US20060154271A1 - Enzymatic nucleic acid treatment of diseases or conditions related to levels of IKK-gamma and PKR - Google Patents

Enzymatic nucleic acid treatment of diseases or conditions related to levels of IKK-gamma and PKR Download PDF

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US20060154271A1
US20060154271A1 US11/255,139 US25513905A US2006154271A1 US 20060154271 A1 US20060154271 A1 US 20060154271A1 US 25513905 A US25513905 A US 25513905A US 2006154271 A1 US2006154271 A1 US 2006154271A1
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nucleic acid
rna
cugaugag gccguuaggc
gccguuaggc cgaa
ikk
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James McSwiggen
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Sirna Therapeutics Inc
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Definitions

  • the present invention relates to therapeutic compositions and methods for the treatment or diagnosis of diseases or conditions related to IKK gamma (IKKG) and PKR levels, such as cancer, inflammatory, and autoimmune diseases and/or disorders.
  • IKKKG IKK gamma
  • PKR levels such as cancer, inflammatory, and autoimmune diseases and/or disorders.
  • NFKB nuclear factor kappa B
  • IKK kinases IKK kinases
  • protein kinase PKR protein kinase
  • Nuclear factor kappa B is a multiunit transcription factor which regulates the expression of genes involved in a number of physiologic and pathologic processes. NFKB is a key component of the TNF signaling pathway. These processes include, but are not limited to: apoptosis, immune, inflammatory and acute phase responses.
  • the REL-A gene product (a.k.a. RelA or p65), and p50 subunits of NFKB, have been implicated in the induction of inflammatory responses and cellular transformation.
  • NFKB exists in the cytoplasm as an inactive heterodimer of the p50 and p65 subunits.
  • NFKB is complexed with an inhibitory protein complex, IkappaB (IKK complex), until activated by the appropriate stimuli.
  • IKK complex an inhibitory protein complex
  • NFKB activation can occur following stimulation of a variety of cell types by inflammatory mediators, for example TNF and IL-1, and reactive oxygen intermediates.
  • NFKB can stimulate production of pro-inflammatory cytokines such as TNF-alpha, IL-1-beta, IL-6 and iNOS, thereby perpetuating a positive feedback loop.
  • NFKB appears to play a role in a number of disease processes including: ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, arthritis, and cancer.
  • NFKB nuclear DNA-binding protein
  • NFKB NFKB1
  • NFKB2 NFKB2
  • p100 NFKB1
  • REL-A The p65 subunit of NFKB
  • NFKB2/RelA p49/p65
  • NFKB1/RelA p50/p65
  • blocking rel A gene expression with antisense oligonucleotides specifically blocks embryonic stem cell adhesion; blocking NFKB1 gene expression with antisense oligonucleotides had no effect on cellular adhesion (Narayanan et al., 1993, Mol. Cell. Biol., 13, 3802-3810).
  • NFKB NFKB binding sites
  • MAD-3 an Ikappa-B family member
  • NFkB is required for phorbol ester-mediated induction of IL-6 (Kitajima, et al., 1992, Science, 258, 1792-5) and IL-8 (Kunsch and Rosen, 1993, Mol. Cell. Biol., 13, 6137-46).
  • NFkB is required for induction of the adhesion molecules ICAM-1 (Eck, et al., 1993, Mol. Cell. Biol., 13, 6530-6536), VCAM-1 (Shu et al., supra), and E-selectin (Read, et al., 1994, J. Exp. Med., 179, 503-512) on endothelial cells.
  • NFkB is involved in the induction of the integrin subunit, CD18, and other adhesive properties of leukocytes (Eck et al., 1993 supra).
  • HER2/Neu overexpression induces NFKB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IKB-alpha.
  • Breast cancer has been shown to typify the aberrant expression of NFKB/REL factors (Pianetti et al., 2001, Oncogene, 20, 1287-1299; Sovak et al., 1999, J. Clin. Invest., 100, 2952-2960).
  • NFKB has been shown to regulate cyclooxygenase-2 expression and cell proliferation in human gastric cancer cells (Joo Weon et al., 2001, Laboratory Investigation, 81, 349-360).
  • NFKB is integrally involved in the induction of cytokines and adhesion molecules by inflammatory mediators and is involved in the transformation of cancerous cells.
  • Glucocorticoid receptor inhibits NFKB-mediated induction of IL-6 (Ray and Prefontaine, 1994 Proc. Natl. Acad. Sci USA, 91, 752-756).
  • the IKK complex that sequesters NFKB in the cytoplasm comprises IkappaB (I ⁇ B) proteins (I ⁇ B-alpha, I ⁇ B-beta, I ⁇ B-epsilon, p105, and p100).
  • I ⁇ B IkappaB
  • the phosphorylation of I ⁇ B proteins results in the release of NFKB from the I ⁇ B complex which is transported to the nucleus via the unmasking of nuclear translocation signals.
  • Phosphorylation marks IkB proteins for ubiquitination and degradation via the proteosome pathway.
  • IKK I ⁇ B kinase
  • IKK1 I ⁇ B kinase
  • IKK2 I ⁇ B kinase
  • IKK1 I ⁇ B kinase
  • IKK2 I ⁇ B kinase
  • IKK2 I ⁇ B kinase
  • the IKK complex contains regulatory subunits, including IKK-gamma (NEMO/IKKAP1).
  • IKK-gamma is a protein that is critical for the assembly of the IKK complex.
  • IKK-gamma directly binds to IKK-beta and is required for activation of NFKB, for example by TNF-alpha, IL-1-beta, lipopolysaccharide, phorbol 12-myristate 13-acetate, the human T-cell lymphotrophic virus (HTLV-1), or double stranded RNA. Genomic rearrangements in IKK-gamma have been shown to impair NFKB activation and result in incontinentia pigmenti.
  • IKK-1 MEK kinase
  • NIK NFKB inducing kinase
  • RIP receptor interacting protein
  • IKAP IKK-associated protein
  • RNA-dependent protein kinase PKR is a signal transducer for NFKB and IFN regulatory factor-1. PKR is required for activation of NFKB by IFN-gamma via a STAT-1 independent pathway (Amitabha et al., 2001, J. Immunol., 166, 6170-6180). The induction of NFKB by PKR takes place though phosphorylation of I ⁇ B-alpha, and appears not to require the catalytic activity of PKR, thereby proceeding independently of the dsRNA-binding properties of PKR (Ishii et al., 2001, Oncogene, 20, 1900-1912). PKR also plays an important role in the regulation of protein synthesis by modulating the activity of eukaryotic initiation factor 2 (eIF-2-alpha) through interferon induction.
  • eIF-2-alpha eukaryotic initiation factor 2
  • Kamiya, JP 2000253884 describes specific antisense oligonucleotides for inhibiting I ⁇ B-kinase subunit expression.
  • Krappmann et al., 2001, J. Biol. Chem . describe specific antisense oligonucleotides to IKK-gamma.
  • the present invention features a nucleic acid molecule, such as decoy RNA, dsRNA, siRNA, aptamers, antisense nucleic acid molecules, and enzymatic nucleic acid molecule which down regulates expression of a sequence encoding an IkappaB kinase (IKK) subunit.
  • the invention also features an enzymatic nucleic acid molecule which down regulates expression of a sequence encoding protein kinase PKR.
  • an enzymatic nucleic acid molecule of the invention comprises a sequence selected from the group consisting of SEQ ID NOs. 632-1261, 1762-2260, 2480-2698, 2904-3485, 3814-4360, 4555-4748, 5253-5756, 6034-6310, 6380-6789, 7142-7770, and 7884-8001.
