylation. Thus, based on the expression of this DCAM kinase homolog in the brain, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of learning and memory deficits that are a result of aging or neurodegenerative disease and also in the treatment of neurologic disorders themselves, including Alzheimer's disease. Moderate to low levels of expression are also seen in a variety of samples from normal tissues, including testis, fetal and adult heart and skeletal muscle and fetal lung.

In addition, this gene is expressed at much higher levels in fetal lung (CT=32.3) when compared to expression in the adult counterpart (CT=40). Thus, expression of this gene may be used to differentiate between the fetal and adult source of this tissue.

Panel 1.3D Summary: Agl860/Ag31 12 Two experiments with the same probe and primer set produce results that are in excellent agreement, with highest expression of the CG57109-01 gene in the spinal cord (CTs=31.7). Expression of this gene is restricted to the nervous system and the testis. Thus, expression of this gene could be used to differentiate between neural and non-neural tissue. Please see Panel 1.4 for further discussion of utility of this gene in the CNS.

Panel 2.2 Summary: Agl860 Expression of the CG57109-01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown.)

Panel 3D Summary: Ag31 12 Expression of the CG57109-01 gene is restricted to a sample derived from a lung cancer cell line (CT=32.6). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker to detect the presence of lung cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of lung cancer.

Panel 4.1D Summary: Agl 860 This CG57109-01 transcript is highly expressed in activated dermal fibroblasts, endothelial cells, and astrocytes after treatment with IL-1 or TNFalpha. Highest expression is seen in treated HPAECs (CT=31.3). Please see panel 4D for discussion of utility of this gene in inflammation.

Panel 4D Summary: Agl 860 This transcript is highly expressed in activated dermal fibroblasts, endothelial cells, and astrocytes after treatment with IL-1 or TNFalpha, with highest expression in TNF alpha and IL-1 beta treated HPAECs (CT=30.9). This protein has homology to protein kinase and may be involved in leukocyte extravasation from the peripheral blood into tissues. (Borbiev T, Am J Physiol Lung Cell Mol Physiol 2001 May;280(5):L983-90) Therefore, antagonistic therapeutics designed against the protein encoded by this transcript may reduce or inhibit inflammation due to asthma, allergy, emphysema, osteoarthritis, colitis, psoriasis, or delayed type hypersensitivity. Agonistic therapies may also direct leukocyte traffic into tumors or sites of infection. Ag3112 Highest expression of the transcript is seen in IL-1 beta treated dermal fibroblasts (CT=30.4). Expression is in agreement with the profile seen with Agl 860, except no expression is seen in astrocytes.

Panel CNS_1 Summary: Agl 860 This panel confirms expression of the CG57109-01 gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General oncology screening panel_v_2.4 Summary: Agl 860 Expression of the CG57109-01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown.) Ag6051 Expression of the CG57109-06 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown.)

S. CG57366-01: Kiaal223

Expression of gene CG57366-01 was assessed using the primer-probe set Ag3219, described in Table SA. Results of the RTQ-PCR runs are shown in Tables SB, SC, SD and SE.

Table SA. Probe Name Ag3219

03/01032

03/010327

Table SD. Panel 2.2

Bronchial epithelium

.Primarv Thl rest jl.6 124.3 TNFalpha + IL1 beta

CNS_neurodegeneration_vl.O Summary: Ag3219 Two experiments with the same probe and primer set produce results that are in excellent agreement. This gene is downregulated in the temporal cortex of Alzheimer's disease patients when compared with non-demented controls (p = 0.001 when analyzed by Ancova, estimate of total cDNA loaded per well used asa covariate). Therefore, up-regulation of this gene or its protein product, or treatment with specific agonists for this receptor may be of use in reversing the dementia/memory loss and neuronal death associated with this disease.

Panel 1.3D Summary: Ag3219 Highest expression of the CG57366-01 gene is seen in an ovarian cancer cell line (CT=29.9). In addition, expression appears to be significant in all the cell lines on this panel. In addition, this gene appears to be expressed in most of the samples on this panel, suggesting a role for this gene product in cell survival and proliferation. Thus, expression of this gene could be used as a marker of ovarian cancer. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of cancer. Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, thyroid, skeletal muscle, heart, and adult and fetal liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

This gene is also expressed at moderate to low levels in the CNS, including the hippocampus, thalamus. substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

Panel 2.2 Summary: Ag3219 Highest expression of the CG57366-01 gene is seen in breast cancer (CT=29.3). In addition, significant expression is seen in a cluster of breast cancer samples. Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker to detect the presence of breast cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of breast cancer.

Panel 4D Summary: Ag3219 Highest expression of the CG57366-01 gene is seen in untreated HUVEC (CT=27.7). Expression on this panel is seen mainly in endothelial cells and fibroblasts from lung and skin, basophils and astrocytes, and normal lung, thymus and kidney. Thus, this gene product may be involved in pathological and inflammatory lung and skin conditions, including asthma, emphysema, allergy and psoriasis. T. CG57368-01: Adenylate Cyclase Type IV

Expression of gene CG57368-01 was assessed using the primer-probe set Ag3221, described in Table TA. Results of the RTQ-PCR runs are shown in Tables TB, TC, TD and TE.

Table TA. Probe Name Ag3221

Table TB. CNS neurodegeneration vl.O

Table TC. Panel 1.3D jRel. Exp.(%) jRel. Exp.(%)Ag3221,

Tissue Name !Ag3221.Run (Tissue Name 'Run 168014001 ;168014001 jLiver adenocarcinoma .4 kidney (fetal) 73.2 •Pancreas 9.3 •Renal ca.786-0 0.0

Table TD. Panel 2.2

O 030

Table TE. Panel 4D

03/010327

CNS_neurodegeneration_vl.0 Summary: Ag3221 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

Panel 1.3D Summary: Ag3221 Highest expression of the CG57368-01 gene is detected in mammary gland (CT=30). High expression of this gene is seen mainly in the normal tissue samples suggesting an important role in cellular function. Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Panel 2.2 Summary: Ag3221 Highest expression of the CG57368-01 gene is detected in control kidney (OD04348) sample (CT=32.7). Expression of this gene is generally higher in the normal control margin samples as compared to the cancer tissues. Interestingly, expression of this gene is higher in kidney cancer nuclear grade 2 (OD04338) (Ct=33.5) as compared to corresponding control sample (Ct=36.4). Therefore, expression of this gene can be used as a diagnostic marker for nuclear grade 2 kidney cancer and therapeutic modulation of this gene could be beneficial in the treatment of kidney cancer. Panel 4D Summary: Ag3221 Highest expression of the CG57368-01 gene is detected in TNFalpha + IL-lbeta treated lung microvascular EC (CT=28). In addition, moderate to low expression of the gene is also seen in resting primary and secondary Thl,Th2,Trl, B lymphocytes, LAK cells, dendritic cells, monocytes, macrophages, endothelial cells, eosinophils, small airway epithelium, dermal fibroblasts, lupus kidney and normal tissues represented by colon, lung, thymus and kidney. Therefore, therapeutic modulation of this gene through the use of small molecul drug may be useful in the treatment of autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis

Panel CNS_1 Summary: Ag3221 Results from one experiment with the CG57368-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

U. CG59955-01: GPCR

Expression of gene CG59955-01 was assessed using the primer-probe set Ag3637. described in Table UA.

Table UA. Probe Name Ag3637

CNS_neurodegeneration_vl.0 Summary: Ag3637 Expression of the CG59955- 01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown.)

General_screening_panel_vl.4 Summary: Ag3637 Expression of the CG59955- 01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown.)

Panel 4.1D Summary: Ag3637 Expression of the CG59955-01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown.)

General oncology screening panel_v_2.4 Summary: Ag3637 Expression of the CG59955-01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown.) V. CG89211-01: GPCR

Expression of gene CG89211-01 was assessed using the primer-probe set Ag3691, described in Table VA. Results of the RTQ-PCR runs are shown in Table VB.

Table NA. Probe Name Ag3691

,. . ^■ Start SEQ ID

Primers iSequences • Length _. . .

! • Position No

Forwardj5 ' -tgcatt .ttaattcgtccagttc- 3 ' ^■ 22 , 464 281

Probe ITET- S ' - CS ictcccgataatctatct catctaccg- 3 ' -TAMRA¹ 28 ; 492 282 Reverse |5 ' -atgagc :ctgacaaaatggtaaa- ₃ > ! 22 , 520 283

Table NB. Genera il oncology screening panel_v_2.4

01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown.)

General_screening_panel_vl.4 Summary: Ag3691 Expression of the CG8921 1 - 01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown.)

Panel 4.1D Summary: Ag3691 Expression of the CG8921 1-01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown.)

General oncology screening panel_ _2.4 Summary: Ag3691 Expression of the CG89211-01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown.)

W. CG90530-02: Ubiquitin-Conugating Enzyme

Expression of full length physical clone CG90530-02 was assessed using the primer-probe sets Ag3410 and Ag4036, described in Tables WA and WB. Results of the RTQ-PCR runs are shown in Tables WC, WD, WE and WF.

Table WA. Probe Name Ag3410

Table WB. Probe Name Ag4036

Table WC. CNS neurodegeneration vl.O

IAD 4 Hippo 1 1 ;AD 2 Occipital Ctx

0.0 ^'(Missing)

AD 5 Hippo 80.7 ■AD 3 Occipital Ctx 11.6

AD 6 Hippo ;32.3 lAD 4 Occipital Ctx 114.1

Control 2 Hippo G0.4 {AD 5 Occipital Ctx 148.3

JControl 4 Hippo O.8 IAD 6 Occipital Ctx _ ' 10.2

JControl (Path) 3

0.9 jControl 1 Occipital Ctx |θ.5 ■Hippo

.AD 1 Temporal 4.5 Control 2 Occipital Ctx !76.8 ^!Ctx

AD 2 Temporal 29.3 Control 3 Occipital Ctx 7.0 Ctx

AD 3 Temporal

1.7 Control 4 Occipital Ctx .^' 1 .9 Ctx

Temporal Ctx I Ctx

Table WD. General_screening_panel_vl.4

Table WE. Panel 4D

Dendritic cells LPS ^'0.1 JDermal fibroblast IL-4 5.8

^■Dendritic cells anti-

IBD Colitis 2 0.4

,CD40 jMonocytes rest lo. i 1IBD Crohn's .l

Monocytes LPS 0.0 Colon 0.9

Macrophages rest 2.7 Lung 0.6

Macrophages LPS 0.1 Thymus 0.4

HUVEC none 8.0 Kidney 8.1

HUVEC starved 28.1

Table WF. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.0 Summary: Ag3410 This panel does not s ow differential expression of the CG90530-02-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Ag3410/Ag4036 Two experiments with the same probe and primer set produce results that are in excellent agreement. Highest expression of the CG90530-02 gene is seen in a colon cancer cell line (CTs=25- 26). In addition, expression is significantly higher in all the cancer cell lines on this panel when compared to expression in the normal tissues. Thus, expression of this gene could be used as a marker of cancer. In addition, this gene is expressed at much higher levels in fetal lung, liver, kidney and heart tissue (CTs=28-30) when compared to expression in the adult counteφart (CTs=33-36). Thus, expression of this gene may be used to differentiate between the fetal and adult source of these tissues. This gene encodes a putative member of the ubiquitin conjugating enzyme family. Ubiquitin-dependent protein degradation plays a role in many cellular processes and has been shown to be upregulated in some cancers (Eliseeva E. Cell Growth Differ 2001 Aug;12(8):427-33) Furthermore, higher levels of expression of this gene in cancer cell lines and fetal tissues suggests that therapeutic modulation of the expression or function of this gene may be useful in the treatment of cancer.

Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

This gene is also expressed at moderate levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex.

Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

Panel 4D Summary: Ag3410 Highest expression of the CG90530-02 is seen in PWM stimulated B lymphocytes (CT=23.7). High levels of expression are also seen in activated T cells, LAK cells, dermal fibroblasts and the pulmonary mucoepidermoid cell line NCI-H292. Thus, therapeutic regulation of the transcript or the protein encoded by the transcript could be important in immune modulation and in the treatment of T and B cell- mediated diseases such as asthma, arthritis, psoriasis, IBD, and lupus.

General oncology screening panel_v_2.4 Summary: Ag3410/Ag4036 Two experiments with the same probe and primer set produce results that are in excellent agreement. Highest expression of the CG90530-02 gene is seen in lung cancer (CTs=28- 31). In addition, this gene appears to be overexpressed in lung, kidney and colon cancers when compared to expression in normal adjacent tissue. Thus, expression of this gene could be used as a marker of lung and colon cancer. Ubiquitinylation is a cyclical process operating in all cells to target specific proteins (eg, p53) for degradation. Abnormal accumulations of ubiquitinylated proteins have been identified in colorectal carcinoma. This gene encodes a putative ubiquitin conjugating enzyme. Therefore, therapeutic modulation of the expression or function of this gene could be effective in the treatment of lung, kidney and colon cancer.

X. CG93076-01: GPCR

Expression of full length physical clone CG93076-01 was assessed using the primer-probe set Ag2129, described in Table XA. Results of the RTQ-PCR runs are shown in Tables XB and XC.

Table XA. Probe Name Ag2129

Table XB. Panel 1.3D

Panel 1.3D Summary: Ag2129 Expression of the CG93076-01 gene is restricted to a sample derived from a lung cancer cell line (CT-34.3). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker to detect the presence of lung cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of lung cancer.

Panel 4D Summary: Ag2129 Expression of the CG93076-01 gene is highest in liver cirrhosis (CT=31.8). Low but significant levels of expression are seen in primary resting T cells, colon, kidney, lung, LAK cells, and untreated CD4s. Expression of this gene is not detected in normal liver in Panel 1.3D, suggesting that its expression is unique to liver cirrhosis. This gene encodes a putative GPCR; therefore, antibodies or small molecule therapeutics could reduce or inhibit fibrosis that occurs in liver cirrhosis. In addition, antibodies to this putative GPCR could also be used for the diagnosis of liver cirrhosis.

Y. CG94235-01 : Thymidylate Kinase

Expression of gene CG94235-01 was assessed using the primer-probe sets Agl980 and Ag3909, described in Tables YA and YB. Results of the RTQ-PCR runs are shown in Tables YC, YD, YE, YF, YG, YH, YI and YJ.

Table YA. Probe Name Agl980

Table YB. Probe Name Ag3909

Start SEQ ID

Primers (Sequences Length

1 i Position No

Forward 15 ' -caggtgccacgtctaactagat-3 ' j 22 1307 296

Probe TET-5 ' -tgttgtttgaaacatctacatccacca-3 ' -TAMRA] 27 1333 297

Reverse 15 ' -gaaatttgggaacactgcataa-3 ' |^~ 22 1364 298

Table YC. Al comprehensive panel vl.O

Table YD. CNS neurodegeneration vl.O

O 03/010

Table YE. General_screeningjpanel_vl.4

Table YF. Panel 1.3D

Table YG. Panel 2D

Table YH. Panel 4.1D

ΪRel. Exp.(%) IRel. Exp.(%)

Tissue Name ^;Ag3909. Run Tissue Name Ag3909, Run

170127176 170127176

Secondary Thl act 0.9 HUVEC IL-lbeta 0. Secondary Th2 act 32.3 iHUVEC IFN gamma ^■0.9

030

Table YI. Panel 4D

Table YJ. Panel 5 Islet

AI_comprehensive panel_vl.O Summary: Agl 980 Two experiments with the same probe and primer produce results that are in excellent agreement, with highest expression in normal tissue adjacent to psoriasis (CTs=30.5-31.2). This target is induced in bone tissue, synovial fluid, synovial fluid cells and synovium from arthritis patients (rheumatoid-RA and osteoarthritis-OA); In addition, the expression of this transcript in these samples from normal patients is much lower. Other tissues including skin and lung also express this transcript. However, a consistent expression in diseased tissue, as compared to adjacent tissue or normal lung, is not apparent. This may be due to contamination with activated monocytes which highly express this transcript (see panel 4.1D)

CNS_neurodegeneration_vl.0 Summary: Ag3909 This panel does not show differential expression of the CG94235-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system. General_screening_panel_vl.4 Summary: Ag3909 Two experiments with the same probe and primer produce results that are in excellent agreement, with highest expression of the CG94235-01 gene in a gastric cancer cell line (CTs=23.6-24.4). Thus, expression of this gene could be used as to differentiate this sample from other samples on this panel and as a marker of gastric cancer. This gene encodes a putative thymidylate kinase, a DNA synthesis enzyme necessary for cell growth. Thus, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of gastric cancer. Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic disorders. Dysregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

In addition, this gene is expressed at much higher levels in fetal lung, liver and skeletal muscle tissue (CTs=28-30) when compared to expression in the adult counterpart (CTs=32.5-35). Thus, expression of this gene may be used to differentiate between the fetal and adult source of these tissues.

This gene is also expressed at moderate to low levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

Panel 1.3D Summary: Agl 980 Highest expression of the CG94235-01 gene in this panel is seen in a gastric cancer cell line (CT=26). Overall, expression is in reasonable agreement with the results in Panel 1.4. Moderate to low levels of expression are seen in metabolic tissues including adipose, adult and fetal liver, skeletal muscle, heart, pituitary, thyroid, adrenal and pituitary. Moderate to low levels of expression are seen in all CNS regions examined.

In addition, higher levels of expression are seen in fetal liver (CT=30.2) when compared to expression in adult liver (CT=33.7). Thus, expression of this gene could be used to differentiate between the adult and fetal sources of this tissue. Panel 2D Summary: Agl 980 Highest expression of the CG94235-01 gene is seen in normal bladder (CT=27.3). In addition, higher levels of expression are seen in ovarian, bladder and lung cancers when compared to expression in normal adjacent tissue. Thus, expression of this gene could be used as a marker of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of ovarian, bladder and lung cancers.

Panel 4.1D Summary: Ag3909 Highest expression of the CG94235-01 gene is seen in LPS treated monocytes. (CT=25.4). Prominent levels of expression are also seen in LPS activated macrophages and dendritic cells. This transcript may encode a protein that is important in the normal regulation of cytokines. Inappropriate regulation of the protein encoded by this gene may result in the enhanced and uncontrolled expression of inflammatory cytokines. Therefore, designing therapies that could regulate the expression (such as antisense therapies) or function of the protein encoded by this gene may be important in the treatment of osteoarthritis and rheumatoid arthritis as well as other diseases.

Panel 4D Summary: Agl980 The expression profile of the CG94235-01 gene in this panel is similar to the expression pattern seen in Panel 4. ID using the Ag3909 probe and primer set, except it is also expressed in LAK cells. This may reflect differences between panel 4 and 4.1 or slightly different amplicons. Please see panel 4. ID for discussion of utility of this gene in inflammation.

Panel 5 Islet Summary: Ag3909 Highest expression of the CG94235-01 gene is seen in islet cells (CT=33.4). Low but significant levels of expression are seen in other metabolic tissues, including adipose, placenta and skeletal muscle. Please see Panel 1.4 for discussion of utility of this gene in metabolic disease.

General oncology screening panel_v_2.4 Summary: Ag3909 Results from one experiment with the CG94235-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Z. CG94235-02: Splice Variant of CG94235-01

Expression of gene CG94235-02 was assessed using the primer-probe sets Ag3909 and Ag6052, described in Tables ZA and ZB. Results of the RTQ-PCR runs are shown in Tables ZC, ZD, ZE, ZF, ZG and ZH. Table ZA. Probe Name Ag3909

Start j SEQ ID^'

Primers Sequences Length Position j No

Forward 5 ' -caggtgccacgtctaactagat-3 ' 22 1529 } 299

Probe TET- 5 ' -tgttgtttgaaacatctacatccacca-3 ' -TAMRA 27 1498 | 300

Reverse 5 ' -gaaatttgggaacactgcataa- 3 ' 22 1472 j 301

Table ZB. Probe Name Ag6 952

Table ZD. General_screening_panel_vl.4

Table ZE. General_screening_panel_vl.5

Table ZF. Panel 4.1D

Table ZG. Panel 5 Islet

Table ZH. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag3909 This panel does not show differential expression of the CG94235-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system. A second experiment with the probe and primer set Ag6052, which is specific for the CG94235-02 variant, shows low/undetectable levels of expression in all the samples on this panel (CTs>35). (Data not shown.)

General_screening_panel_vl.4 Summary: Ag3909 Two experiments with the same probe and primer produce results that are in excellent agreement, with highest expression of the CG94235-01 gene in a gastric cancer cell line (CTs=23.6-24.4). Thus, expression of this gene could be used as to differentiate this sample from other samples on this panel and as a marker of gastric cancer. This gene encodes a putative thymidylate kinase, a DNA synthesis enzyme necessary for cell growth. Thus, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of gastric cancer. Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

In addition, this gene is expressed at much higher levels in fetal lung, liver and skeletal muscle tissue (CTs=28-30) when compared to expression in the adult counteφart (CTs=32.5-35). Thus, expression of this gene may be used to differentiate between the fetal and adult source of these tissues. This gene is also expressed at moderate to low levels in the CNS. including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease. Parkinson's disease. schizophrenia, multiple sclerosis, stroke and epilepsy. General_screeningjpanel_vl.5 Summary: Ag6052 Expression of the CG94235-

02 variant appears to be restricted to a gastric cancer cell line (CT=31.2) and normal bladder (CT=34.2) in this panel. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of gastric cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric cancer. Panel 4.1D Summary: Ag3909/Ag6502 Two experiments with two different probe and primer sets produce results that are in very good agreement. Highest expression of the CG94235-01 gene is seen in LPS treated monocytes. (Ag3909 CT=25.4; Ag6502 CT=31.1). Prominent levels of expression are also seen in LPS activated macrophages and dendritic cells. This transcript may encode a protein that is important in the normal regulation of cytokines. Inappropriate regulation of the protein encoded by this gene may result in the enhanced and uncontrolled expression of inflammatory cytokines. Therefore, designing therapies that could regulate the expression (such as antisense therapies) or function of the protein encoded by CG94325-01this gene may be important in the treatment of osteoarthritis and rheumatoid arthritis as well as other diseases.

General oncology screening panel_v_2.4 Summary: Ag3909 Results from one experiment with the CG94235-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run. A second experiment with the probe and primer set Ag6052, which is specific for the CG94235-02 variant, shows low/undetectable levels of expression in all the samples on this panel (CTs>35). (Data not shown.)

AA. CG94692-01 and CG94692-02: Carnitine/Acylcarnitin Translocase Expression of gene CG94692-01 and full length physical clone CG94692-02 was assessed using the primer-probe set Ag3941 , described in Table AAA. Results of the RTQ-PCR runs are shown in Tables AAB, AAC, AAD and AAE. Please note that CG94692-02 represents a full-length physical clone of the CG94692-01 gene, validating the prediction of the gene sequence. Table AAA. Probe Name Ag3941

Table AAB. CNS_neurodegeneration_vl.O

Table AAC. General_screeningjpanel_vl.4

Table AAD. Panel 4.1D

CNS neurodegeneration vl.O Summary: Ag3941 The CG94692-01 gene appears to be slightly dow nregulated in the brains of Alzheimer's patients, when compared to expression in normal control brains. Therefore, up-regulation of this gene or its protein product, or treatment with specific agonists for this receptor may be of use in reversing the dementia/memory loss and neuronal death associated with this disease.

General_screening_panel_vl.4 Summary: Ag3941 This gene is widely expressed in this panel, with highest expression in a breast cancer cell line (CT=28.6). Prominent levels of expression are also seen in samples derived from prostate cancer, ovarian cancer and melanoma. Thus, expression of this gene could be used to differentiate these samples from the rest of the samples on this panel and as a marker of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of breast, ovarian, prostate and melanoma cancers. Overall, the widespread expression of this gene suggests a role for this gene in cell survival and growth. Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes. In addition, this gene is expressed at much higher levels in fetal lung (CT=30.5) when compared to expression in the adult counterpart (CT=35.2). Thus, expression of this gene may be used to differentiate between the fetal and adult source of this tissue.

This gene is also expressed at moderate to low levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex.

Panel 4.1D Summary: Ag3941 Highest expression of the CG94692-01 gene is seen in primary resting Trl cells (CT=30.9). The transcript is expressed at higher levels in lymphocytes, which is consistent with the expression in the thymus and lymph node on Panel 1.4. Therefore, therapeutics designed with this sequence or the protein it encodes could be important in regulating T cell activation and be important for immune modulation and in treating T and B cell mediated diseases such as asthma, allergy, COPD. arthritis, psoriasis, lupus and IBD.

General oncology screening panel_v_2.4 Summary: Ag3941 Highest expression of the CG94692-01 gene is seen in kidney cancer (CT=29.5). In addition, significant levels of expression are also seen in kidney cancers and lung cancers when compared to normal adjacent tissue. Thus, expression of this gene could be used to differentiate these samples from the rest of the samples on this panel and as a marker of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of kidney and lung cancers.

AB. CG94724-01: Acylcarnitine Translocase Expression of gene CG94724-01 was assessed using the primer-probe set Ag4071, described in Table ABA. Results of the RTQ-PCR runs are shown in Table ABB.

Table ABA. Probe Name Ag4071

Table ABB. Panel 4. ID

CNS_neurodegeneration_vl.O Summary: Ag4071 Expression of the CG94724- 01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General_screening_panel_vl.4 Summary: Ag4071 Expression of the CG94724- 01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 4.1D Summary: Ag4071 Expression of the CG94724-01 gene is exclusively seen in kidney (CT=32.9). Therefore, expression of this gene can be used to distinguish kidney sample from other samples in this panel. In addition, therapeutic modulation of this gene through the use of small molecule target may be beneficial in the treatment of autoimmune and inflammatory diseases that affect kidney, including lupus and glomerulonephritis.

The CG94724-01 gene codes for carnitine/acylcarnitine translocase (CACT) homologue. Carnitine-acylcarnitine translocase is 1 of 10 closely related mitochondrial- membrane carrier proteins that shuttle substrates between cytosol and the intramitochondrial matrix space. Deficiency in CACT causes defect in the co-transport of free and esterifϊed carnitine across the inner mitochondrial membrane. Recently, Choong et al (2001, Pediatr Dev Pathol 4(6):573-9, PMID: 1 1826365) reported a case of lethal cardiac tachyarrhythmia in a newborn who died at 72 h of age from severe, intractable cardiac tachyarrhythmia, despite an improvement in his neurological and biochemical status caused due to CACT deficiency. Postmortem examination showed marked steatosis of myocardium, liver, and kidney. Thus, the CG94724-01 gene may also play a role in the pathology of disorders associated with CACT deficiency and therapeutic modulation of this gene product could be useful in the treatment of these disorders including lethal cardiac tachyarrhythmia .

Panel 5 Islet Summary: Ag4071 Expression of the CG94724-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag4071 Expression of the CG94724-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

AC. CG94946-01 and CG94946-02 and CG94946-04 and CG94946-05 and CG94946- 06 and CG94946-07: Agrin Precursor

Expression of gene CG94946-01 and variants CG94946-02, CG94946-04, CG94946-05, CG94946-06 and CG94946-07 was assessed using the primer-probe sets Ag3605 and Ag3974, described in Tables ACA and ACB. Results of the RTQ-PCR runs are shown in Tables ACC, ACD, ACE, ACF, ACG and ACH. Please note that variants CG94946-02, CG94946-04 and CG94946-07 correspond to the probe and primer set Ag3974 only. Table ACA. Probe Name Ag3605

Table ACB. Probe Name Ag3974

Table ACC. CNSjneurodegeneration vl.O

Table ACD. General_screening_panel_vl.4

Table ACE. Panel 2.2

Table ACF. Panel 4.1D

Table ACG. Panel CNS 1

BA17 Depressιon2 141.2 Cing Gyr Depressιon2 32.5

Table ACH. General oncology screening panel_v_2.4

•Lung cancer 2 1100.0 JAdenocarcinoma of the prostate 8 Tung NAT 2 13.9 j Adenocarcinoma of the prostate 9 110.7

CNS_neurodegeneration_vl.0 Summary: Ag3605/Ag3974 Two experiments with two different probe and primer sets confirm the expression of this gene at moderate levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screeningjpanel_vl.4 Summary: Ag3605/Ag3974 Two experiments with the same probe and primer set produce results that are in excellent agreement. The expression of the CG94946-01 gene appears to be highest in a sample derived from a breast cancer cell line (T47D) (CTs=22.5-25.3). In addition, there appears to be substantial expression in other samples derived from breast cancer cell lines, ovarian cancer cell lines, kidney cancer cell lines, lung cancer cell lines, colon cancer cell lines and brain cancer cell lines. Thus, the expression of this gene could be used to distinguish T47D cells from other samples in the panel. Moreover, therapeutic modulation of this gene, through the use of small molecule drugs, protein therapeutics, or antibodies could be of benefit in the treatment of breast, ovarian, kidney, lung, colon or brain cancer.

Among metabolic tissues, this gene has low-to-moderate levels of expression in adrenal, pituitary, adult and fetal heart, adult and fetal liver, adult and fetal skeletal muscle, and adipose. This gene product has high levels of expression (CT values = 27) in pancreas and thyroid. Thus, this gene product may be important for the pathogenesis, diagnosis, and/or treatment of metabolic and endocrine diseases, including obesity. Types 1 and 2 diabetes and thyroidopathies. In support of this hypothesis, decreased glomerular expression of agrin has been observed in diabetic nephropathy (Yard B A, Exp Nephrol 2001;9(3):214-22 ).