  • an enzymatic nucleic acid molecule of the invention comprises at least one binding arm wherein one or more of said binding arms comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1-631, 1263-1761, 2261-2479, 2699-2903, 3486-3813, 4361-4554, 4749-5252, 5757-6033, 6311-6379, 6790-7141, and 7771-7883.
  • an antisense nucleic acid molecule of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1-631, 1263-1761, 2261-2479, 2699-2903, 3486-3813, 4361-4554, 4749-5252, 5757-6033, 6311-6379, 6790-7141, and 7771-7883.
  • an nucleic acid molecule of the invention is adapted to treat cancer.
  • an enzymatic nucleic acid molecule of the invention has an endonuclease activity to cleave RNA having IKK-gamma or PKR nucleic acid sequence.
  • an enzymatic nucleic acid molecule of the invention is in an Inozyme, Zinzyme, G-cleaver, Amberzyme, DNAzyme, or Hammerhead configuration.
  • an Inozyme of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1263-1761, 4749-5252, 7781-7787, 7796-7800, 7822-7846, and 7866-7870.
  • an Inozyme of the invention comprises a sequence selected from the group consisting of SEQ ID NOs. 1762-2260, 5253-5756, 7894-7900, 7909-7913, 7938-7962, and 7982-7986.
  • a Zinzyme of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 2261-2479, 5757-6033, 7788-7790, 7847-7860, and 7871-7895.
  • a Zinzyme of the invention comprises a sequence selected from the group consisting of SEQ ID NOs 2480-2698, 6034-6310, 7901-7903, 7963-7976, and 7987-7991.
  • an Amberzyme of the invention comprises a sequence selected from the group consisting of SEQ ID NOs 3814-4360, 7142-7770, 7924-7928, and 7997-8001.
  • a DNAzyme of the invention comprises a sequence selected from the group consisting of SEQ ID NOs 2904-3485, 6380-6789, 7919-7923, and 7992-7996.
  • a Hammerhead of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1-631, 4361-4554, 7771-7780, 7791-7795, 7813-7821, and 7861-7865.
  • a Hammerhead of the invention comprises a sequence selected from the group consisting of SEQ ID NOs 632-1262, 4555-4748, 7884-7894, 7904-7908, 7929-7937, 7977-7981.
  • a nucleic acid molecule of the invention comprises between 12 and 100 bases complementary to RNA having an IKK-gamma or PKR nucleic acid sequence. In another embodiment, a nucleic acid molecule of the invention comprises between 14 and 24 bases complementary to RNA having an IKK-gamma or PKR nucleic acid sequence.
  • a nucleic acid molecule of the invention is chemically synthesized.
  • a nucleic acid molecule or antisense nucleic acid molecule of the invention comprises at least one 2′-sugar modification, at least one nucleic acid base modification, or at least one phosphate backbone modification.
  • a siRNA molecule of the invention comprises a double stranded RNA wherein one strand of the RNA is complimentary to the RNA of IKK-gamma or PKR gene.
  • a siRNA molecule of the invention comprises a double stranded RNA wherein one strand of the RNA comprises a portion of a sequence of RNA having IKK-gamma or PKR gene sequence.
  • a siRNA molecule of the invention comprises a double stranded RNA wherein both strands of RNA are connected by a non-nucleotide linker.
  • a siRNA molecule of the invention comprises a double stranded RNA wherein both strands of RNA are connected by a nucleotide linker, such as a loop or stem loop structure.
  • a single strand component of a siRNA molecule of the invention is from about 14 to about 50 nucleotides in length. In another embodiment, a single strand component of a siRNA molecule of the invention is about 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 nucleotides in length. In yet another embodiment, a single strand component of a siRNA molecule of the invention is about 23 nucleotides in length. In one embodiment, a siRNA molecule of the invention is from about 28 to about 56 nucleotides in length. In another embodiment, a siRNA molecule of the invention is about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 nucleotides in length. In yet another embodiment, a siRNA molecule of the invention is about 46 nucleotides in length.
  • an enzymatic nucleic acid molecule, antisense nucleic acid molecule, decoy RNA, dsRNA, siRNA, or aptamer molecules of the invention comprises at least one 2′-sugar modification.
  • an enzymatic nucleic acid molecule, antisense nucleic acid molecule, decoy RNA, dsRNA, siRNA, or aptamer, nucleic acids of the invention comprises at least one nucleic acid base modification.
  • an enzymatic nucleic acid molecule, antisense nucleic acid molecule, decoy RNA, dsRNA, siRNA, or aptamer, nucleic acids of the invention comprises at least one phosphate backbone modification.
  • the invention features a mammalian cell, for example a human cell, including an nucleic acid molecule of the invention.
  • the present invention features method of down-regulating PKR activity in a cell, comprising contacting the cell with an enzymatic nucleic acid molecule or antisense nucleic acid molecule, or other nucleic acid molecule of the invention, under conditions suitable for down-regulating of PKR activity.
  • the present invention also features method of treatment of a subject having a condition associated with the level of PKR, comprising contacting cells of the subject with an enzymatic nucleic acid molecule or antisense nucleic acid molecule or other nucleic acid molecule of the invention under conditions suitable for the treatment.
  • the present invention features method of down-regulating IKK-gamma activity in a cell, comprising contacting the cell with an enzymatic nucleic acid molecule or antisense nucleic acid molecule or other nucleic acid molecule of the invention, under conditions suitable for down-regulating of IKK-gamma activity.
  • the present invention also features method of treatment of a subject having a condition associated with the level of IKK-gamma, comprising contacting cells of the subject with the enzymatic nucleic acid molecule or antisense nucleic acid molecule or other nucleic acid molecule of the invention, under conditions suitable for the treatment.
  • a method of treatment of the invention comprises the use of one or more drug therapies under conditions suitable for said treatment.
  • the present invention features methods of cleaving RNA comprising a PKR nucleic acid sequence comprising contacting an enzymatic nucleic acid molecule of the invention with the RNA under conditions suitable for the cleavage.
  • the present invention also features methods of cleaving RNA comprising a IKK-gamma nucleic acid sequence comprising contacting an enzymatic nucleic acid molecule of the invention with the RNA under conditions suitable for the cleavage.
  • a method of cleavage of the invention is carried out in the presence of a divalent cation, for example Mg2+.
  • an enzymatic nucleic acid or antisense nucleic acid molecule or other nucleic acid molecule of the invention comprises a cap structure, wherein the cap structure is at the 5′-end, or 3′-end, or both the 5′-end and the 3′-end, for example a 3′,3′-linked or 5′,5′-linked deoxyabasic derivative.
  • the present invention also features an expression vector comprising a nucleic acid sequence encoding at least one enzymatic nucleic acid molecule, antisense, or other nucleic acid molecule of the invention in a manner which allows expression of the nucleic acid molecule.
  • the invention features a mammalian cell, for example a human cell, including an expression vector contemplated by the invention.
  • an expression vector of the invention further comprises an antisense nucleic acid molecule complementary to RNA of a subunit of IKK-gamma or PKR.
  • an expression vector of the invention comprises a nucleic acid sequence encoding two or more enzymatic nucleic acid molecules, which can be the same or different.
  • the present invention also features a method for treatment of cancer, for example breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, esophageal cancer, stomach cancer, bladder cancer, pancreatic cancer, cervical cancer, head and neck cancer, ovarian cancer, melanoma, lymphoma, glioma, or multidrug resistant cancer, comprising administering to a subject an enzymatic nucleic acid molecule or antisense nucleic acid molecule or other nucleic acid molecule of the invention under conditions suitable for said treatment.