In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. The CG94946-01 gene encodes a protein with homology to agrin, a neuronal aggregating factor that induces the aggregation of acetylcholine receptors and other postsynaptic proteins on muscle fibers and is crucial for the formation of the neuromuscular junction. Agrin also plays an important role in defining neuronal responses to excitatory neurotransmitters both in vitro and in vivo (Hilgenberg LG,Mol Cell Neurosci 2002 Jan;19(l):97-1 10 and Bixby JL, J Neurobiol 2002 Feb 5;50(2): 164-79). The CG59841-01 gene expression in the central nervous system is consistent with the hypothesis that this protein may have similar functions as agrin. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Agrin has also been implicated in the formation of senile plaques in Alzheimer's disease and in the acetylcholine synapse/neuromuscular junction (van Horssen J, Acta Neuropathol (Berl) 2001 Dec;102(6):604-14). In addition, an agrin minigene rescued dystrophic symptoms in a mouse model of muscular dystrophy (Moll J, Nature. 2001 Sep 20;413(6853):302-7). Therefore, this gene product may be used as a treatment or cure for congenital muscular dystrophies. Furthermore, this gene product is also an excellent drug target in AD or in any disease involving the neuromuscular junction or the acetylcholine system.

Panel 2.2 Summary: Ag3605 Expression of the CG94946-01 gene is highest in a sample of normal kidney (CT = 27.4). In addition, expression of this gene appears to be upregulated in a number of ovarian and renal cancers when compared to the matched control margins. Thus, expression of this gene could be used as a marker for ovarian and renal carcinoma. Furthermore, therapeutic modulation of the activity of this gene or its protein product, using small molecule drugs, antibodies or protein therapeutics, could be of benefit in the treatment of renal and ovarian cancer.

Panel 4.1D Summary: Ag3605/Ag3974 Two experiments with two different probe and primer sets produce results that are in very good agreement. Highest expression of the CG94946-01 gene is highest in lung microvascular endothelial cells (CTs=27.3- 28.5), microvascular dermal endothelial cells, mucoepidermoid cell line NCI-H292, astrocytes, and keratinocytes. This gene encodes a protein with homology to agrin. Recently, it has been demonstrated that agrin, an aggregating protein crucial for formation of the neuromuscular junction, is also important for T cell signaling in the immune system (Khan AA, Science 2001 Jun 1 ;292(5522): 1681 -6). In additin, agrin has been identified as a potential disease target for autoimmune disorders at the neuromuscular junction, including multiple sclerosis (Liyanage Y, Muscle Nerve 2002 Jan;25(l):4-16)Therefore, small molecule drug, antibody or protein therapeutics designed against the protein encoded by the CG59841-01 gene could reduce or inhibit inflammation in asthma, emphysema, allergy, psoriasis, muscular dystrophy and multiple sclerosis.

Panel CNS__1 Summary: Ag3605 This panel confirms the expression of the CG94946-01 gene at low levels in the brains of an independent group of individuals. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders

General oncology screening panel_v_2.4 Summary: Ag3605 Highest expression of the CG94946-01 gene is seen in lung cancer (CT=26.8). In addition, higher levels of expression are seen in lung and kidney cancers when compared to expression in normal adjacent tissue. Thus, expression of this gene could be used as a marker of lung and kidney cancers. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of lung and kidney cancers.

AD. CG95165-01: Adenylate Cyclase, Type II

Expression of gene CG95165-01 was assessed using the primer-probe set Ag3991 , described in Table ADA. Results of the RTQ-PCR runs are shown in Tables ADB, ADC and ADD.

Table ADA. Probe Name Ag3991

Start ^; SEQ ID

Primers jSequences ; Length I

: i Position No

Forward '5 ' -aacgtggcatcctgaagagt-3 ' 20 ! 3261 3 17

Probe ^;TET- 5 ' -caccttcattttggcaagaagactgt-3 ' -TA RA^; 26 3281 3 1 8 iReverse 5 ' -gttgcagtcagaaagtgtgtga-3 ' 22 3 19

Table ADB. CNS_neurodegeneration_vl.0

Table ADC. Panel 4.1D

^"f ^•

Rel.

Rel. Exp.(%) Exp.(%)

Tissue Name |Ag3991.Run Tissue Name Ag3991, i 170739808 Run

170739808

CNS_neurodegeneration_vl.0 Summary: Ag3991 This panel confirms the expression of the CG95165-01 gene at low levels in the brains of an independent group of individuals, but no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. However, expression in the brain suggests that this gene may play a role in central nervous system disorders such as Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

The CG95165-01 gene codes for a homologue of rat adenylyl cyclase. In Drosophila, mutations in adenylyl cyclase and other members of cAMP pathway have been shown to reduce the ability of fruit flies to learn or to remember (Waddell S and Quinn WG, 2001, Trends Genet 17(12):719-26, PMID: 1 1718926). In addition, derangement of second messenger, adenylyl cyclase, system closely parallels ischemic neuronal damage and persistent enhancement of this cAMP signaling pathway is important for neuronal survival in acute cerebral ischemia (Tanaka K, 2001, Prog Neurobiol

65(2): 173-207, PMID: 1 1403878). Therefore, therapeutic modulation of adenylyl cyclase encoded by this gene may be useful in the treatment of learning disorders and acute cerebral ischemia.

General screening panel vl.4 Summary: Ag3991 Results from one experiment with the CG95165-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 4.1D Summary: Ag3991 Highest expression of the CG95165-01 gene is detected in kidney (CT=32). In addition, moderate to low expression of this gene is seen in thymus, colon, dermal fibroblast and astrocytes. Thus, expression of this gene can be used to distinguish these samples from other samples used in this panel. In addition, therapeutic modulation of this gene may be beneficial in the treatment of autoimmune and inflammatory diseases that affect brain, colon and kidney, including inflammatory bowel diseases, lupus and glomerulonephritis.

General oncology screening panel_v_2.4 Summary: Ag3991 Highest expression of the CG95165-01 gene is detected in kidney cancer (CT=27.8). Interestingly, expression of this gene is higher in cancer sample compared to the adjacent control sample (CT= 0). In addition, moderate expression of this gene is seen in prostate adenocarcinoma and melanoma. This expression is low/undetectable in the normal samples used in this panel. Therefore, therapeutic modulation of this gene product through the use of small molecule drug or antibodies could be beneficial in the treatment of melanoma, prostate and kidney cancers. AE. CG95175-01: Ephrin Type-A Receptor 7 Precursor

Expression of gene CG95175-01 was assessed using the primer-probe sets Ag3992 and Ag612, described in Tables AEA and AEB. Results of the RTQ-PCR runs are shown in Table AEC.

Table AEA. Probe Name Ag3992

Table AEB. Probe Name Ag612

Table AEC. Panel 4D

CNS_neurodegeneration_vl.O Summary: Ag3992 Expression of the CG95175- 01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General_screening_panel_vl.4 Summary: Ag3992 Expression of the CG95175- 01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 4.1 D Summary: Ag3992 Expression of the CG95175-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 4D Summary: Ag612 Highest expression of the CG95175-01 gene is detected in IFN ga a treated NCI-H292 cells (CT=33). Moderate to low expression of this gene is also seen in cytokine treated and untreated NCI-H292 cells, liver cirrhosis and colon tissue samples. Therefore, expression of this gene can be used to distinguish these samples from other samples used in this panel. In addition, therapeutic modulation of this gene can be used for the treatment of chronic obstructive pulmonary disease, asthma, allergy, and emphysema, liver cirrhosis, autoimmune and inflammatory disease affecting colon including Crohn's disease and ulcerative colitis.

Panel CNS_1 Summary: Ag3992 Expression of the CG95175-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag3992 Expression of the CG95175-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

AF. CG95693-01: DPY-19 Protein I Like Protein

Expression of gene CG95693-01 was assessed using the primer-probe set Ag4026, described in Table AFA. Results of the RTQ-PCR runs are shown in Tables AFB, AFC, AFD and AFE.

Table AFA. Probe Name Ag4026

Table AFB. CNS_neurodegeneration_vl.0

Table AFC. General_screening_panel_vl.4

Ovarian ca. OVCAR-5 M0.2 iSmall Intestine Pool 17.2 _.Ovarian ca. IGROV-1 111.6 Stomach Pool 3.8

Table AFD. Panel 4.1D

Rel. Exp.(%) Rel. Exp.(%)

Tissue Name Ag4026, Run Tissue Name Ag4026, Run 171613290 171613290

Secondary Th 1 act jl .3 HUVEC IL-l beta |0.7

(Secondary Th2 act :4.2 HUVEC IFN gamma Ϊ0.9

HUVEC TNF alpha + IFN j Secondary Trl act gamma

Table AFE. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.0 Summary: Ag4026 This panel confirms the expression of the CG95693-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screeningjpanel_vl.4 Summary: Ag4026 Highest expression of the CG95693-01 gene is detected in CNS cancer SF-295 cell line (CT=28.3). Significant expression of this gene is associated with cluster of cancer cell lines including CNS, colon, renal, lung, breast, ovarian, pancreatic, melanoma and prostate cancer cell lines. Therefore, therapeutic modulation of this gene could be beneficial in the treatement of these cancers. Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT=31 ) when compared to adult liver (CT=40). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases.

In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease. Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4026 Highest expression of the CG95693-01 gene is detected in PMA/ionomycin treated basophils (CT=31). In addition, this gene is expressed to a lesser extent in untreated KU-812 cells. Therefore, antibody or small molecule therapies designed with the protein encoded for by this gene could block or inhibit inflammation or tissue damage due to basophil activation in response to asthma, allergies, hypersensitivity reactions, psoriasis, and viral infections.

Moderate to low levels of expression of this gene is also detected in Ramos B cells, activated lymphocytes, IL-2 treated LAK cells, TNF alpha treated dermal fibroblasts, and normal tissues respresented by colon, lung, thymus and kidney. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. General oncology screening panel_v_2.4 Summary: Ag4026 In this panel the highest expression of the CG95693-01 gene is detected in a kidney cancer sample (CT=31.4). Interestingly, expression of this gene is higher in kidney, prostate, and lung cancer samples as compared to adjacent control samples as well as the melanoma samples in this panel. Therapeutic modulation of this gene, through the use of small molecule drugs, protein therapeutics or antibodies could be of benefit in the treatment of melanomas as well as kidney, prostate and lung cancers.

AG. CG95814-01 : Rho-GTPase-Activating Protein 4 Expression of gene CG95814-01 was assessed using the primer-probe set Ag4031, described in Table AGA. Results of the RTQ-PCR runs are shown in Tables AGB, AGC, AGD, AGE and AGF.

Table AGA. Probe Name Ag4031

. ! Start ' SEQ I D

Rrimers ^Sequences 'Len^gt '

^& . Position ! No r •_τ Forward'5 ' -aaccaatgcatctgtcttcaag-3 ' 22 ; 1053 1 329 iProbe ;TET- 5 ' -tccatgacctatctgaccttattgatca-3 TAMRA 28 ! 1082 J 330

{Reverse ^"5 ' -tgcatggtagcctaagtcaca-3 ' 21 1 ^{, 114} 1 331

Table AGB. CNS_neurodegeneration_vl.0

Table AGC. General_screening_panel_vl.4

Table AGP. Panel 4.1D

Table AGE. Panel CNS 1

CNS_neurodegeneration_vl.O Summary: Ag4031 This panel confirms the expression of the CG95814-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screeningjpanel_vl.4 Summary: Ag4031 Highest expression of the CG95814-01 gene is detected in brain (cerebellum) sample (CT=25.6). High expression of this gene is seen in all the region of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

The CG95814-01 gene codes for a homolog of RHO-GTPase activating protein (RHOGAP). RHOGAP stimulats the GTPase activity of Rho protein. Since Rho proteins have been implicated in ischemia (Trapp et al., 2001, Mol Cell Neurosci 17(5):883-94, PMID: 11358485), inhibitors for the RHOGAP encoded by this gene may have a therapeutic utility in the treatment of pathological aspects following brain damage including neuronal death. High expression of this gene is also observed in cluster of cancer cell lines including pancreatic, CNS, colon, renal, lung, breast, ovarian, prostate, squamous cell carcinoma, and melanoma cancer cell lines. Therefore, therapeutic modulation of this gene can be useful in treatment of these cancers.

Interestingly, this gene is expressed at much higher levels in fetal (CT=27-28) when compared to adult lung and liver (CTs=30-32). This observation suggests that expression of this gene can be used to distinguish fetal from adult lung and liver. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance growth or development of lung and liver in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver and lung related diseases.

Panel 4.1D Summary: Ag4031 Highest expression of the CG95814-01 gene is detected in activated secondary Th2 cells (CT=27). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in

General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. Panel CNS_1 Summary: Ag4031 This panel confirms the expression of the

CG95814-01 gene at low levels in the brains of an independent group of individuals.

Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General oncology screening panel_v_2.4 Summary: Ag4031 Highest expression of the CG95814-01 gene is detected in lung cancer sample (CT=27). Higher expression of this gene is also seen in melanoma, colon, kidney, prostate cancers and this expression is lower in corresponding control samples. Thus, expression of this gene can be used as diagnostic marker and therapeutic modulation of this gene product may be useful in the treatment of these cancers.

AH. CG95824-01: Rho GAP

Expression of gene CG95824-01 was assessed using the primer-probe set Ag4032. described in Table AHA. Results of the RTQ-PCR runs are shown in Tables AHB, AHC,

AHD and AHE. Table AHA. Probe Name Ag4032

Table AHB. CNS neurodegeneration vl.O

Lungca. NCI-H 146 il 0.4 iCNS cancer (glio) SNB-19 12.0

Table AHD. Panel 4.1D

CNS_neurodegeneration_vl.O Summary: Ag4032 This panel confirms the expression of the CG95824-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders. General_screening_panel_vl.4 Summary: Ag4032 Highest expression of the CG95824-01 gene is detected in fetal brain (CT=29.8). High expression of this gene is seen all the regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as

Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression and therapeutic modulation of this gene product may be beneficial in the treatment of these CNS disorders.

The CG95824-01 gene codes for a RHO-GTPase activating protein (RHOGAP). RHOGAP stimulats the GTPase activity of Rho proteins. Since Rho proteins have been implicated in ischemia (Trapp et al., 2001, Mol Cell Neurosci 17(5):883-94, PMID: 1 1358485), inhibitors for the RHOGAP encoded by this gene may have a therapeutic utility in the treatment of pathological aspects following brain damage including neuronal death. Moderate levels of expression of this gene is also seen in cluster of cancer cell lines including melanoma, CNS, colon, breast, ovarian, lung, gastric, renal, pancreatic and prostate cancer cell lines. Therefore, therapeutic modulation of this gene product through the use of small molecule target may be useful in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adrenal gland, thyroid, fetal heart, and fetal skeletal muscle. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, expression of this gene is higher in fetal (CTs=32-33) as compared to adult lung, heart and skeletal muscle (CTs>36). Therefore, expression of this gene can be used to distinguish fetal from these adult tissue samples. In addition, the relative overexpression of this gene in fetal suggests that the protein product may enhance growth or development of these tissues in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the RHOGAP encoded by this gene could be useful in treatment of muscle, lung and heart related diseases. Panel 4.1D Summary: Ag4032 Highest expression of the CG95824-01 gene is detected in IFN gamma treated NCI-H292 cells (CT=33.4). Moderate to low expression of this gene is seen in NCI-H292 cells, HPAEC, lung fibroblasts, IL-4 treated dermal fibroblasts. Therefore, therapeutics designed with the protein encoded by this gene may reduce or eliminate symptoms caused by inflammation in lung epithelia, in chronic obstructive pulmonary disease, asthma, allergy, and emphysema.

Panel CNS_1 Summary: Ag4032 This panel confirms the expression of the CG95824-01 gene at low levels in the brains of an independent group of individuals. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

Al. CG96231-01 and CG96231-02: OTU-Like Cysteine Protease

Expression of gene CG96231-01 and full length physical clone CG96231-02 was assessed using the primer-probe set Ag4043, described in Table AIA. Results of the RTQ- PCR runs are shown in Tables AIB, AIC, AID and AIE. Please note that CG96231-02 represents a full-length physical clone of the CG96231-01 gene, validating the prediction of the gene sequence.

Table AIA. Probe Name Ag4043

Start SEQ ID j

Primers Sequences Length _. Position No ■

;Forward 5 ' -agcgtaacttccctgatcca-3 ' 20 i 815

'Probe TET-5 ' -cacctcctctgaccattttctcctct-3 ' -TAMRA 26 839

[Reverse [5 ' -tcatctgctaattccagtgctt-3 ' 22 887 337

Table AIB. CNS neurodegeneration vl.O

Table AIC. General_screening_panel_vl.4

Table AID. Panel 4.1D

HUVEC starved .5

CNS_neurodegeneration_vl.O Summary: Ag4043 This panel does not show differential expression of the CG96231-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Ag4043 Expression of the CG96231- 01 gene is highest in fetal liver (CT=25.6). This gene is also expressed at moderate levels in other metabolic tissues, including pancreas, thyroid, adrenal, pituitary, adipose, and adult and fetal heart and skeletal muscle. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

In addition, this gene is expressed at much higher levels in fetal liver when compared to expression in the adult counterpart (CT=33.1). Thus, expression of 'this gene may be used to differentiate between the fetal and adult source of this tissue. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver disease.

Expression is also slightly higher in cell lines derived from gastric, breast, ovarian, and prostate cancers. Overall, this gene is ubiquitously expressed in this panel suggesting a role for this gene product in cell growth and/or proliferation.

Panel 4.1 D Summary: Ag4043 Expression of the CG96231 -01 gene is highest in the KU-812 basophil cell line treated with PMA/ionomycin (CT=27.2), with ubiquitous expression in this panel. Basophils release histamines and other biological modifiers in reponse to allergens and play an important role in the pathology of asthma and hypersensitivity reactions. Therefore, therapeutics designed against the putative protein encoded by this gene may reduce or inhibit inflammation by blocking basophil function in these diseases. In addition, these cells are a reasonable model for the inflammatory cells that take part in various inflammatory lung and bowel diseases, such as asthma. Crohn's disease, and ulcerative colitis. Therefore, therapeutics that modulate the function of this gene product may reduce or eliminate the symptoms of patients suffering from asthma. Crohn's disease, and ulcerative colitis.

General oncology screening panel_v_2.4 Summary: Ag4043 Highest expression of the CG96231-01 gene on this panel is seen in lung cancer (CT=28.9). In addition, this gene is overexpressed in lung and colon cancer when compared to expression in the normal adjacent tissue. Thus, expression of this gene could be used as a marker of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of lung and colon cancer.

AJ. CG96260-01: Phospholipase A2 Expression of gene CG96260-01 was assessed using the primer-probe set Ag4048, described in Table AJA. Results of the RTQ-PCR runs are shown in Tables AJB, AJC and AJD.

Table AJA. Probe Name Ag4048

Table AJB. CNS_neurodegeneration_vl.O

Table AJC. General_screening_panel_vl.4

Table AJD. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.0 Summary: Ag4048 This panel confirms the expression of the CG96260-01 gene at low levels in the temporal cortex of brain (CT=34.3). However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. The the CG96260-01 gene codes for a homolog of rat phospholipase A2 (PLA(2)). Mouse deficient in cytosolic PLA(2), a member of PLA(2) family, has been shown to suffer smaller infarcts and fewer neurological deficits after transient occlusion of the middle cerebral artery and have less injury after administration ofa dopaminergic selective neurotoxin (Sapirstein A, and Bonventre JV, 2000, Biochim Biophys Acta 2000 Oct 31 ;1488(1 -2): 139-48, PMID: 1 1080683). Thus, PLA(2) encoded by this gene could also play a role in inflammation and injuries of brain and pharmacological targeting of this enzyme may have important therapeutic benefits.

General_screening_panel_vl.4 Summary: Ag4048 Highest expression of the CG96260-01 gene is detected in renal cancer A498 cell line (CT=33). Therefore. therapeutic modulation of this gene product may be beneficial in the treatment of renal cancer.

In addition, moderate to low expression of this gene is seen in samples derived from normal tissues including testis, prostate, breast, kidney, lymphnode. thymus and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in treatment of diseases associated with these tissues.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in pancreas, and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

The the CG96260-01 gene codes for a homolog of rat phospholipase A2 (PLA(2)). PLA(2) has been implicated in the pathogenesis and pathophysiology of acute pancreatitis (Nevalainen et al., 1999, Hepatogastroenterology 46(29):2731-5, PMID: 10576338). In addition, in blood plasma, PLA(2) modifies the circulating lipoproteins and so induce formation of small dense LDL particles, which are associated with increased risk for cardiovascular disease (Hurt-Camejo et al, 2001, Circ Res 89(4):298-304, PMID: 11509445). Furthermore, the cytoplasmic PLA(2) knockout mouse has revealed important roles of cPLA(2) in normal fertility, generation of eicosanoids from inflammatory cells, brain injuries and allergic responses (Sapirstein A, and Bonventre JV, 2000, Biochim Biophys Acta 2000 Oct 31;1488(l-2):139-48, PMID: 11080683). Therefore, therapeutic modulation of PLA(2) encoded by this gene may be useful in the treatment of pancreatitis, neurological disorders, allergies and cardiovascular diseases. Panel 4.1D Summary: Ag4048 Expression of the CG96260-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel CNS_1 Summary: Ag4048 Expression of the CG96260-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown). General oncology screening panel_v_2.4 Summary: Ag4048 Highest expression of the CG96260-01 gene is detected in prostate adenocarcinoma samples (CTs=33). In addition, low expression of this gene is also seen in a single colon cancer and the adjacent normal tissue sample. The CG96260-01 gene codes for a homolog of rat phospholipase A2 (PLA(2)). Phospholipase A2 has recently been recognized to be involved in a wide number of pathophysiological situations, ranging from systemic and acute inflammatory conditions to cancer (Balsinde et al, 1999, Annu Rev Pharmacol Toxicol 39:175-89. PMID: 10331081). Therefore, therapeutic modulation of this gene product through the use of small molecule drug may be useful in the treatment of colon and prostate cancers, [mpattu, 29-Mar-02]

AK. CG96364-01: ADP/ATP Translocase 2 Like protein

Expression of gene CG96364-01 was assessed using the primer-probe set Ag4073, described in Table AKA. Results of the RTQ-PCR runs are shown in Tables AKB, AKC. AKD, AKE and AKF. Table AKA. Probe Name Ag4073

Table AKB. AI_comprehensive panel_vl.0

Table AKD. General_screening_panel_vT.4

Testis Pool 2.0 ■^'Colon ca. HT29 34.6

_.Prostate ca.* (bone met) i

40.9 ^'68.3 jPC-3

Lung ca. NCI-H526 ; 12.4 Brain (cerebellum) !6.7

Lung ca. NCI-H23 j31.6 Brain (fetal) 5.2

Lung ca. NCI-H460 15.3 Brain (Hippocampus) Pool 14.2

ILung ca. HOP-62 11 1.8 Cerebral Cortex Pool 5.1

Lung ca. NCI-H522 117.7 Brain (Substantia nigra) Pool 6.6

ILiver Ϊ2.0 jBrain (Thalamus) Pool

Fetal Liver Ϊ8.0 Brain (whole) 4.1 iLiver ca. HepG2 J21.8 [Spinal Cord Pool 2.6 _.Kidney Pool !3.0 (Adrenal Gland J4.6

Fetal Kidney p .J _.Pituitary gland Pool iθ.8

Renal ca. 786-0 M 5.2 _.Salivary Gland 4.4

Renal ca. A498 :5.7 Thyroid (female) jRenal ca. ACHN ! 18.9 Pancreatic ca. CAPAN2 30.4 _.Renal ca. UO-31 ! 12.9 I Pancreas Pool 14.5

Table AKE. Panel 4.1D

6i:

ILAK cells IL-2 42.9 ILiver cirrhosis |6.8 jLAK cells IL-2+IL-12 3 1.0 INCI-H292 none |61.6

Table AKF. General oncology screening panel_v_2.4

AI_comprehensive panel_vl.O Summary: Ag4073 Highest expression of the CG96364-01 gene is detected in osteoarthritic bone sample (CT=27). Low to moderate levels of expression of this gene are detected in samples derived from osteoarthritic (OA) bone and adjacent bone as well as OA cartilage, OA synovium and OA synovial fluid samples. Moderate level expression is also detected in cartilage, bone, synovium and synovial fluid samples from rheumatoid arthritis patients. Low level expression of this gene is also detected in normal samples derived from cartilage, synovium. bone or synovial fluid cells, normal lung samples. COPD lung, emphysema, atopic asthma, asthma, allergy, Crohn's disease (normal matched control and diseased), ulcerative colitis(normal matched control and diseased), and psoriasis (normal matched control and diseased). Therefore, therapeutic modulation of this gene product may ameliorate symptoms/conditions associated with autoimmune and inflammatory disorders including psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis CNS_neurodegeneration_vl.O Summary: Ag4073 This panel confirms the expression of the CG96364-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4073 Highest expression of the CG96364-01 gene is detected in a gastric cancer KATO III cell line (CT=22). High expression of this gene is seen in cluster of breast, ovarian, colon, gastric, renal, lung, pancreatic, CNS, hepatic, prostate cancer cell lines and melanoma cell lines. Thus, therapeutic modulation of this gene product could be beneficial in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. The CGI 00466-01 gene codes for adenine nucleotide translocator (ANT 2) homolog. Dysfunctioning of the ANT2 have been shown to to induce myopathies in mouse and in humans (Fiore et al., 2001, Clin Chim Acta 311(2): 125-35, PMID: 1 1566172). ANT has a role in mtDNA maintenance and mutation in ANT has been implicated in autosomal dominant progressive external ophthalmoplegia and other mitochondrial diseases (Kaukonen et al., 2000, Science 289(5480):782-5, PMID: 10926541). Mice deficient in the heart/muscle specific isoform of the ANT1 exhibit many of the hallmarks of human oxidative phosphorylation (OXPHOS) disease, including a dramatic proliferation of skeletal muscle mitochondria (Murdoch et al., 1999, J Biol Chem 274(20): 14429-33, PMID: 10318868). Therefore, therapeutic modulation of the ANT protein encoded by the CGI 00466-01 gene through the use of small molecule drug could be useful in the treatment mitochondria related diseases.

Panel 4.1D Summary: Ag4073 Highest expression of the CG96364-01 gene is detected in activated primary Trl and ionomycin treated Ramos B cell (CTs=25.4). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B- cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screeningjpanel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. General oncology screening panel_v_2.4 Summary: Ag4073 Highest expression of the CG96364-01 gene is detected in colon cancer OD06297-04 sample (CT=24.3). Higher expression of this gene is seen in colon cancer and lung cancer compared to the normal adjacent tissues. Therapeutic modulation of this gene product could be beneficial in the treatment of these cancers. Please see Panel 1.4 for additional discussion of the potential utility of this gene in treatment of cancers.

AL. CG96422-01: ADP/ATP Translocase 3

Expression of gene CG96422-01 was assessed using the primer-probe set Ag4057, described in Table ALA. Results of the RTQ-PCR runs are shown in Tables ALB and ALC.

Table ALA. Probe Name Ag4057

Table ALB. Panel 4.1D

Table ALC. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.0 Summary: Ag4057 Results from one experiment with the CG96422-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screening_panel_vl.4 Summary: Ag4057 Results from one experiment with the CG96422-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 4.1D Summary: Ag4057 Highest expression of the CG96422-01 gene is detected in PMA/ionomycin treated basophils (CT27.4). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell. B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in

General_screening__panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

General oncology screening panel_v_2.4 Summary: Ag4057 Highest expression of the CG96422-01 gene is detected in colon malignant cancer sample (CT=27.5). In addition, significant expression of this gene is associated with kidney cancer, prostate adenocarcinoma, bladder cancer, melanoma, lung and colon cancers.

Therefore, therapeutic modulation of this gene product through the use of small molecule target may be beneficial in the treatment of these cancers.

AM. CG96442-01: Acyl CoA-Domain Protein Expression of gene CG96442-01 was assessed using the primer-probe set Ag4058, described in Table AMA. Results of the RTQ-PCR runs are shown in Tables AMB and AMC. Table AMA. Probe Name Ag4058

Table AMB. General_screening_panel_vl.4

Lung ca. NCI-H23 14.7 [Brain (fetal) 5.8

Lun *σ— ca. NCI-H460 0.0 jBrain (Hippocampus) Pool 6.6

Lung ca. HOP-62 0.0 Cerebral Cortex Pool 8.0

Lung ca. NCI-H522 3.2 Brain (Substantia nigra) Pool 1 1.7

Liver j . Brain (Thalamus) Pool 9.0

Fetal Liver 4.2 JBrain (whole) ^" 0.0

Liver ca. HepG2 0.0 jSpinal Cord Pool 0.0

Kidney Pool 20.0 jAdrenal Gland 16.4

Fetal Kidney 23.8 iPituitary gland Pool 8.0

Renal ca. 786-0 0.0 (Salivary Gland 8.3

Renal ca. A498 0.0 jThyroid (female) 0.0

; iRenal ca. ACH _™_N__„ 27.9 (Pancreatic ca. CAPAN2 .7.4 iRenal ca. UO-31 121 .2 .Pancreas Pool =8.7

Table AMC. Panel 4.1D

622

AI_comprehensive panel_vl.0 Summary: Ag4058 Expression of the CG96442- 01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

CNS_neurodegeneration_vl.O Summary: Ag4058 Results from one experiment with the CG96442-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screening_panel_vl.4 Summary: Ag4058 Highest expression of the CG96442-01 gene is detected in spleen (CT=31.4). In addition, moderate to low expression of this gene is seen in pancreas, adrenal gland, gastrointestinal tract, kidney, and testis. Therefore, therapeutic modulation of this gene can be useful in the treatment of diseases associated with these tissues, including diabetes, obesity, inflammatory bowel disease, lupus and glomeruloncphritis.