  • cancer for example breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, esophageal cancer, stomach cancer, bladder cancer, pancreatic cancer, cervical cancer, head and neck cancer, ovarian cancer, melanoma, lymphoma, glioma, or multidrug resistant cancer
  • a nucleic acid molecule of the invention comprises at least five ribose residues, at least ten 2′-O-methyl modifications, and a 3′-end modification such as a 3′-3′ inverted abasic moiety, and/or phosphorothioate linkages on at least three of the 5′ terminal nucleotides.
  • other drug therapies contemplated by the invention include monoclonal antibodies, IKK-gamma or PKR-specific inhibitors, chemotherapy, or radiation therapy.
  • Specific chemotherapy contemplated by the invention include paclitaxel, docetaxel, cisplatin, methotrexate, cyclophosphamide, 5-fluoro uridine, Leucovorin, Irinotecan (CAMPTOSAR® or CPT-11 or Camptothecin-11 or Campto), Paclitaxel, Carboplatin doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, or vinorelbine or a combination thereof.
  • the invention also features a method for treatment of an inflammatory disease, for example rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury, glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, or infection, comprising the step of administering to a subject an enzymatic nucleic acid or antisense nucleic acid molecule of the invention under conditions suitable for the treatment.
  • an inflammatory disease for example rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury, glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, or infection.
  • compositions comprising the enzymatic nucleic acid and/or antisense nucleic acid molecules of the invention in a pharmaceutically acceptable carrier.
  • the invention also features a method of administering to a cell, such as mammalian cell (e.g. human cell), where the cell can be in culture or in a mammal, such as a human, an enzymatic nucleic acid molecule or antisense molecule of the instant invention, comprising contacting the cell with the enzymatic nucleic acid molecule or antisense molecule or other nucleic acid molecule of the invention under conditions suitable for such administration.
  • the method of administration can be in the presence of a delivery reagent, for example a lipid, cationic lipid, phospholipid, or liposome.
  • FIG. 1 shows examples of chemically stabilized ribozyme motifs.
  • HH Rz represents hammerhead ribozyme motif (Usman et al., 1996, Curr. Op. Struct. Bio., 1, 527);
  • NCH Rz represents the NCH ribozyme motif (Ludwig & Sproat, International PCT Publication No. WO 98/58058);
  • G-Cleaver represents G-cleaver ribozyme motif (Kore et al., 1998, Nucleic Acids Research 26, 4116-4120, Eckstein et al., International PCT publication No. WO 99/16871).
  • N or n represent independently a nucleotide which can be same or different and have complementarity to each other; rI, represents ribo-Inosine nucleotide; arrow indicates the site of cleavage within the target.
  • Position 4 of the HH Rz and the NCH Rz is shown as having 2′-C-allyl modification, but those skilled in the art will recognize that this position can be modified with other modifications well known in the art, so long as such modifications do not significantly inhibit the activity of the ribozyme.
  • FIG. 2 shows an example of the Amberzyme ribozyme motif that is chemically stabilized (see for example Beigelman et al., International PCT publication No. WO 99/55857).
  • FIG. 3 shows an example of the Zinzyme A ribozyme motif that is chemically stabilized (see for example Beigelman et al., Beigelman et al, International PCT publication No. WO 99/55857).
  • FIG. 4 shows an example of a DNAzyme motif described by Santoro et al., 1997, PNAS, 94, 4262.
  • the invention features nucleic acid molecules, for example enzymatic nucleic acid molecules, antisense nucleic acid molecules, 2,5-A chimeras, decoys, double stranded RNA, triplex oligonucleotides, and/or aptamers, and methods to modulate gene expression, for example, genes encoding a member of the I ⁇ B kinase IKK complex, such as IKK-alpha (IKK1), IKK-beta (IKK2), or IKK-gamma (IKK ⁇ ) and/or a protein kinase PKR protein.
  • the instant invention features nucleic-acid based molecules and methods to modulate the expression of IKK-gamma (IKK ⁇ ) and protein kinase PKR.
  • the invention features one or more enzymatic nucleic acid-based molecules and methods that independently or in combination modulate the expression of gene(s) encoding a member of the I ⁇ B kinase IKK complex or PKR.
  • the invention features nucleic acid-based molecules and methods that modulate the expression of a member of the I ⁇ B kinase IKK complex, for example IKK-alpha (IKK1), IKK-beta (IKK2), or IKK-gamma (IKK ⁇ ) and/or a protein kinase PKR protein, such as IKK-alpha (IKK1) gene (Genbank Accession No.
  • IKK-beta (IKK2) gene for example (Genbank Accession No.AF080158), IKK-gamma (IKK ⁇ ) gene, for example (Genbank Accession No. NM — 003639), and protein kinase PKR gene, for example (Genbank Accession No. NM — 002759).
  • IKK-gamma is also known as NEMO/IKKAP1.
  • the various aspects and embodiments are also directed to other genes which encode other subunits of the IKK complex, such as IKK-alpha (IKK1) or IKK-beta (IKK2).
  • IKK1 IKK-alpha
  • IKK2 IKK-beta
  • Those additional genes can be analyzed for target sites using the methods described for IKK-gamma or PKR.
  • the inhibition and the effects of such inhibition of the other genes can be performed as described herein.
  • the invention features the use of an enzymatic nucleic acid molecule, preferably in the hammerhead, NCH, G-cleaver, amberzyme, zinzyme and/or DNAzyme motif, to down-regulate the expression of IKK-gamma or PKR genes.
  • inhibitor or “down-regulate” it is meant that the expression of the gene, or level of RNAs or equivalent RNAs encoding one or more protein subunits, or activity of one or more protein subunits, such as IKK-gamma or PKR subunit(s), is reduced below that observed in the absence of the nucleic acid molecules of the invention.
  • inhibition or down-regulation with enzymatic nucleic acid molecule preferably is below that level observed in the presence of an enzymatically inactive or attenuated molecule that is able to bind to the same site on the target RNA, but is unable to cleave that RNA.
  • inhibition or down-regulation with antisense oligonucleotides is preferably below that level observed in the presence of, for example, an oligonucleotide with scrambled sequence or with mismatches.
  • inhibition or down-regulation of IKK-gamma or PKR with the nucleic acid molecule of the instant invention is greater in the presence of the nucleic acid molecule than in its absence.
  • up-regulate is meant that the expression of the gene, or level of RNAs or equivalent RNAs encoding one or more protein subunits, or activity of one or more protein subunits, such as IKK-gamma or PKR subunit(s), is greater than that observed in the absence of the nucleic acid molecules of the invention.
  • the expression of a gene, such as IKK-gamma or PKR gene can be increased in order to treat, prevent, ameliorate, or modulate a pathological condition caused or exacerbated by an absence or low level of gene expression.
  • module is meant that the expression of the gene, or level of RNAs or equivalent RNAs encoding one or more protein subunits, or activity of one or more protein subunit(s) is up-regulated or down-regulated, such that the expression, level, or activity is greater than or less than that observed in the absence of the nucleic acid molecules of the invention.
  • zymatic nucleic acid molecule it is meant a nucleic acid molecule which has complementarity in a substrate binding region to a specified gene target, and also has an enzymatic activity which is active to specifically cleave target RNA. That is, the enzymatic nucleic acid molecule is able to intermolecularly cleave RNA and thereby inactivate a target RNA molecule. These complementary regions allow sufficient hybridization of the enzymatic nucleic acid molecule to the target RNA and thus permit cleavage.
  • nucleic acids can be modified at the base, sugar, and/or phosphate groups.
  • enzymatic nucleic acid is used interchangeably with phrases such as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA, aptazyme or aptamer-binding ribozyme, regulatable ribozyme, catalytic oligonucleotides, nucleozyme, DNAzyme, RNA enzyme, endoribonuclease, endonuclease, minizyme, leadzyme, oligozyme or DNA enzyme. All of these terminologies describe nucleic acid molecules with enzymatic activity.