Low expression of this gene is also detected in brain thalamus and substantia nigra samples. Therefore, therapeutic modulation of this gene product can be beneficial in neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Low expression of this gene is associated with cluster of cancer cell lines including renal cancer, gastric cancer, breast cancer, ovarian cancer, lung cancer and melanoma cell lines and colon cancer tissue. Therefore, therapeutic modulation of this gene product can be beneficial in the treatment of these cancers.

Interestingly, this gene is expressed at much higher levels in fetal (CT=34.5) when compared to adult skeletal muscle and lung (CT>38). Thus, expression of this gene can be used to distinguish fetal from adult skeletal muscle and lung. In addition, the relative overexpression of this gene in fetal skeletal muscle suggests that the protein product may enhance growth or development of muscle and lung in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of muscle and lung related diseases. Panel 4.1D Summary: Ag4058 Highest expression of the CG96442-01 gene is detected in kidney (CT=31.4). Therefore, expression of this gene can be used to distinguish this sample from other samples in the panel. In addition, small molecule therapies designed with the protein encoded for by this gene could modulate kidney function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney, including lupus and glo erulonephritis.

Low level expression of this gene is also detected in TNF alpha + IL-1 beta treated HPAEC, liver cirrhosis, and monocytes. Therefore, therapeutic modulation of this gene product can be useful in the treatment of inflammatory and autoimmune diseases such as asthma, IBD, and psoriasis and liver cirrhosis.

General oncology screening panel_v_2.4 Summary: Ag4058 Expression of the CG96442-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

AN. CG96501-01: Brain Mitochondrial Carrier Protein-1 Like protein

Expression of gene CG96501 -01 was assessed using the primer-probe set Ag4059, described in Table ANA. Results of the RTQ-PCR runs are shown in Tables ANB, ANC and AND.

Table ANA. Probe Name Ag4059

Table ANB. General_screening_panel_vl.4

Table ANC. Panel 4.1D

CNS_neurodegeneration_vl.O Summary: Ag4059 Results from one experiment with the CG96501-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screening_panel_vl.4 Summary: Ag4059 Highest expression of the CG96501-01 gene is detected in pancreas (CT=24.6). In addition, moderate expression of this gene is seen among the tissues with metabolic or endocrine function such as pancreas, adipose, adrenal gland, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

The CG96501-01 gene codes for homolog of mouse mitochondrial uncoupling protein 5 (UCP 5). Proteins belonging to UCP family play important role in thermoregulatory responses, including acute hypothermia usually followed by temperature recovery (Yu et al., 2000, Am J Physiol Endocrinol Metab 279(2):E433-46). In addition, mutation in UCP3, another member of UCP family, causes severe obesity and type II diabetes (Brown et al., 1999, Hum. Mutat. 13: 508 only). Therefore, therapeutic modulation of this gene product can be useful in treatment of disorders affecting thermoregulatory responses, obesity and type II diabetes.

Significant expression of this gene is also seen in cluster of cancer cell lines including pancreatic cancer, CNS cancer, colon and gastric cancer, renal cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma and melanoma cell lines. Therefore, therapeutic modulation of this gene product can be beneficial in the treatment of these cancers.

Also, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1 D Summary: Ag4059 Highest expression of the CG96501-01 gene is detected in kidney (CT=32). This gene is expressed at low to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. General oncology screening panel_v_2.4 Summary: Ag4059 Highest expression of the CG96501-01 gene is detected in tow metastatic melanoma samples (CTs=31.7). Interestingly, significant expression of this gene is also seen in cluster of cancer samples including kidney, prostate adenocarcinoma, metastatic melanoma, lung and colon cancers. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of these cancers.

AO. CG96557-01 : L-ALLO-Threonine Aldolase-Like Protein

Expression of gene CG96557-01 was assessed using the primer-probe set Ag4067, described in Table AOA.

Table AOA. Probe Name Ag4067

Primers I .^'Sequences I Length I; „ St .art . S ' SEQ ID No

: I " . Position ,

(Forward J5 ' -tggagcactgtgactctgtgt-3 ' j 21 j 614 j 353

Probe jTET-5 ' -ctttctgcctctccaagggcctg-3 ' -TAMRA 23 , 635 354

Reverse ;5 ' -aggcttcttcaatgaagtcctt-3 ' 1 22 ' 691 • 355

CNS_neurodegeneration_vl.O Summary: Ag4067 Results from one experiment with the CG96557-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screening_panel_vl.4 Summary: Ag4067 Expression of the CG96557- 01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 2.2 Summary: Ag4067 Expression of the CG96557-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 4. ID Summary: Ag4067 Expression of the CG96557-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown). Results from one experiment (run 171808741) with the CG96557-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

AP. CG96581-01: RP42 Expression of gene CG96581-01 was assessed using the primer-probe set Ag4070, described in Table APA. Results of the RTQ-PCR runs are shown in Tables APB, APC, APD and APE.

Table APA. Probe Name Ag4070

Table APB. CNS_ncurodegeneration_vl.O

Rel. Exp.(%)

Tissue Name Ag4070, Run 214294588

Control (Path) 3 Temporal Ctx 0.1 jControl (Path) 4 Temporal Ctx 126.6

JAD 1 Occipital Ctx | l 6.8

Temporal Ctx

Table APC. Panel 4.1D

Table APD. Panel CNS 1

Table APE. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4070 This panel confirms the expression of the CG96581-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Furthermore, low expression of this gene in brain suggests that this gene may play a role in central nervous system disorders such as Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. The CG96581-01 gene codes for RP42 homolog. The mouse RP42 gene is expressed in proliferating neuroblasts, whose human orthologs map to susceptibility loci for autism (Mas et al., 2000, Genomics 65: 70-74, PubMed ID: 10777668). Therefore, this gene may also play a role in autism and therapeutic modulation of this gene may be useful in the treatment of autism and other neurological disorders. General_screening_panel_vl.4 Summary: Ag4070 Results from one experiment with the CG96581-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 4. ID Summary: Ag4070 Highest expression of the CG96581-01 gene is detected in thymus (CT=30.3). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell. B-cell, endothelial cell, macrophage/monocyte. and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Panel CNS_1 Summary: Ag4070 This panel confirms the expression of the CG96581-01 gene at low levels in the brains. Please see Panel CNS_neurodegeneration_vl.O for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General oncology screening panel_v_2.4 Summary: Ag4070 Highest expression of the CG96581-01 gene is detected in lung cancer sample (CT=30). Interestingly, expression of this gene is higher in number of cancer samples including lung, prostate, colon, melanoma and kidney cancers (CTs=30-33) as compared to control normal samples (CTs>35). Therefore, expression of this gene can be used as diagnostic marker for these cancers and therapeutic modulation of this gene can be beneficial in the treatment of these cancers.

AQ. CG96624-01 and CG96624-02: Putative Seven Pass Transmembrane Protein

Expression of gene CG96624-01 and variant CG96624-02 was assessed using the primer-probe sets Agl 372 and Ag4082, described in Tables AQA and AQB. Results of the RTQ-PCR runs are shown in Tables AQC, AQD, AQE and AQF.

Table AQA. Probe Name Agl372

Start SEQ ID

Primers _'Sequences 1 Length; Position No

Forward;5 ' -ctttgttccccaggtcattc-3 ' I 0 j 792 359

Probe ;TET- 5 ' - cgcctggtcagacacattgtaccagt- 3 ' - TAMRA; 26 i 758 360

Reverse i5 ' -ggctggacaccttcgattac-3 ' o _t o 737 361

Table AQB. Probe Name Ag4082

Table AQC. CNS_neurodegeneration_vl.O

Table AQD. General_screening_panel_vl.4

Table AQE. Panel 1.2

Trachea iMelanoma LOX IMVI _.2.6 iKidney :50.3 iMelanoma* (met) SK-MEL-5 |4.4 iKidney (fetal) 3.1

Table AQF. Panel 4. ID

Rel. Exp.(%) Rel. Exp.(%)

Tissue Name Ag4082, Run Tissue Name Ag4082, Run 171809988 171809988

Secondary Th 1 act 44.1 HUVEC IL- l beta 29.3

Secondary Th2 act 55.5 HUVEC IFN gamma 24.7

^" HUVEC TNF alpha + IFN Secondary Trl act 45.1 29.5 mamma

Secondary Th 1 rest 19.2 HUVEC TNF alpha + IL4 [47.0

.Secondary Th2 rest ! 10.8 IHUVEC IL-1 1 13.9

LAK cells IL-2+IFN

14.7 NCI-H292 IL-4 0.2 gamma :

LAK cells IL-2+ IL- 18 25.9 NCI-H292 IL-9 100.0

LAK cells PMA/ionomycin 27.4 NCI-H292 IL-13 83.5 :

NK Cells IL-2 rest 55.9 NC1-H292 IFN gamma 99.3 i ϊ

Two Way MLR 3 day 45 1 HPAEC none 16.5

Two Way MLR 5 day 36.9 HPAEC TNF alpha + IL-1 beta 68.3

Two Way MLR 7 day 17.9 Lung fibroblast none 27.0

Lung fibroblast TNF alpha + IL-

: PBMC rest 9.6 29.7 1 beta

PBMC PWM 49.3 Lun *a-* fibroblast IL-4 29.9 PBMC PHA-L 25.5 Lung fibroblast IL-9 28.3

CNS_neurodegeneration_vl.O Summary: Ag4082 This panel does not show differential expression of the CG96624-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Ag4082 Highest expression of the CG96624-01 gene is seen in a breast cancer cell line (CT=25.8). Significant levels of expression are also seen in a cluster of samples derived from breast, brain, colon, lung, ovarian, prostate and melanoma cancer cell lines.

In addition, this gene is expressed at much higher levels in fetal lung (CT=28.9) when compared to expression in the adult counterpart (CT=36.7). Thus, expression of this gene may be used to differentiate between the fetal and adult source of this tissue. The ubiquitous expression of this gene in this panel and the higher levels of expression in cancer cell lines and some fetal tissues suggest a role for this gene product in cell survival and proliferation.

Among tissues with metabolic function, this gene is expressed at moderate levels in pituitary, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart. and liver and at low but significant levels in adipose. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

This gene is also expressed at high to moderate levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex.

Panel 1.2 Summary: Ag4082 Highest expression of the CG96624-01 gene is seen in the cerebral cortex (CT=23.8). Expression of this gene is ubiquitous in this panel, with prominent levels of expression in lung and breast cancer cell lines and normal kidney (CT=24.8). Thus, expression of this gene could be used as a marker of lung and breast cancer and to differentiate kidney from fetal kidney (0^=28.8). Please see Panel 1.4 for further discussion of utility of this gene. Panel 4.1D Summary: Ag4082 Highest expression of the CG96624-01 gene is seen in IL-9 treated NCI-H292 cells (CT=29.6). In addition, this gene is expressed at moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

AR. CG96747-01: Noltage-Dependent Calcium Channel Gamma-3 Subunit - Like Protein

Expression of gene CG96747-01 was assessed using the primer-probe set Ag4076, described in Table ARA. Results of the RTQ-PCR runs are shown in Tables ARB and ARC.

Table ARA. Probe Name Ag4076

Table ARB. CNS_neurodegeneration_vl.O

Table ARC. General_screening_panel_ l.4

Tetal Lung JCNS cancer (neuπ met) SK-N-AS JO.O iLunε ca. NCI-N41 7 .O 'CNS cancer (astro) SF-539 0.0

CNS_neurodegeneration_vl.O Summary: Ag4076 This panel confirms the expression of the CG96747-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders. General_screening_panel_vl.4 Summary: Ag4076 Highest expression of the

CG96747-01 gene is detected in substantia nigra of brain (CT=30.1). Interestingly expression of this gene is exclusive to brain regions examined. Therefore, expression of this gene can be used to distinguish brain from other other samples used in this panel. Furthermore, therapeutic modulation of this gene through use of small molecule target may be useful in the treatment of neurological disorders such as Alzheimer's disease. Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

The CG96747-01 gene codes for a protein belonging to PMP- 22/EMP/MP20/Claudin family. Proteins belonging to this family are small integral membrane glycoproteins which are evolutionarily related including eye lens specific membrane protein 20 (MP20 or MP19); epithelial membrane protein-1 (EMP-1/TMP). epithelial membrane protein-2 (EMP-2). and peripheral myelin protein 22 (PMP-22). PMP-22 plays a role both in myelinization and in cell proliferation. Mutations affecting PMP-22 are associated with hereditary motor and sensory neuropathies such as Charcot- Marie-Tooth disease type 1 A (CMT-1 A) in human or the trembler phenotype in mice (Jetten AM, Suter U, 2000, Prog Nucleic Acid Res Mol Biol 64:97-129, PMID: 10697408; PFAM: IPR004031). Thus, the CG96747-01 gene product may also play a role in hereditary motor and sensory neuropathies such as CMT-1 A and therapeutic modulation of this gene product may be useful in the treatment of this disease.

Panel 4.1D Summary: Ag4076 Expression of the CG96747-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag4076 Expression of the CG96747-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

AS. CG97462-01: Prohibitin

Expression of gene CG97462-01 was assessed using the primer-probe set Ag41 11, described in Table ASA. Table ASA. Probe Name Ag4111

CNS_neurodegeneration_vl.O Summary: Ag41 1 1 Expression of the CG97462- 01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General_screening_panel_vl.4 Summary: Ag411 1 Expression of the CG97462- 01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 4.1D Summary: Ag41 1 1 Expression of the CG97462-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag41 1 1 Expression of the CG97462-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

AT. CG97472-01: Glucose Transporter Expression of gene CG97472-01 was assessed using the primer-probe set Ag4113, described in Table ATA. Results of the RTQ-PCR runs are shown in Tables ATB, ATC, ATD and ATE.

Table ATA. Probe Name Ag4113

Table ATB. General_screening_panel_vl.4

Tissue Name Rel. Exp.(%) Tissue Name Rel.

97487 Patient-09ut uterus J30.8 j94730_Donor 3 AM - A_adipose jO.O j97488_Patient-

0.0 Ϊ9473 l_Donor 3 AM - B_adipose o.o i09pl_placenta

CNS_neurodegeneration_vl.O Summary: Ag4113 Results from one experiment with the CG97472-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screening_panel_vl.4 Summary: Ag41 13 Highest expression of the CG97472-01 gene is detected in kidney (CT=29.5). Therefore, therapeutic modulation of this gene may be useful in the treatment of kidney related disease including lupus and glomerulonephritis. Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at moderate to low levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Low level expression of this gene is also seen in cluster of ovarian cancer, breast, lung, renal, colon and CNS cancer. Therefore, therapeutic modulation of this gene may be useful in the treatment of these cancers.