  • enzymatic nucleic acid molecules described in the instant application are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site which is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving and/or ligation activity to the molecule (Cech et al., U.S. Pat. No. 4,987,071; Cech et al., 1988, 260 JAMA 3030).
  • enzymatic nucleic acids act by first binding to a target RNA. Such binding occurs through the target binding portion of a enzymatic nucleic acid which is held in close proximity to an enzymatic portion of the molecule that acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds a target RNA through complementary base-pairing, and once bound to the correct site, acts enzymatically to cut the target RNA.
  • RNA Strategic cleavage of such a target RNA will destroy its ability to direct synthesis of an encoded protein. After an enzymatic nucleic acid has bound and cleaved its RNA target, it is released from that RNA to search for another target and can repeatedly bind and cleave new targets.
  • a single ribozyme molecule is able to cleave many molecules of target RNA.
  • the ribozyme is a highly specific inhibitor of gene expression, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can completely eliminate catalytic activity of a ribozyme.
  • nucleic acid molecule as used herein is meant a molecule having nucleotides.
  • the nucleic acid can be single, double, or multiple stranded and can comprise modified or unmodified nucleotides or non-nucleotides or various mixtures and combinations thereof.
  • enzymatic portion or “catalytic domain” is meant that portion/region of the enzymatic nucleic acid molecule essential for cleavage of a nucleic acid substrate (for example see FIGS. 1-4 ).
  • substrate binding arm or “substrate binding domain” is meant that portion/region of a enzymatic nucleic acid which is able to interact, for example via complementarity (i.e., able to base-pair with), with a portion of its substrate.
  • complementarity i.e., able to base-pair with
  • such complementarity is 100%, but can be less if desired.
  • as few as 10 bases out of 14 can be base-paired (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al., 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). Examples of such arms are shown generally in FIGS. 1-4 .
  • these arms contain sequences within a enzymatic nucleic acid which are intended to bring enzymatic nucleic acid and target RNA together through complementary base-pairing interactions.
  • the enzymatic nucleic acid of the invention can have binding arms that are contiguous or non-contiguous and can be of varying lengths.
  • the length of the binding arm(s) are preferably greater than or equal to three nucleotides and of sufficient length to stably interact with the target RNA; preferably 12-100 nucleotides; more preferably 14-24 nucleotides long (see for example Werner and Uhlenbeck, supra; Hamman et al., supra; Hampel et al., EP0360257; Berzal-Herranz et al., 1993, EMBO J., 12, 2567-73).
  • the design is such that the length of the binding arms are symmetrical (i.e., each of the binding arms is of the same length; e.g., five and five nucleotides, or six and six nucleotides, or seven and seven nucleotides long) or asymmetrical (i.e., the binding arms are of different length; e.g., six and three nucleotides; three and six nucleotides long; four and five nucleotides long; four and six nucleotides long; four and seven nucleotides long; and the like).
  • Inozyme or “NCH” motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as NCH Rz in FIG. 1 .
  • Inozymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet NCH/, where N is a nucleotide, C is cytidine and H is adenosine, uridine or cytidine, and/represents the cleavage site.
  • H is used interchangeably with X.
  • Inozymes can also possess endonuclease activity to cleave RNA substrates having a cleavage triplet NCN/, where N is a nucleotide, C is cytidine, and/represents the cleavage site.
  • “I” in FIG. 1 represents an Inosine nucleotide, preferably a ribo-Inosine or xylo-Inosine nucleoside.
  • G-cleaver motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as G-cleaver Rz in FIG. 1 .
  • G-cleavers possess endonuclease activity to cleave RNA substrates having a cleavage triplet NYN/, where N is a nucleotide, Y is uridine or cytidine and/represents the cleavage site.
  • G-cleavers can be chemically modified as is generally shown in FIG. 1 .
  • Amberzyme motif or configuration an enzymatic nucleic acid molecule comprising a motif as is generally described in FIG. 2 .
  • Amberzymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet NG/N, where N is a nucleotide, G is guanosine, and/represents the cleavage site.
  • Amberzymes can be chemically modified to increase nuclease stability through substitutions as are generally shown in FIG. 2 .
  • differing nucleoside and/or non-nucleoside linkers can be used to substitute the 5′-gaa-3′ loops shown in the figure.
  • Amberzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2′-OH) group within its own nucleic acid sequence for activity.
  • Zinzyme motif or configuration an enzymatic nucleic acid molecule comprising a motif as is generally described in FIG. 3 .
  • Zinzymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet including but not limited to YG/Y, where Y is uridine or cytidine, and G is guanosine and/represents the cleavage site.
  • Zinzymes can be chemically modified to increase nuclease stability through substitutions as are generally shown in FIG. 3 , including substituting 2′-O-methyl guanosine nucleotides for guanosine nucleotides.
  • Zinzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2′-OH) group within its own nucleic acid sequence for activity.
  • DNAzyme is meant, an enzymatic nucleic acid molecule that does not require the presence of a 2′-OH group within its own nucleic acid sequence for activity.
  • the enzymatic nucleic acid molecule can have an attached linker(s) or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2′-OH groups.
  • DNAzymes can be synthesized chemically or expressed endogenously in vivo, by means of a single stranded DNA vector or equivalent thereof. An example of a DNAzyme is shown in FIG. 4 and is generally reviewed in Usman et al., U.S. Pat. No.
  • sufficient length is meant an oligonucleotide of greater than or equal to 3 nucleotides that is of a length great enough to provide the intended function under the expected condition.
  • “sufficient length” means that the binding arm sequence is long enough to provide stable binding to a target site under the expected binding conditions. Preferably, the binding arms are not so long as to prevent useful turnover of the nucleic acid molecule.
  • stably interact is meant interaction of the oligonucleotides with target nucleic acid (e.g., by forming hydrogen bonds with complementary nucleotides in the target under physiological conditions) that is sufficient to the intended purpose (e.g., cleavage of target RNA by an enzyme).
  • RNA to IKK-gamma is meant to include those naturally occurring RNA molecules having homology (partial or complete) to IKK-gamma proteins or encoding for proteins with similar function as IKK-gamma proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites.
  • the equivalent RNA sequence also includes in addition to the coding region, regions such as 5′-untranslated region, 3′-untranslated region, introns, intron-exon junction and the like.
  • RNA to PKR is meant to include those naturally occurring RNA molecules having homology (partial or complete) to PKR proteins or encoding for proteins with similar function as PKR proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites.
  • the equivalent RNA sequence also includes in addition to the coding region, regions such as 5′-untranslated region, 3′-untranslated region, introns, intron-exon junction and the like.
  • nucleotide sequence of two or more nucleic acid molecules is partially or completely identical.
  • antisense nucleic acid a non-enzymatic nucleic acid molecule that binds to target RNA by means of RNA-RNA or RNA-DNA or RNA-PNA (protein nucleic acid; Egholm et al., 1993 Nature 365, 566) interactions and alters the activity of the target RNA (for a review, see Stein and Cheng, 1993 Science 261, 1004 and Woolf et al., U.S. Pat. No. 5,849,902).
  • antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule.
  • an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop.
  • the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both.
  • antisense DNA can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex.
  • the antisense oligonucleotides can comprise one or more RNAse H activating region, which is capable of activating RNAse H cleavage of a target RNA.
  • Antisense DNA can be synthesized chemically or expressed via the use of a single stranded DNA expression vector or equivalent thereof.
  • RNase H activating region is meant a region (generally greater than or equal to 4-25 nucleotides in length, preferably from 5-11 nucleotides in length) of a nucleic acid molecule capable of binding to a target RNA to form a non-covalent complex that is recognized by cellular RNase H enzyme (see for example Arrow et al., U.S. Pat. No. 5,849,902; Arrow et al., U.S. Pat. No. 5,989,912).