Panel 4.1D Summary: Ag4113 Highest expression of the CG97472-01 gene is detected in kidney (CT=31 ). This gene is expressed at low to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell. endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screeningjpanel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Panel 5D Summary: Ag4113 Highest expression of the CG97472-01 gene is detected in adipose (CT=34.4). Low level of expression of this gene is seen exclusively in adipose and skeletal muscle samples. Therefore, expression of this gene can be used to distinguish these samples from other samples used in this panel. Please see Panel 1.4 for a discussion of the potential utility of this gene

General oncology screening panel_v_2.4 Summary: Ag4113 Highest expression of the CG97472-01 gene is detected in metastatic melanoma sample (CT=31). Interestingly, significant expression of this gene is seen in number of cancer samples including kidney, metastatic melanoma, prostate adenocarcinoma and lung cancer. Therefore, expression of this gene may be used as diagnostic marker for these cancers and therapeutic modulation of this gene can be useful in the treatment of these cancers.

AU. CG97528-01: Guanylate Binding Protein

Expression of gene CG97528-01 was assessed using the primer-probe set Ag4107, described in Table AUA. Results of the RTQ-PCR runs are shown in Tables AUB and AUG.

Table AUA. Probe Name Ag4107

Start I SEQ ID

Trimers (Sequences ! Length Position i No

|Forwardj5 ' -aacaggcccgagtactaaagg-3 ' 1814 574

_.Probe |TET- 5 ' -tgccaaggtgaaagtacccaacttca-3 ' -TAMRA 26 1840 375 jReverse 5 ' -tcagggtcttctgtagcttttg-3 ' 22 1876 376

Table AUB. General_screening_panel_vl.4

Table AUC. General oncology screening panel_v_2.4

Colon cancer 2 Bladder cancer NAT 4 2.4

Colon cancer NAT 2 119.5 'Adenocarcinoma of the prostate 1 69.7

Colon cancer 3 16.1 Adenocarcinoma of the prostate 2 |6.5

Colon cancer NAT 3 66.4 Adenocarcinoma of the prostate 3 119.8

Colon malignant cancer 4 64.6 Adenocarcinoma of the prostate 4 151.1

Colon normal adjacent

28.2 Prostate cancer NAT 5 ^;7.1 tissue 4

Lung cancer 1 2J.J I Adenocarcinoma of the prostate 6 ^'4.8

Tung NAT 1 15.8 lAdenocarcinoma of the prostate 7 [6.4 iLung cancer 2 JAdenocarcinoma of the prostate 8 ' 1.6 Lung NAT 2 15.4 'Adenocarcinoma of the prostate 9 28.5

CNS_neurodegeneration_vl.O Summary: Ag4107 Results from one experiment with the CG97528-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screeningjpanel_vl.4 Summary: Ag4107 Highest expression of the CG97528-01 gene is detected in gastric cancer cell line (CT=25). High expression of this gene is also seen in cluster of cancer cell lines including CNS, colon, renal, breast, ovarian, prostate, squamous cell carcinoma and melanoma. Therefore, therapeutic modulation of this gene may be useful in the treatment of these cancers. Significant expression is also detected in fetal and adult lung. Interestingly, this gene is expressed at much higher levels in fetal (CT = 27.8) when compared to adult lung (CT=32). This observation suggests that expression of this gene can be used to distinguish fetal from adult lung. In addition, the relative overexpression of this gene in fetal lung suggests that the protein product may enhance lung growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of lung related diseases.

Panel 4.1D Summary: Ag4107 Results from one experiment with the CG97528- 01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General oncology screening panel_v_2.4 Summary: Ag4107 Highest expression of the CG97528-01 gene is detected in kidney cancer (CT=27). Interestingly, expression of this gene is higher in number of cancer samples including kidney, adenocarcinoma of the prostate, melanoma, lung, and colon cancers. Therefore, therapeutic modulation of this gene may be useful in the treatment of these cancers.

AN. CG97629-01: Cell Division Protein Kinase 7

Expression of gene CG97629-01 was assessed using the primer-probe set Ag4122, described in Table AVA.

Table AVA. Probe Name Ag4122

Forward ' -gggacattttgctacagcctat-3 ' | 22 142 377

Probe jTET-5 ' -agaacaccaaccaaatcgtcaccatt-3 ' -TAMRA | 26 177 378

Reverse J5 ' -agcttctgacctgtgtccaa-3 ' ] 20 216 379

CNS_neurodegeneration_vl.O Summary: Ag4122 Expression of the CG97629- 01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General_screening_panel_vl.4 Summary: Ag4122 Expression of the CG97629- 01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 4.1D Summary: Ag4122 Expression of the CG97629-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel CNS_1 Summary: Ag4122 Expression of the CG97629-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag4122 Expression of the CG97629-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

AW. CG97648-01: G Protein-Coupled Receptor Kinase GRK7

Expression of gene CG97648-01 was assessed using the primer-probe sets Ag3046 and Ag4125, described in Tables AWA and AWB. Results of the RTQ-PCR runs are shown in Tables AWC, AWD. AWE and AWF.

Table AWA. Probe Name Ag3046

Table AWB. Probe Name Ag4125

Table AWC. Panel 1.3D

Table AWD. Panel 2D

Table AWE. Panel 4.1D

Table AWF. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.0 Summary: Ag3046 Expression of this gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Ag4125 Results from one experiment with this gene are not included. The amp plot indicates that there were experimental difficulties with this run (data not shown). General_screening_panel_vl.4 Summary: Ag4125 Expression of this gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 1.3D Summary: Ag3046 Expression of this gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 2D Summary: Ag3046 Significant expression of this gene is seen exclusively in a breast cancer sample (CT = 25.2). Therefore, expression of this gene may be used to distinguish breast cancers from the other samples on this panel. Furthermore, therapeutic modulation of the activity of the GPCR encoded by this gene may be beneficial in the treatment of breast cancer.

Panel 3D Summary: Ag3046 Expression of this gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 4. ID Summary: Ag4125 This gene is only expressed at detectable levels in the kidney (CT = 32.6). The putative GPCR encoded for by this gene could allow cells within the kidney to respond to specific microenvironmental signals (For example, ref. 1). Therefore, antibody or small molecule therapies designed with the protein encoded for by this gene could modulate kidney function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney, including lupus and glomerulonephritis.

References: 1. Mark M.D., Wittemann S., Herlitze S. (2000) G protein modulation of recombinant P/Q-type calcium channels by regulators of G protein signalling proteins. J. Physiol. 528 Pt 1: 65-77.

1. Fast synaptic transmission is triggered by the activation of presynaptic Ca2+ channels which can be inhibited by Gbetagamma subunits via G protein-coupled receptors (GPCR). Regulators of G protein signalling (RGS) proteins are GTPase-accelerating proteins (GAPs), which are responsible for > 100-fold increases in the GTPase activity of G proteins and might be involved in the regulation of presynaptic Ca2+ channels. In this study we investigated the effects of RGS2 on G protein modulation of recombinant P/Q- type channels expressed in a human embryonic kidney (HEK293) cell line using whole- cell recordings. 2. RGS2 markedly accelerates transmitter-mediated inhibition and recovery from inhibition of Ba2+ currents (IBa) through P/Q-type channels heterologously expressed with the muscarinic acetylcholine receptor M2 (mAChR M2). 3. Both RGS2 and RGS4 modulate the prepulse facilitation properties of P/Q-type Ca2+ channels. G protein reinhibition is accelerated, while release from inhibition is slowed. These kinetics depend on the availability of G protein alpha and betagamma subunits which is altered by RGS proteins. 4. RGS proteins unmask the Ca2+ channel beta subunit modulation of Ca2+ channel G protein inhibition. In the presence of RGS2, P/Q-type channels containing the beta2a and beta3 subunits reveal significantly altered kinetics of G protein modulation and increased facilitation compared to Ca2+ channels coexpressed with the beta lb or beta4 subunit.

PMID: 11018106

Panel 4D Summary: Ag3046 Expression of this gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown). General oncology screening panel_v_2.4 Summary: Ag3046/Ag4125 Two experiments with same probe and primer set are in excellent agreement. Significant expression of this gene is seen exclusively in a kidney cancer sample (CT=34.6). Therefore, expression of this gene may be used to distinguish kidney cancers from the other samples on this panel. Furthermore, therapeutic modulation of the activity of the GPCR encoded by this gene may be beneficial in the treatment of kidney cancer.

AX. CG97658-01: Human Protein Tyrosine Phosphotase Expression of gene CG97658-01 was assessed using the primer-probe set Ag4128, described in Table AXA. Results of the RTQ-PCR runs are shown in Tables AXB, AXC, AXD and AXE.

Table AXA. Probe Name Ag4128

Primers Sequences .Length Start Position SEQ ID No

Forward 15 ' -aagcagaagagcttcatgaaaa-3 ' ! 22 784 386

Probe TET-5 ' -cctttcctgctgcaggcggaatt-3 - TAMRA, 23 816 387

Reverse 5 ' -aaagttcatggggatttcaaag-3 ' i 22 839 388

Table AXB. CNS_neurodegeneration_vl.0

Table AXC. General_screening_panel_vl.4

Table AXD. Panel 4.1D

Table AXE. General oncology screening panel_v_2.4

expression of the CG97658-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders. General_screening_panel_vl.4 Summary: Ag4128 Highest expression of the

CG97658-01 gene is seen in thalamus (CT=25.7). High expression of this gene is detected in all regions of the central nervous system (CNS) examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, expression of this gene can be used to distinguish CNS samples from other samples in this panel. Furthermore, therapeutic modulation of this gene may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Panel 4.1D Summary: Ag4128 Highest expression of the CG97658-01 gene is detected in TNFalpha + IL-lbeta treated coronery artery SMC cells. Therefore, exression of this gene can be used to distinguish this sample from other samples in this panel. In addition, low expression of this gene is seen in lung. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of lung related disorders such as chronic obstructive pulmonary disease, asthma, allergy and emphysema. General oncology screening panel_v_2.4 Summary: Ag4128 Highest expression of the CG97658-01 gene is detected in metastic melanoma (CT=31.5).

Significant expression of this gene is associated with kidney cancer, melanoma and lung cancer. Therefore, therapeutic modulation of this gene may be useful in the treatment of these cancers.

AY. CG97842-01 : Protein Kinase-Formin-Like Protein Expression of gene CG97842-01 was assessed using the primer-probe set Ag4130, described in Table AYA. Results of the RTQ-PCR runs are shown in Tables AYB, AYC and AYD.

Table AYA. Probe Name Ag4130

Table AYB. CNS neurodegeneration vl.O

Renal ca. UO-31 Pancreas Pool 20.0

Table AYD. Panel 4.1D

jLAK cells PMA/ionomycin 81.2 iNCI-H292 IL-13 141 .8

CNS_neurodegeneration_vl. Summary: Ag4130 This panel confirms the expression of the CG97842-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4130 Highest expression of the CG97842-01 gene is detected in a breast cancer cell line (CT=25.6). High expression of this gene is seen a cluster of cancer cell lines including CNS, colon, gastric, renal, lung, breast, ovarian, prostate, melanoma, squamous cell carcinoma and pancreatic cancer cell lines. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of these cancers.

Interestingly, this gene is expressed at much higher levels in fetal (CT=27) when compared to adult liver and lung (CT=30-32). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver and lung, respectively. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance growth or development of lung and liver in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver and lung related diseases.

Panel 4.1D Summary: Ag4130 Highest expression of the CG97842-01 gene is detected in TNFalpha + ILlbeta treated bronchial epithelium (CT=28.7). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General__screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

AZ. CG98021-01: Synaptotagmin III Expression of gene CG98021-01 was assessed using the primer-probe set Ag4138, described in Table AZA. Results of the RTQ-PCR runs are shown in Tables AZB, AZC, AZD and AZE.

Table AZA. Probe Name Ag4138

Table AZC. General_screening_panel_yl.4

Breast ca. T47D 1.1 Skeletal Muscle Pool 0.0 1 Breast ca. MDA-N 0.1 Spleen Pool 0.1

Breast Pool 0.2 Thymus Pool 0.0

Trachea 0.0 CNS cancer (glio/astro) U87-MG 0.0

CNS cancer (glio/astro) U-1 18-

Lung 0.0 0.1 MG

Fetal Lung 0.9 CNS cancer (neuro;met) SK-N-AS 1.1

Lung ca. NCI-N417 0.2 CNS cancer (astro) SF-539 0.0

Lung ca. LX-1 0.0 CNS cancer (astro) SNB-75 0.0

Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 0.3

Lung ca. SHP-77 0.0 CNS cancer (glio) SF-295 0.7

Lung ca. A549 0.7 Brain (Amygdala) Pool 1 1.7

Lung ca. NCI-H526 0.0 Brain (cerebellum) 98.6

Lung ca. NCI-H23 3.7 Brain (fetal) 100.0

Lung ca. NCI-H460 0.5 Brain (Hippocampus) Pool 12.3

Lung ca. HOP-62 0.1 Cerebral Cortex Pool 24.5

Lung ca. NCI-H522 3.2 Brain (Substantia nigra) Pool 17.7

Liver 0.0 Brain (Thalamus) Pool 29.3

Fetal Liver 0.0 Brain (whole) 18.3

Liver ca. HepG2 0.0 Spinal Cord Pool 3.0

Kidney Pool 0.1 Adrenal Gland 1.0

Fetal Kidney 1.2 Pituitary gland Pool 1.9

Renal ca. 786-0 0.0 Salivary Gland 0.1

Table AZD. Panel 4.1D

CNS_neurodegeneration_vl.O Summary: Ag4138 T s panel con irms t e expression of the CG98021-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4138 Highest expression of the CG98021-01 gene is detected in cerebellum and fetal brain (CT=28). In addition high expression of this gene is detected exclusively in all the region of central nervous system examined. Therefore, expression of this gene can be used to distinguish CNS samples from other samples used in this panel. In addition, therapeutic modulation of this gene may be useful in the treatment of CNS disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Low expression of this gene is also seen in a few of colon cancer, renal cancer, lung cancer, breast, ovarian and melanoma cell lines. Therefore, therapeutic modulation of this gene may be beneficial in the treatement of these cancers. Low expression of this gene is also detected in fetal lung. Interestingly, this gene is expressed at much higher levels in fetal (CT=34.8) when compared to adult lung (CT=40). This observation suggests that expression of this gene can be used to distinguish fetal from adult lung. In addition, the relative overexpression of this gene in fetal lung suggests that the protein product may enhance lung growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of lung related diseases.