  • the RNase H enzyme binds to the nucleic acid molecule-target RNA complex and cleaves the target RNA sequence.
  • the RNase H activating region comprises, for example, phosphodiester, phosphorothioate (preferably at least four of the nucleotides are phosphorothiote substitutions; more specifically, 4-11 of the nucleotides are phosphorothiote substitutions); phosphorodithioate, 5′-thiophosphate, or methylphosphonate backbone chemistry or a combination thereof.
  • the RNase H activating region can also comprise a variety of sugar chemistries.
  • the RNase H activating region can comprise deoxyribose, arabino, fluoroarabino or a combination thereof, nucleotide sugar chemistry.
  • 2-5A chimera is meant an oligonucleotide, for example an antisense nucleic acid molecule or enzymatic nucleic acid molecule, containing a 5′-phosphorylated 2′-5′-linked adenylate residue.
  • These chimeras bind to target RNA in a sequence-specific manner and activate a cellular 2-5A-dependent ribonuclease which, in turn, cleaves the target RNA (Torrence et al., 1993 Proc. Natl. Acad. Sci. USA 90, 1300; Silverman et al., 2000, Methods Enzymol., 313, 522-533; Player and Torrence, 1998, Pharmacol. Ther., 78, 55-113).
  • triplex forming oligonucleotides or “triplex oligonucleotide” is meant an oligonucleotide that can bind to a double-stranded DNA in a sequence-specific manner to form a triple-strand helix. Formation of such triple helix structure has been shown to inhibit transcription of the targeted gene (Duval-Valentin et al., 1992 Proc. Natl. Acad. Sci. USA 89, 504; Fox, 2000, Curr. Med. Chem., 7, 17-37; Praseuth et. al., 2000, Biochim. Biophys. Acta, 1489, 181-206).
  • double stranded RNA or “dsRNA” is meant a double stranded RNA that matches a predetermined gene sequence that is capable of activating cellular enzymes that degrade the corresponding messenger RNA transcripts of the gene.
  • dsRNAs are referred to as short intervening RNA (siRNA) and can be used to inhibit gene expression (see for example Elbashir et al., 2001 , Nature, 411, 494-498; and Bass, 2001 , Nature, 411, 428-429).
  • double stranded RNA or “dsRNA” as used herein refers to a double stranded RNA molecule capable of RNA interference “RNAi”, including short interfering RNA “siRNA” see for example Bass, 2001, Nature, 411, 428-429; Elbashir et al., 2001, Nature, 411, 494-498; and Kreutzer et al., International PCT Publication No. WO 00/44895; Zernicka-Goetz et al., International PCT Publication No. WO 01/36646; Fire, International PCT Publication No. WO 99/32619; Plaetinck et al., International PCT Publication No.
  • RNA RNA sequences including but not limited to structural genes encoding a polypeptide.
  • “Complementarity” refers to the ability of a nucleic acid to form hydrogen bond(s) with another RNA sequence by either traditional Watson-Crick or other non-traditional types.
  • the binding free energy for a nucleic acid molecule with its target or complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., enzymatic nucleic acid cleavage, antisense or triple helix inhibition. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al., 1987, CSH Symp. Quant. Biol . LII pp.
  • a percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementary).
  • Perfectly complementary means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.
  • RNA is meant a molecule comprising at least one ribonucleotide residue.
  • ribonucleotide or “2′-OH” is meant a nucleotide with a hydroxyl group at the 2′ position of a ⁇ -D-ribo-furanose moiety.
  • decoy is meant a nucleic acid molecule, for example RNA or DNA, or aptamer that is designed to preferentially bind to a predetermined ligand. Such binding can result in the inhibition or activation of a target molecule.
  • the decoy or aptamer can compete with a naturally occurring binding target for the binding of a specific ligand. For example, it has been shown that over-expression of HIV trans-activation response (TAR) RNA can act as a “decoy” and efficiently binds HIV tat protein, thereby preventing it from binding to TAR sequences encoded in the HIV RNA (Sullenger et al., 1990, Cell, 63, 601-608).
  • TAR HIV trans-activation response
  • a decoys can be designed to bind to IKK-gamma or PKR and block the binding of IKK-gamma or PKR or a decoy can be designed to bind to IKK-gamma or PKR and prevent interaction with the IKK-gamma or PKR protein.
  • aptamer or “nucleic acid aptamer” as used herein is meant a nucleic acid molecule that binds specifically to a target molecule wherein the nucleic acid molecule has sequence that is distinct from sequence recognized by the target molecule in its natural setting.
  • an aptamer can be a nucleic acid molecule that binds to a target molecule where the target molecule does not naturally bind to a nucleic acid.
  • the target molecule can be any molecule of interest.
  • the aptamer can be used to bind to a ligand binding domain of a protein, thereby preventing interaction of the naturally occurring ligand with the protein.
  • nucleic acid molecules of the instant invention can bind to IKK-gamma or PKR to block activity of the respective proteins.
  • the enzymatic nucleic acid molecule, antisense nucleic acid or other nucleic acid molecules of the invention that down regulate IKK-gamma or PKR gene expression represent a therapeutic approach to treat a variety of inflammatory-related diseases and conditions, including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, incontinentia pigmenti, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other inflammatory disease or condition which respond to the modulation of IKK-gamma or PKR function.
  • rheumatoid arthritis restenosis
  • asthma Crohn's disease
  • incontinentia pigmenti diabetes
  • obesity autoimmune disease
  • lupus multiple sclerosis
  • transplant/graft rejection transplant/graft
  • the enzymatic nucleic acid molecule, antisense nucleic acid or other nucleic acid molecules of the invention that down regulate IKK-gamma or PKR gene expression also represent a therapeutic approach to treat a variety of cancers, including but not limited to breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, and/or other cancers which respond to the modulation of IKK-gamma or PKR function.
  • the enzymatic nucleic acid molecule is formed in a hammerhead or hairpin motif, but can also be formed in the motif of a hepatitis delta virus, group I intron, group II intron or RNase P RNA (in association with an RNA guide sequence), Neurospora VS RNA, DNAzymes, NCH cleaving motifs, or G-cleavers.
  • Group II introns are described by Griffin et al., 1995, Chem. Biol. 2, 761; Michels and Pyle, 1995, Biochemistry 34, 2965; Pyle et al., International PCT Publication No. WO 96/22689; of the Group I intron by Cech et al., U.S. Pat. No. 4,987,071 and of DNAzymes by Usman et al., International PCT Publication No. WO 95/11304; Chartrand et al., 1995, NAR 23, 4092; Breaker et al., 1995, Chem. Bio.
  • a nucleic acid molecule of the instant invention can be between about 10 and 100 nucleotides in length.
  • Exemplary enzymatic nucleic acid molecules of the invention are shown in Tables III to VII.
  • enzymatic nucleic acid molecules of the invention are preferably between about 15 and 50 nucleotides in length, more preferably between about 25 and 40 nucleotides in length, e.g., 34, 36, or 38 nucleotides in length (for example see Jarvis et al., 1996, J. Biol. Chem., 271, 29107-29112).
  • Exemplary DNAzymes of the invention are preferably between about 15 and 40 nucleotides in length, more preferably between about 25 and 35 nucleotides in length, e.g., 29, 30, 31, or 32 nucleotides in length (see for example Santoro et al., 1998, Biochemistry, 37, 13330-13342; Chartrand et al., 1995, Nucleic Acids Research, 23, 4092-4096).
  • Exemplary antisense molecules of the invention are preferably between about 15 and 75 nucleotides in length, more preferably between about 20 and 35 nucleotides in length, e.g., 25, 26, 27, or 28 nucleotides in length (see for example Woolf et al., 1992, PNAS, 89, 7305-7309; Milner et al., 1997, Nature Biotechnology, 15, 537-541).
  • Exemplary triplex forming oligonucleotide molecules of the invention are preferably between about 10 and 40 nucleotides in length, more preferably between about 12 and 25 nucleotides in length, e.g., 18, 19, 20, or 21 nucleotides in length (see for example Maher et al., 1990, Biochemistry, 29, 8820-8826; Strobel and Dervan, 1990, Science, 249, 73-75).
  • the nucleic acid molecule be of sufficient length and suitable conformation for the nucleic acid molecule to interact with its target and/or catalyze a reaction contemplated herein.
  • the length of the nucleic acid molecules of the instant invention are not limiting within the general limits stated.
  • a nucleic acid molecule that modulates, for example, down-regulates IKK-gamma or PKR expression comprises between 12 and 100 bases complementary to a RNA molecule of IKK-gamma or PKR. Even more preferably, a nucleic acid molecule that modulates, for example IKK-gamma or PKR expression comprises between 14 and 24 bases complementary to a RNA molecule of IKK-gamma or PKR.
  • the invention provides a method for producing a class of nucleic acid-based gene modulating agents which exhibit a high degree of specificity for the RNA of a desired target.
  • the enzymatic nucleic acid molecule is preferably targeted to a highly conserved sequence region of target RNAs encoding IKK-gamma or PKR (specifically IKK-gamma or PKR genes) such that specific treatment of a disease or condition can be provided with either one or several nucleic acid molecules of the invention.
  • Such nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required.
  • the nucleic acid molecules e.g., ribozymes and antisense
  • cell is used in its usual biological sense, and does not refer to an entire multicellular organism.
  • the cell can, for example, be in vitro, e.g., in cell culture, or present in a multicellular organism, including, e.g., birds, plants and mammals such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats.
  • the cell can be prokaryotic (e.g., bacterial cell) or eukaryotic (e.g., mammalian or plant cell).
  • IKK-gamma proteins a peptide or protein comprising a IKK-gamma or NEMO/IKKAP1 component of the IKK complex, for example a regulatory IKK subunit involved in the assembly of the high molecular weight IKK complex and/or induction of NFKB.
  • PTK proteins is meant, a peptide or protein comprising a protein kinase PKR activity, for example the activation of NFKB.
  • highly conserved sequence region is meant, a nucleotide sequence of one or more regions in a target gene does not vary significantly from one generation to the other or from one biological system to the other.
  • Nucleic acid-based inhibitors of IKK-gamma or PKR function are useful for the prevention and/or treatment of cancers and cancerous conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, and any other diseases or conditions that are related to or will respond to the levels of IKK-gamma or PKR in a cell or tissue, alone or in combination with other therapies.
  • cancers and cancerous conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, and any other diseases or conditions that are related to or will respond to the levels of IKK-gamma or PKR in a cell or tissue, alone or in combination with other
  • Nucleic acid-based inhibitors of IKK-gamma or PKR function are also useful for the prevention and/or treatment of inflammatory related diseases and conditions, including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, incontinentia pigmenti, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other inflammatory disease or condition which respond to the modulation of IKK-gamma or PKR function.
  • inflammatory related diseases and conditions including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, incontinentia pigmenti, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and my
  • the nucleic acid-based inhibitors of the invention are added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues.
  • the nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through injection or infusion pump, with or without their incorporation in biopolymers.
  • the enzymatic nucleic acid inhibitors comprise sequences, which are complementary to the substrate sequences in Tables III to XIII. Examples of such enzymatic nucleic acid molecules also are shown in Tables III to XIII. Examples of such enzymatic nucleic acid molecules consist essentially of sequences defined in these tables.
  • the invention features antisense nucleic acid molecules and 2-5A chimera including sequences complementary to the substrate sequences shown in Tables III to XIII.
  • nucleic acid molecules can include sequences as shown for the binding arms of the enzymatic nucleic acid molecules in Tables III to XIII.
  • triplex molecules can be provided targeted to the corresponding DNA target regions, and containing the DNA equivalent of a target sequence or a sequence complementary to the specified target (substrate) sequence.
  • antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule.
  • an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop.
  • the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both.
  • consists essentially of is meant that the active nucleic acid molecule of the invention, for example, an enzymatic nucleic acid molecule, contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind RNA such that cleavage at the target site occurs. Other sequences can be present which do not interfere with such cleavage.
  • a core region can, for example, include one or more loop, stem-loop structure, or linker which does not prevent enzymatic activity.
  • the underlined regions in the sequences in Tables III, IV, VIII, and IX can be such a loop, stem-loop, nucleotide linker, and/or non-nucleotide linker and can be represented generally as sequence “X”.
  • a core sequence for a hammerhead enzymatic nucleic acid can comprise a conserved sequence, such as 5′-CUGAUGAG-3′ and 5′-CGAA-3′ connected by “X”, where X is 5′-GCCGUUAGGC-3′ (SEQ ID NO 8002), or any other Stem II region known in the art, or a nucleotide and/or non-nucleotide linker.
  • nucleic acid molecules of the instant invention such as Inozyme, G-cleaver, amberzyme, zinzyme, DNAzyme, antisense, 2-5A antisense, triplex forming nucleic acid, and decoy nucleic acids
  • other sequences or non-nucleotide linkers can be present that do not interfere with the function of the nucleic acid molecule.
  • Sequence X can be a linker of ⁇ 2 nucleotides in length, preferably 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 26, 30, where the nucleotides can preferably be internally base-paired to form a stem of preferably ⁇ 2 base pairs.
  • the nucleotide linker X can be a nucleic acid aptamer, such as an ATP aptamer, HIV Rev aptamer (RRE), HIV Tat aptamer (TAR) and others (for a review see Gold et al., 1995, Annu. Rev. Biochem., 64, 763; and Szostak & Ellington, 1993, in The RNA World , ed. Gesteland and Atkins, pp.
  • nucleic acid aptamer as used herein is meant to indicate a nucleic acid sequence capable of interacting with a ligand.
  • the ligand can be any natural or a synthetic molecule, including but not limited to a resin, metabolites, nucleosides, nucleotides, drugs, toxins, transition state analogs, peptides, lipids, proteins, amino acids, nucleic acid molecules, hormones, carbohydrates, receptors, cells, viruses, bacteria and others.
  • sequence X can be a non-nucleotide linker.
  • non-nucleotide further means any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity.
  • the group or compound can be abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine.
  • the invention features an enzymatic nucleic acid molecule having one or more non-nucleotide moieties, and having enzymatic activity to cleave an RNA or DNA molecule.
  • enzymatic nucleic acid molecules or antisense molecules that interact with target RNA molecules and down-regulate IKK-gamma or PKR (specifically IKK-gamma or PKR gene) activity are expressed from transcription units inserted into DNA or RNA vectors.
  • the recombinant vectors are preferably DNA plasmids or viral vectors.
  • Enzymatic nucleic acid molecule or antisense expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus.
  • the recombinant vectors capable of expressing the enzymatic nucleic acid molecules or antisense are delivered as described above, and persist in target cells.
  • viral vectors can be used that provide for transient expression of enzymatic nucleic acid molecules or antisense. Such vectors can be repeatedly administered as necessary. Once expressed, the enzymatic nucleic acid molecules or antisense bind to the target RNA and down-regulate its function or expression. Delivery of enzymatic nucleic acid molecule or antisense expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient or subject followed by reintroduction into the patient or subject, or by any other means that would allow for introduction into the desired target cell. Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector.
  • vectors any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid.