Panel 4.1D Summary: Ag4138 Highest expression of the CG98021-01 gene is detected in kidney (CT=29.6). In addition low expression of this gene is also detected in thymus, eosinophils and PMA/ionomycin treated basophils. Therefore, expression of this gene can be used to distinguish these samples from other samples used in this panel. In addition, therapeutic modulation of this gene may be useful in the treatment of inflammation and autoimmune disease that affect kidney including lupus and glomerulonephritis.

General oncology screening panel_v_2.4 Summary: Ag4138 Highest expression of the CG98021-01 gene is detected in kidney (CT=34.5). In addition, low expression of this gene is also seen in lung cancer sample. Please see Panel 1.4 and 4. ID for a discussion of the potential utility of this gene.

BA. CG98030-01: Tyrosine Phosphatase

Expression of gene CG98030-01 was assessed using the primer-probe set Ag4139, described in Table BAA. Results of the RTQ-PCR runs are shown in Tables BAB and BAC.

Table BAA. Probe Name Ag4139

Table BAB. CNS neurodegeneration vl.O

Table BAC. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4139 This panel confirms the expression of the CG98030-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

Panel 4.1D Summary: Ag4139 Expression of the CG98030-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag4139 Highest expression of the CG98030-01 gene is detected in malignant colon cancer sample (CT=29). Interestingly, higher expression of this gene is associated with number of cancer samples examined including colon, lung, melanoma, metastic melanoma, adenocarcinoma of the prostate, and kidney cancers. Therefore, expression of this gene may be used as diagnostic markers for these cancers. In addition, therapeutic modulation of this gene may be be useful in the treatments of these cancers.

BB. CG98030-02: Tyrosine Phosphatase Expression of full length physical clone CG98030-02 was assessed using the primer-probe set Ag6401, described in Table BBA. Results of the RTQ-PCR runs are shown in Table BBB.

Table BBA. Probe Name Ag6401

Table BBB. Panel 4.1D

Panel 4.1D Summary: Ag6401 Highest expression of the CG98030-02 is detected in lung microvascular endothelial cells and keratinocytes (CT=32.8). In addition, low levels of expression of this gene is also seen in dermal fibroblast, lung fibroblast, TNF 03/010327

alpha + IL-1 beta treated HPAEC, HUVEC, resting LAK cells, activated primary Thl, Th2, and Trl cells, activated CD4 lymphocytes and kidney. Therefore, therapeutic modulation of this tyrosine phosphotase encoded by this gene may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus. psoriasis, rheumatoid arthritis, and osteoarthritis.

BC. CG98061-01 and CG98061-02: Novel Protein containing Histidine acid phosphatase domain

Expression of gene CG98061-01 and variant CG98061-02 was assessed using the primer-probe set Ag4141, described in Table BCA. Results of the RTQ-PCR runs are shown in Tables BCB, BCC and BCD.

Table BCA. Probe Name Ag4141

Table BCB. CNS_neurodegeneration_vl.O

Table BCC. Panel 4.1D

CNS_neurodegeneration_vl.0 Summary: Ag4141 This panel confirms the expression of the CG98061-01 gene at low levels in the brain in an independent group of individuals. This gene is found to be slightly upregulated in the temporal cortex of Alzheimer's disease patients. Therefore, therapeutic modulation of the expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease.

General_screening_panel_vl.4 Summary: Ag4141 Results from one experiment with the CG98061-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 4.1D Summary: Ag4141 Highest expression of the CG98061-01 gene is detected in activated secondary Th2 cells (CT=29.6). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

General oncology screening panel_v_2.4 Summary: Ag4141 Highest expression of the CG98061 -01 gene is detected in kidney cancer sample (CT=31.8). In addition, significant expression of this gene is also seen in lung cancer, metastatic melanoma, kidney cancer and adenocarcinoma of the prostate. Therefore, therapeutic modulation of this gene mav be beneficial in the treatment of these cancers.

BD. CG98131-01: MDJ6

Expression of gene CG98131-01 was assessed using the primer-probe set Ag4144, described in Table BDA. Results of the RTQ-PCR runs are shown in Tables BDB, BDC and BDD.

Table BDA. Probe Name Ag4144

Table BDB. CNS_neurodegeneration_vl.0

Table BDC. General_screening_panel_vl.4

iO.O ;CNS cancer (neuro;met) SK-N-

Tetal Luna Us 2.0

Table BDD. Panel 4.1D

B lymphocytes PWM 0.0 ΪDermal fibroblast CCD 1070 rest 0.0 !

JDermal fibroblast CCD 1070 TNF ;

B lymphocytes CD40L and IL-4 0.0 jalpha iDermal fibroblast CCDl 070 IL-1

EOL-1 dbcAMP 0.0 ϊbeta

EOL-1 dbcAMP

0.0 IDermal fibroblast IFN gamma 0.0 PMA/ionomycin i

Dendritic cells none 0.0 iDermal fibroblast IL-4 0.0

Dendritic cells LPS 0.0 jDermal Fibroblasts rest 0.0

Dendritic cells anti-CD40 0.0 [Neutrophils TNFa+LPS 0.0

Monocytes rest 7.2 Neutrophils rest 0.0 Monocytes LPS 6.4 Colon 0.0

Macrophages rest 0.0 [Lung 0.0

CNS_neurodegeneration_vl.O Summary: Ag4144 Highest expression of the CG98131-01 gene is detected in superior temporal cortex of an Alzheimer's disease patient (CT=34.1). Therefore, therapeutic modulation of the expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease.

General_screeningjpanel_vl.4 Summary: Ag4144 Highest expression of the CG98131-01 gene is detected in testis (CT=29). Therefore, expression of this gene may be used to distinguish testis from other samples used in this panel and therapeutic modulation of this gene product may be useful in the treatment of disorders associated with testis such as fertility and hypogonadism.

In addition, low expression of this gene is also seen in a CNS cancer, pancreatic cancer and an ovarian cancer cell lines. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of these cancers. Panel 4.1D Summary: Ag4144 Highest expression of the CG98131-01 gene is detected in exclusively in kidney (CT=32). Therefore, expression of this gene may be used to distinguish kidney from other samples used in this panel. In addition, therapeutic modulation of this gene product may be beneficial in the treatment of autoimmune and inflammatory diseases that affect kidney including lupus and glomerulonephritis.

BE. CG98164-01 and CG98164-02: LRR and Kinase Domain Protein

Expression of gene CG98164-01 and full length physical clone CG98164-02 was assessed using the primer-probe sets Ag4145 and Ag4145, described in Tables BEA and BEB. Results of the RTQ-PCR runs are shown in Tables BEC, BED, BEE and BEF. Please note that CG98164-02 represents a full-length physical clone of the CG98164-01 gene, validating the prediction of the gene sequence.

Table BEA. Probe Name Ag4145

Start ■ SEQ ID

[Primers Sequences Length:

Position , No

'Forward ^'5 ' -agtgacagtgagaccgaagaga- 3 n 2340 407 iProbe ;TET- 5 ' - cccggaaagcactacctatacaatca-3 ' - TAMRA, 26 ! 2362 408

_.Reverse -,5 ' - agtgttgtctgtgttggtgaga-3 22 2406 409

Table BEB. Probe Name Ag4145

Table BEC. CNS neurodegeneration vl.O

'Control (Path) 1 Temporal Ctx 190.8 •Control (Path) 3 Parietal Ctx 29.5

'Control (Path) 2 Temporal Ctx 160.3 Control (Path) 4 Parietal Ctx

Table BED. General_screening_panel_vl.4

Table BEE. Panel 4. ID

_. iDendritic cells none 145.7 ^■Dermal fibroblast IL-4

Dendritic cells LPS 116.0 Dermal Fibroblasts rest .O

Dendritic cells anti-CD40 123.5 Neutrophils TNFa+LPS [o.o

Monocytes rest |20.2 Neutrophils rest io.o Monocytes LPS Il5.7 Colon lo.o

Macrophages rest |l 9.1 Lung .15.7

Macrophages LPS :o.o Thymus :s.2

HUVEC none jo.o Kidney i 15.6 HUVEC starved io.o ^{" f}

Table BEF. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4145 This panel confirms the expression of the CG98164-01 gene at low levels in the brain in an independent group of individuals. This gene appears to be slightly upregulated in the temporal cortex of Alzheimer's disease patients. Therefore, therapeutic modulation of the expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease.

General_screening_panel_vl.4 Summary: Ag4145 Highest expression of the CG98164-01 gene is seen in a melanoma cell line (CT=30). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker to detect the presence of melanoma. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of melanoma.

In addition, this gene is expressed at much higher levels in fetal lung (CT=32.5) when compared to expression in the adult counterpart (CT=40). Thus, expression of this gene may be used to differentiate between the fetal and adult source of this tissue. General_screening_panel_vl.5 Summary: Ag4145 Results from one experiment with the CG98164-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 4.1D Summary: Ag4145 Expression of the CG98164-01 gene is restricted to ionomycin and untreated samples from the B cell line Ramos (CTs=34.5). B cells represent a principle component of immunity and contribute to the immune response in a number of important functional roles, including antibody production. Production of antibodies against self-antigens is a major component in autoimmune disorders. Since B cells play an important role in autoimmunity, inflammatory processes and inflammatory cascades, therapeutic modulation of this gene product may reduce or eliminate the symptoms of patients suffering from asthma, allergies, chronic obstructive pulmonary disease, emphysema, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, osteoarthritis, systemic lupus erythematosus and other autoimmune disorders. Two additional experiments with the same probe and primer show low/undetectable levels of expression (CTs>35). (Data not shown.)

General oncology screening panel_v_2.4 Summary: Ag4145 Highest expression of the CG98164-01 gene is detected in lung cancer (CT=29). Significant expression of this gene is seen in number of cancer samples including colon, lung, adenocarcinoma of prostate, bladder and kidney cancers. . Thus, the expression of this gene could be used to distinguish colon, lung and prostate cancers from the normal tissues. Therapeutic modulation of this gene product may be useful in the treatment of these cancers.

BF. CG99588-01: Novel Transmembrane Protein

Expression of gene CG99588-01 was assessed using the primer-probe set Ag4148, described in Table BFA. Results of the RTQ-PCR runs are shown in Tables BFB, BFC, BFD and BFE.

Table BFA. Probe Name Ag4148

Start SEQ ID

Trimers , Sequences Length

I __\ _ _ . . _ „ . _ Position No

;Forward 5 ' -ggtcactgtggtgaagagtga- 3 ⁽ 21 12 413

Probe TET- 5 ' -acccaaactggtgccgttcttcaag-3 ' -TAMRA 25 36 , 414

Reverse |5 ' -cagccagagcacaaaatacac-3 ' 21 70 415

Table BFB. CNS_neurodegeneration vl.O

Table BFC. General_screening_panel_vl.4

Table BFD. Panel 4.1D

Table BFE. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4148 This panel confirms the expression of the CG99588-01 gene at low levels in the brain in an independent group of individuals. This gene is found to be slightly upregulated in the temporal cortex of Alzheimer's disease patients. Therefore, therapeutic modulation of the expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease.

General_screening_panel_vl.4 Summary: Ag4148 Highest expression of the CG99588-01 gene is detected in breast cancer cell line (CT=30.41). Significant expression of this gene is also seen in cluster of cancer cell lines including CNS, colon, gastric, renal, lung, breast, ovarian, prostate, squamous cell carcinoma, and melanoma cell lines.

Therefore, therapeutic modulation of this gene product may be useful in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Ag4148 Results from one experiment (run 220982871) with the this gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 4.1D Summary: Ag4148 Highest expression of the CG99588-01 gene is detected in kidney (CT=30.3). In addition, moderate to low levels of expression of this gene is also seen primary and secondary Thl , Th2 and Trl cells, LAK cells, dendritic cells, monocytes, macrophages, endothelial cells, bronchial and small airway epithelial cells, coronery artery SMC. NCI-H292, astrocytes and normal tissues represent by colon, lung, and thymus. Therefore, therapeutic modulation of the gene product may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

General oncology screening panel_v_2.4 Summary: Ag4148 Highest expression of the CG99588-01 gene is detected in metastic melanoma (CT=29). In addition, significant expression of this gene is also seen in number of cancer samples including kidney, colon, adenocarcinoma of prostate, lung and bladder cancer. Therefore, therapeutic modulation of this gene product through the use of small molecule drug may be beneficial in the treatment of these cancers.

BG. CG99618-01: Protein-Tyrosine Phosphatase 2C

Expression of gene CG99618-01 was assessed using the primer-probe set Ag4151, described in Table BGA. Results of the RTQ-PCR runs are shown in Tables BGB, BGC and BGD.

Table BGA. Probe Name Aε4151

Start SEQ ID

Primers Sequences Length] Position No

Forward 5 ' -catcatgggcaattaaaagaga-3 ' 22^~J 258 416

Probe TET-5 ' -aaaatcctctgaactgtgcagatcct-3 ' -TAMRA 26 f 304 417

Reverse 5 ' -catgaaaccacctttgagaagt-3 ' j 22 j 330 418

Table BGB. CNS_neurodegeneration_vl.0

Table BGC. General_screening_panel_vl.4

Prostate Pool 4.2 Colon ca. CaCo-2 0.1

Placenta 1.5 Colon cancer tissue 0.4

Uterus Pool 0.7 Colon ca. SW11 16 0.1

Ovarian ca. OVCAR-3 1.1 Colon ca. Colo-205 0.0

Ovarian ca. SK-OV-3 0.5 Colon ca. SW-48 0.0

IOvarian ca. OVCAR-4 0.5 Colon Pool 4.2

IOvarian ca. OVCAR-5 0.4 jSmall Intestine Pool 2.2

Ovarian ca. IGROV-1 0.0 iStomach Pool 0

Ovarian ca. OVCAR-8 1.5 Bone Marrow Pool 1

Ovary 3.0 Fetal Heart 4.5

Breast ca. MCF-7 0.1 Heart Pool 1.0

Breast ca. MDA-MB-231 0.5 Lymph Node Pool 12.1

Breast ca. BT 549 3.5 Fetal Skeletal Muscle O

Breast ca. T47D 0.2 Skeletal Muscle Pool 11 .6

Breast ca. MDA-N 0.2 jSpleen Pool Il .l

Breast Pool 1.6 [Thymus Pool ^;4.0

Table BGD. Panel 4.1D

'Dendritic cells LPS 10.0 iDermal Fibroblasts rest 0.0

CNS_neurodegeneration_vl.0 Summary: Ag4151 This panel confirms the expression of the CG99618-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screeningjpanel_vl.4 Summary: Ag4151 Highest expression of the CG99618-01 gene is detected in melanoma SK-MEL-5 cell line (CT=29.6). Therefore, expression of this gene can be used to distinguish this sample from other samples in the panel. Low expression of this gene is also detected in a breast cancer and a CNS cancer cell lines. Therefore, therapeutic modulation of this gene product may be useful in the treatment of melanoma, breast and CNS cancers.