  • subject is meant an organism, which is a donor or recipient of explanted cells or the cells themselves. “subject” also refers to an organism to which the nucleic acid molecules of the invention can be administered.
  • a subject is a mammal or mammalian cells. More preferably, a subject is a human or human cells.
  • enhanced enzymatic activity is meant to include activity measured in cells and/or in vivo where the activity is a reflection of both the catalytic activity and the stability of the nucleic acid molecules of the invention.
  • the product of these properties can be increased in vivo compared to an all RNA enzymatic nucleic acid or all DNA enzyme.
  • the activity or stability of the nucleic acid molecule can be decreased (i.e., less than ten-fold), but the overall activity of the nucleic acid molecule is enhanced, in vivo.
  • nucleic acid molecules of the instant invention can be used to treat diseases or conditions discussed above.
  • the subject can be treated, or other appropriate cells can be treated, as is evident to those skilled in the art, individually or in combination with one or more drugs under conditions suitable for the treatment.
  • the described nucleic acid molecules can be used in combination with other known treatments to treat conditions or diseases discussed above.
  • the described molecules can be used in combination with one or more known therapeutic agents to treat breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, incontinentia pigmenti, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other cancerous disease or inflammatory disease or condition which respond to the modulation of IKK-gamma or PKR
  • the invention features nucleic acid-based inhibitors (e.g., enzymatic nucleic acid molecules (eg; ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, dsRNA, antisense nucleic acids containing RNA cleaving chemical groups) and methods for their use to down regulate or inhibit the expression of genes (e.g., IKK-gamma or PKR) capable of progression and/or maintenance of cancer, inflammatory diseases, and/or other disease states which respond to the modulation of IKK-gamma or PKR expression.
  • genes e.g., IKK-gamma or PKR
  • Antisense molecules can be modified or unmodified RNA, DNA, or mixed polymer oligonucleotides and primarily function by specifically binding to matching sequences resulting in inhibition of peptide synthesis (Wu-Pong, November 1994, BioPharm, 20-33).
  • the antisense oligonucleotide binds to target RNA by Watson Crick base-pairing and blocks gene expression by preventing ribosomal translation of the bound sequences either by steric blocking or by activating RNase H enzyme.
  • Antisense molecules can also alter protein synthesis by interfering with RNA processing or transport from the nucleus into the cytoplasm (Mukhopadhyay & Roth, 1996, Crit. Rev. in Oncogenesis 7, 151-190).
  • antisense molecules have been described that utilize novel configurations of chemically modified nucleotides, secondary structure, and/or RNase H substrate domains (Woolf et al., International PCT Publication No. WO 98/13526; Thompson et al., International PCT Publication No. WO 99/54459; Hartmann et al., U.S. Ser. No. 60/101,174 which was filed on Sep. 21, 1998) all of these are incorporated by reference herein in their entirety.
  • antisense deoxyoligoribonucleotides can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex.
  • Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector or equivalents and variations thereof.
  • Enzymatic Nucleic Acid Several varieties of enzymatic RNAs are presently known. In addition, several in vitro selection (evolution) strategies (Orgel, 1979, Proc. R. Soc. London , B 205, 435) have been used to evolve new nucleic acid catalysts capable of catalyzing cleavage and ligation of phosphodiester linkages (Joyce, 1989, Gene, 82, 83-87; Beaudry et al., 1992, Science 257, 635-641; Joyce, 1992, Scientific American 267, 90-97; Breaker et al., 1994, TIBTECH 12, 268; Bartel et al., 1993, Science 261:1411-1418; Szostak, 1993, TIBS 17, 89-93; Kumar et al, 1995, FASEB J., 9, 1183; Breaker, 1996, Curr.
  • Nucleic acid molecules of this invention will block to some extent IKK-gamma or PKR and/or IKK-gamma or PKR protein expression and can be used to treat disease or diagnose disease associated with the levels of IKK-gamma or PKR and/or IKK-gamma or PKR.
  • Enzymatic nucleic acid sequences targeting IKK-gamma or PKR RNA and sequences that can be targeted with nucleic acid molecules of the invention to down-regulate IKK-gamma or PKR expression are shown in Tables III to XIII.
  • the enzymatic nature of an enzymatic nucleic acid molecule can allow the concentration of enzymatic nucleic acid molecule necessary to affect a therapeutic treatment to be lower. This reflects the ability of the enzymatic nucleic acid molecule to act enzymatically. Thus, a single enzymatic nucleic acid molecule is able to cleave many molecules of target RNA.
  • the enzymatic nucleic acid molecule is a highly specific inhibitor, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can be chosen to greatly attenuate the catalytic activity of a enzymatic nucleic acid molecule.
  • Nucleic acid molecules having an endonuclease enzymatic activity are able to repeatedly cleave other separate RNA molecules in a nucleotide base sequence-specific manner. Such enzymatic nucleic acid molecules can be targeted to virtually any RNA transcript, and achieve efficient cleavage in vitro (Zaug et al., 324, Nature 429 1986; Uhlenbeck, 1987 Nature 328, 596; Kim et al., 84 Proc. Natl. Acad. Sci. USA 8788, 1987; Dreyfus, 1988, Einstein Quart. J. Bio.
  • trans-cleaving enzymatic nucleic acid molecules can be used as therapeutic agents for human disease (Usman & McSwiggen, 1995 Ann. Rep. Med. Chem. 30, 285-294; Christoffersen and Marr, 1995 J. Med. Chem. 38, 2023-2037).
  • Enzymatic nucleic acid molecules can be designed to cleave specific RNA targets within the background of cellular RNA. Such a cleavage event renders the RNA non-functional and abrogates protein expression from that RNA. In this manner, synthesis of a protein associated with a disease state can be selectively inhibited (Warashina et al., 1999, Chemistry and Biology, 6, 237-250).
  • Enzymatic nucleic acid molecules of the invention that are allosterically regulated (“allozymes”) can be used to modulate IKK-gamma or PKR expression.
  • allosteric enzymatic nucleic acids or allozymes see for example George et al., U.S. Pat. Nos. 5,834,186 and 5,741,679, Shih et al., U.S. Pat. No. 5,589,332, Nathan et al., U.S. Pat. No. 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al., International PCT Publication Nos.
  • WO 00/26226 and 98/27104 are designed to respond to a signaling agent, for example, mutant IKK-gamma protein, wild-type IKK-gamma protein, mutant IKK-gamma RNA, wild-type IKK-gamma RNA, other proteins and/or RNAs involved in IKK-gamma activity, compounds, metals, polymers, molecules and/or drugs that are targeted to IKK-gamma or an IKK subunit, such as IKK-alpha or IKK-beta, expressing cells etc., which in turn modulates the activity of the enzymatic nucleic acid molecule.
  • a signaling agent for example, mutant IKK-gamma protein, wild-type IKK-gamma protein, mutant IKK-gamma RNA, wild-type IKK-gamma RNA, other proteins and/or RNAs involved in IKK-gamma activity, compounds, metals, polymers, molecules and/or drugs that are targeted to IKK-gamma or an I
  • the allosteric enzymatic nucleic acid molecule's activity is activated or inhibited such that the expression of a particular target is selectively down-regulated.
  • the target can comprise wild-type IKK-gamma, mutant IKK-gamma, a component of IKK-gamma, and/or a predetermined cellular component that modulates IKK-gamma activity.
  • allosteric enzymatic nucleic acid molecules that are activated by interaction with a RNA encoding a mutant IKK-gamma protein are used as therapeutic agents in vivo.
  • RNA encoding the mutant IKK-gamma activates the allosteric enzymatic nucleic acid molecule that subsequently cleaves the RNA encoding a mutant IKK-gamma protein resulting in the inhibition of mutant IKK-gamma protein expression. In this manner, cells that express the mutant form of the IKK-gamma protein are selectively targeted.