In addition, this gene is expressed at low levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4151 Highest expression of the CG99618-01 gene is detected in kidney (CT=32.4). Therefore, expression of this gene can be used to distinguish kidney from other samples in this panel. In addition, therapeutic modulation of this gene product may be useful in the treatment of inflammatory and autoimmune diseases that affect kidney such as lupus and glomerulonephritis.

Low levels of expression of this gene is also seen in TNFalpha + IL-lbeta treated keratinocytes. Interestingly, this expression in treated cells is higher (CT=34) as compared to the untreated keratinocytes (CT=38). Therefore, expression of this gene can be used to distinguish the treated from untreated keratinocytes. In addition, therapeutic modulation of this gene product may be useful in the treatment of psoriasis and wound healing.

BH. CG99832-01: Novel Gene Containing NUDIX Hydrolase Domain Expression of gene CG99832-01 was assessed using the primer-probe set Ag4157, described in Table BHA. Results of the RTQ-PCR runs are shown in Tables BHB, BHC, BHD and BHE.

Table BHA. Probe Name Ag4157

Table BHB. CNS_neurodegeneration_vl.0

Table BHC. General_screening_panel_vl.4

Table BHD. Panel 4.1D

Table BHE. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4157 This panel confirms the expression of the CG99832-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screeningjpanel_vl.4 Summary: Ag4157 Highest expression of the CG99832-01 gene is detected in breast cancer T47D cell line (CT=29). Moderate levels of expression of this gene is seen in cluster of cancer lines including pancreatic, CNS, colon, gastric , renal, lung, breast , ovarian, prostate, squamous cell carcinoma, and melanoma cell lines. Therefore, therapeutic modulation of this gene may be useful in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. Interestingly, this gene is expressed at much higher levels in fetal (CT=30) when compared to adult liver (CT=34.8). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases.

In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease. Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4. ID Summary: Ag4157 Highest expression of the CG99832-01 gene is detected in LPS treated monocytes (CT=29). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell. macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screeningjpanel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

General oncology screening panel_v_2.4 Summary: Ag4157 Highest expression of the CG99832-01 gene is detected in metastatic melanoma (CT=29). Higher expression of this gene is seen in cancer samples including colon cancer, kidney cancer, lung cancer, prostate adenocarcinoma and melanoma. Therefore, therapeutic modulation of this gene may be useful in the treatment of these cancers. BI. CG99842-01: Tensin-Like

Expression of gene CG99842-01 was assessed using the primer-probe set Ag4158, described in Table BIA. Results of the RTQ-PCR runs are shown in Tables BIB, BIC and BID.

Table BIA. Probe Name Ag4158

Table BID. Panel 4.1D

CNS_neurodegeneration_vl.O Summary: Ag4158 This panel confirms the expression of the CG99842-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4158 Highest expression of the CG99842-01 gene is detected in colon cancer HCT-1 16 ceH line (CT=30.7). Moderate expression of this gene is associated with cluster of cancer cell lines including pancreatic, CNS, colon, gastric, renal, lung, breast, ovarian, prostate, squamous cell carcinoma and melanoma cancer cell lines. Therefore, therapeutic modulation of this gene product may be useful in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT=33.7) when compared to adult liver (CT=40). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases.

In addition, this gene is expressed at low to moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4158 Highest expression of the CG99842-01 gene is detected in kidney (CT=31). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

BJ. CG99944-01: ABC Transporter

Expression of gene CG99944-01 was assessed using the primer-probe set Ag4184, described in Table BJA. Results of the RTQ-PCR runs are shown in Table BJB.

Table BJA. Probe Name Ag4184

CNS_neurodegeneration_vl.0 Summary: Ag4184 Resu ts from one exper ment with the CG99944-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

General_screeningjpanel_vl.4 Summary: Ag4184 Expression of the CG99944- 01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

Panel 4.1D Summary: Ag4184 Expression of the CG99944-01 gene is low/undetectable (CTs > 35) across all of the samples on this panel (data not shown).

General oncology screening panel_v_2.4 Summary: Ag4184 Highest expression of the CG99944-01 gene is detected exclusively in a melanoma sample (CT=34). Therefore, expression of this gene can be used to distinguish this sample from other samples used in this panel and therapeutic modulation of this gene product may be beneficial in the treatment of melanoma. BK. CG99963-01: Cyclophilin 18

Expression of gene CG99963-01 was assessed using the primer-probe set Ag4160, described in Table BKA. Results of the RTQ-PCR runs are shown in Tables BKB, BKC, BKD and BKE.

Table BKA. Probe Name Ag4160

Start SEQ ID

Primers [Sequences .Length! Position No

Forward;5 ' -ggcaagaccagcaagaagat-3 ^• 20 ! 545 428

Probe JTET- 5 ' -caccattgctgactgtggacaactct-3 ' -TAMRA; 26 565 429

Reverse J5 ' -aaaggaatggtctggtggtt-3 ' 20 617 430

Lung ca. LX-1 31.0 CNS cancer (astro) SNB-75 J51.4

Lung ca. NCI-H 146 9.0 CNS cancer (glio) SNB-19 j 16.2

Lung ca. SHP-77 42.3 CNS cancer (glio) SF-295 J28.9

Lung ca. A549 26.8 Brain (Amygdala) Pool Ϊ7.2

Lung ca. NCI-H526 10.7 Brain (cerebellum) |l0.3

Lung ca. NCI-H23 20.4 Brain (fetal) J9.2

Lung ca. NCI-H460 9.3 Brain (Hippocampus) Pool [6.7

Lung ca. HOP-62 13.8 Cerebral Cortex Pool J9.4

_.Lung ca. NCI-H522 122.5 Brain (Substantia nigra) Pool j7.9

(Liver i l .6 Brain (Thalamus) Pool !6.8 iFetal Liver 11 1.8 Brain (whole) •6.3 iLiver ca. HepG2 19.6 Spinal Cord Pool [3.3

JKidney Pool J7.8 ! Adrenal Gland 19.1 |FetaI Kidney [1 1.3 _.Pituitary gland Pool il .9 JRenal ca. 786-0 120.0 iSalivarv Gland .7

Renal ca. A498 |8.7 Thyroid (female) JRenal ca. ACHN 13.6 Pancreatic ca. CAPAN2 30T 'Renal ca. UO-31 21.6 Pancreas Pool ! 10.4

Table BKD. Panel 4.1D

Table BKE. General oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4160 This panel confirms the expression of the CG99963-01 gene at low levels in the brain in an independent group of individuals. This gene is found to be slightly down-regulated in the temporal cortex of Alzheimer's disease patients. Therefore, up-regulation of this gene or its protein product, or treatment with specific agonists for this protein may be useful in reversing the neuronal death and dementia/memory loss associated with this disease.

The CG99963-01 gene codes for cyclophilin 18 (Cyclophilin A; CyP-A) homolog. Cyp-A, a soluble cytoplasmic immunophilin, is known for its involvement in T cell differentiation and proliferation. Although CyP-A has a pivotal role in the immune response, it is most highly concentrated in brain. It is known to play a role in neuronal differentiation and proliferation of human embryonic brain cells (Nahreini et al., 2001, Cell Mol Neurobiol 21(l):65-79, PMID: 11440199). Therefore, therapeutic modulation of Cyp-A like protein encoded by this gene may be useful in treatment of neurological disorders.

General_screening_panel_vl.4 Summary: Ag4160 Highest expression of the CG99963-01 gene is detected in a breast cancer T47D cell line (CT=21). High expression of this gene is also seen in cluster of cancer cell lines including melanoma, squamous cell carcinoma, pancreatic, CNS, colon, gastric, renal, breast, ovarian, and prostate cancer cell lines. Therefore, therapeutic modulation of this gene through the use of small molecule drug may be beneficial in the treatment of these cancers.

Panel 4.1D Summary: Ag4160 Highest expression of the CG99963-01 gene is detected in IL-9 treated NCI-H292 cells (CT=23). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis. General oncology screening panel_v_2.4 Summary: Ag4160 Highest expression of the CG99963-01 gene is detected in malignant colon cancer (CT=23). In addition, high expression of this gene is also detected in number of cancer samples including squamous cell care

OTHER EMBODIMENTS

Although particular embodiments have been disclosed herein in detail, this has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope of the appended claims, which follow. In particular, it is contemplated by the inventors that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as defined by the claims. The choice of nucleic acid starting material, clone of interest, or library type is believed to be a matter of routine for a person of ordinary skill in the art with knowledge of the embodiments described herein. Other aspects, advantages, and modifications considered to be within the scope of the following claims. The claims presented are representative of the inventions disclosed herein. Other, unclaimed inventions are also contemplated. Applicants reserve the right to pursue such inventions in later claims.

Claims

What is claimed is:What is claimed is:

1. An isolated polypeptide comprising the mature form of an amino acid sequenced selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 101

2. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 101.

3. An isolated polypeptide comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 101.

4. An isolated polypeptide, wherein the polypeptide comprises an amino acid sequence comprising one or more conservative substitutions in the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 101.

5. The polypeptide of claim 1 wherein said polypeptide is naturally occurring.

6. A composition comprising the polypeptide of claim 1 and a carrier.

7. A kit comprising, in one or more containers, the composition of claim 6.

8. The use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease selected from a pathology associated with the polypeptide of claim 1, wherein the therapeutic comprises the polypeptide of claim 1.

9. A method for determining the presence or amount of the polypeptide of claim 1 in a sample, the method comprising:

(a) providing said sample;

(b) introducing said sample to an antibody that binds immunospecifically to the polypeptide; and

(c) determining the presence or amount of antibody bound to said polypeptide, thereby determining the presence or amount of polypeptide in said sample.

10. A method for determining the presence of or predisposition to a disease associated with altered levels of expression of the polypeptide of claim 1 in a first mammalian subject, the method comprising: a) measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and b) comparing the expression of said polypeptide in the sample of step (a) to the expression of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, said disease, wherein an alteration in the level of expression of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to said disease.

11. A method of identifying an agent that binds to the polypeptide of claim 1 , the method comprising:

(a) introducing said polypeptide to said agent; and

(b) determining whether said agent binds to said polypeptide.

12. The method of claim 11 wherein the agent is a cellular receptor or a downstream effector.

13. A method for identifying a potential therapeutic agent for use in treatment ofa pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of the polypeptide of claim 1, the method comprising: (a) providing a cell expressing the polypeptide of claim 1 and having a property or function ascribable to the polypeptide;

(b) contacting the cell with a composition comprising a candidate substance; and

(c) determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition in the absence of the substance, the substance is identified as a potential therapeutic agent.

14. A method for screening for a modulator of activity of or of latency or predisposition to a pathology associated with the polypeptide of claim 1, said method comprising:

(a) administering a test compound to a test animal at increased risk for a pathology associated with the polypeptide of claim 1 , wherein said test animal recombinantly expresses the polypeptide of claim 1:

(b) measuring the activity of said polypeptide in said test animal after administering the compound of step (a); and

(c) comparing the activity of said polypeptide in said test animal with the activity of said polypeptide in a control animal not administered said polypeptide, wherein a change in the activity of said polypeptide in said test animal relative to said control animal indicates the test compound is a modulator activity of or latency or predisposition to, a pathology associated with the polypeptide of claim 1.

15. The method of claim 14, wherein said test animal is a recombinant test animal that expresses a test protein transgene or expresses said transgene under the control ofa promoter at an increased level relative to a wild-type test animal, and wherein said promoter is not the native gene promoter of said transgene.

16. A method for modulating the activity of the polypeptide of claim 1, the method comprising contacting a cell sample expressing the polypeptide of claim 1 with a compound that binds to said polypeptide in an amount sufficient to modulate the activity of the polypeptide.

17. A method of treating or preventing a pathology associated with the polypeptide of claim 1, the method comprising administering the polypeptide of claim 1 to a subject in which such treatment or prevention is desired in an amount sufficient to treat or prevent the pathology in the subject.

18. The method of claim 17, wherein the subject is a human.

19. A method of treating a pathological state in a mammal, the method comprising administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 101 or a biologically active fragment thereof.

20. An isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-l, wherein n is an integer between 1 and 101.

21. The nucleic acid molecule of claim 20, wherein the nucleic acid molecule is naturally occurring.

22. A nucleic acid molecule, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101.

23. An isolated nucleic acid molecule encoding the mature form of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 101.

24. An isolated nucleic acid molecule comprising a nucleic acid selected from the group consisting of 2n-l, wherein n is an integer between 1 and 101.

25. The nucleic acid molecule of claim 20, wherein said nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or a complement of said nucleotide sequence.

26. A vector comprising the nucleic acid molecule of claim 20.

27. The vector of claim 26, further comprising a promoter operably linked to said nucleic acid molecule.

28. A cell comprising the vector of claim 26.

29. An antibody that immunospecifically binds to the polypeptide of claim 1.

30. The antibody of claim 29, wherein the antibody is a monoclonal antibody.

31. The antibody of claim 29, wherein the antibody is a humanized antibody.

32. A method for determining the presence or amount of the nucleic acid molecule of claim 20 in a sample, the method comprising:

(a) providing said sample;

(b) introducing said sample to a probe that binds to said nucleic acid molecule; and

(c) determining the presence or amount of said probe bound to said nucleic acid molecule, thereby determining the presence or amount of the nucleic acid molecule in said sample.

33. The method of claim 32 wherein presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type.

34. The method of claim 33 wherein the cell or tissue type is cancerous.

35. A method for determining the presence of or predisposition to a disease associated with altered levels of expression of the nucleic acid molecule of claim 20 in a first mammalian subject, the method comprising: a) measuring the level of expression of the nucleic acid in a sample from the first mammalian subject; and b) comparing the level of expression of said nucleic acid in the sample of step (a) to the level of expression of the nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of expression of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

36. A method of producing the polypeptide of claim 1 , the method comprising culturing a cell under conditions that lead to expression of the polypeptide, wherein said cell comprises a vector comprising an isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-l, wherein n is an integer between 1 and 101.

37. The method of claim 36 wherein the cell is a bacterial cell.

38. The method of claim 36 wherein the cell is an insect cell.

39. The method of claim 36 wherein the cell is a yeast cell.

40. The method of claim 36 wherein the cell is a mammalian cell.

41. A method of producing the polypeptide of claim 2, the method comprising culturing a cell under conditions that lead to expression of the polypeptide, wherein said cell comprises a vector comprising an isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-l, wherein n is an integer between 1 and 101.

42. The method of claim 41 wherein the cell is a bacterial cell.

43. The method of claim 41 wherein the cell is an insect cell.

44. The method of claim 41 wherein the cell is a yeast cell.

45. The method of claim 41 wherein the cell is a mammalian cell.