  • Such an approach can be used to treat, for example, incontinentia pigmenti.
  • an allozyme can be activated by a IKK-gamma or PKR protein, peptide, or mutant polypeptide that caused the allozyme to inhibit the expression of IKK-gamma or PKR gene, by, for example, cleaving RNA encoded by IKK-gamma or PKR gene.
  • the allozyme acts as a decoy to inhibit the function of IKK-gamma or PKR and also inhibit the expression of IKK-gamma or PKR once activated by the IKK-gamma or PKR protein.
  • nucleic acid molecules of the instant invention are also referred to as GeneBloc reagents, which are essentially nucleic acid molecules (eg; ribozymes, antisense) capable of down-regulating gene expression.
  • Targets for useful enzymatic nucleic acid molecules and antisense nucleic acids can be determined as disclosed in Draper et al., WO 93/23569; Sullivan et al., WO 93/23057; Thompson et al., WO 94/02595; Draper et al., WO 95/04818; McSwiggen et al., U.S. Pat. No. 5,525,468, and hereby incorporated by reference herein in totality.
  • Other examples include the following PCT applications, which concern inactivation of expression of disease-related genes: WO 95/23225, WO 95/13380, WO 94/02595, incorporated by reference herein.
  • Enzymatic nucleic acid molecules and antisense to such targets are designed as described in those applications and synthesized to be tested in vitro and in vivo, as also described.
  • the sequences of human IKK-gamma or PKR RNAs were screened for optimal enzymatic nucleic acid and antisense target sites using a computer-folding algorithm.
  • Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme, or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified.
  • nucleic acid molecules binding/cleavage sites were identified.
  • the nucleic acid molecules are individually analyzed by computer folding (Jaeger et al., 1989 Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the sequences fold into the appropriate secondary structure. Those nucleic acid molecules with unfavorable intramolecular interactions such as between the binding arms and the catalytic core are eliminated from consideration. Varying binding arm lengths can be chosen to optimize activity.
  • Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified and were designed to anneal to various sites in the RNA target.
  • the binding arms are complementary to the target site sequences described above.
  • the nucleic acid molecules were chemically synthesized. The method of synthesis used follows the procedure for normal DNA/RNA synthesis as described below and in Usman et al., 1987 J. Am. Chem. Soc., 109, 7845; Scaringe et al., 1990 Nucleic Acids Res., 18, 5433; and Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684; Caruthers et al., 1992, Methods in Enzymology 211,3-19.
  • nucleic acids greater than 100 nucleotides in length can be difficult using automated methods, and the therapeutic cost of such molecules can be prohibitive.
  • small nucleic acid motifs (“small refers to nucleic acid motifs less than about 100 nucleotides in length, preferably less than about 80 nucleotides in length, and more preferably less than about 50 nucleotides in length; e.g., antisense oligonucleotides, hammerhead or the NCH ribozymes) are preferably used for exogenous delivery.
  • the simple structure of these molecules increases the ability of the nucleic acid to invade targeted regions of RNA structure.
  • Exemplary molecules of the instant invention are chemically synthesized, and others can similarly be synthesized.
  • Oligonucleotides are synthesized using protocols known in the art as described in Caruthers et al., 1992, Methods in Enzymology 211, 3-19, Thompson et al., International PCT Publication No. WO 99/54459, Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al., 1997, Methods Mol. Bio., 74, 59, Brennan et al., 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, U.S. Pat. No. 6,001,311. All of these references are incorporated herein by reference.
  • oligonucleotides makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end.
  • small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 ⁇ mol scale protocol with a 2.5 min coupling step for 2′-O-methylated nucleotides and a 45 sec coupling step for 2′-deoxy nucleotides.
  • Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle.
  • syntheses at the 0.2 ⁇ mol scale can be performed on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, Calif.) with minimal modification to the cycle.
  • Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%.
  • synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); and oxidation solution is 16.9 mM I 2 , 49 mM pyridine, 9% water in THF (PERSEPTIVETM). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-1,2-Benzodithiol-3-one 1,1-dioxide, 0.05 M in acetonitrile) is used.
  • Deprotection of the antisense oligonucleotides is performed as follows: the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65° C. for 10 min. After cooling to ⁇ 20° C., the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCN:H2O/3:1:1, vortexed and the supernatant is then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, are dried to a white powder.
  • RNA and chemically modified RNA including certain enzymatic nucleic acid molecules follows the procedure as described in Usman et al., 1987, J. Am. Chem. Soc., 109, 7845; Scaringe et al., 1990, Nucleic Acids Res., 18, 5433; and Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684 Wincott et al., 1997, Methods Mol. Bio., 74, 59, and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end.
  • common nucleic acid protecting and coupling groups such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end.
  • small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 ⁇ mol scale protocol with a 7.5 min coupling step for alkylsilyl protected nucleotides and a 2.5 min coupling step for 2′-O-methylated nucleotides.
  • Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle.
  • syntheses at the 0.2 ⁇ mol scale can be done on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, Calif.) with minimal modification to the cycle.
  • Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%.
  • synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution is 16.9 mM I 2 , 49 mM pyridine, 9% water in THF (PERSEPTIVETM). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-1,2-Benzodithiol-3-one 1,1-dioxide 0.05 M in acetonitrile) is used.
  • RNA deprotection of the RNA is performed using either a two-pot or one-pot protocol.
  • the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65° C. for 10 min. After cooling to ⁇ 20° C., the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCN:H2O/3:1:1, vortexed and the supernatant is then added to the first supernatant.
  • the combined supernatants, containing the oligoribonucleotide, are dried to a white powder.
  • the base deprotected oligoribonucleotide is resuspended in anhydrous TEA/HF/NMP solution (300 ⁇ l of a solution of 1.5 mL N-methylpyrrolidinone, 750 ⁇ L TEA and 1 mL TEA.3HF to provide a 1.4 M HF concentration) and heated to 65° C. After 1.5 h, the oligomer is quenched with 1.5 M NH 4 HCO 3 .
  • the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO: 1/1 (0.8 mL) at 65° C. for 15 min.
  • the vial is brought to r.t. TEA.3HF (0.1 mL) is added and the vial is heated at 65° C. for 15 min.
  • the sample is cooled at ⁇ 20° C. and then quenched with 1.5 M NH 4 HCO 3 .
  • the quenched NH 4 HCO 3 solution is loaded onto a C-18 containing cartridge that had been prewashed with acetonitrile followed by 50 mM TEAA. After washing the loaded cartridge with water, the RNA is detritylated with 0.5% TFA for 13 min. The cartridge is then washed again with water, salt exchanged with 1 M NaCl and washed with water again. The oligonucleotide is then eluted with 30% acetonitrile.
  • Inactive hammerhead ribozymes or binding attenuated control (BAC) oligonucleotides can be synthesized by substituting a U for G 5 and a U for A 14 (numbering from Hertel, K. J., et al., 1992, Nucleic Acids Res., 20, 3252). Similarly, one or more nucleotide substitutions can be introduced in other enzymatic nucleic acid molecules to inactivate the molecule and such molecules can serve as a negative control.
  • BAC binding attenuated control
  • the average stepwise coupling yields are typically >98% (Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684).
  • the scale of synthesis can be adapted to be larger or smaller than the example described above including but not limited to 96 well format, with the ratio of chemicals being used in the reaction adjusted accordingly.
  • nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example by ligation (Moore et al., 1992, Science 256, 9923; Draper et al., International PCT publication No. WO 93/23569; Shabarova et al., 1991, Nucleic Acids Research 19, 4247; Bellon et al., 1997, Nucleosides & Nucleotides, 16, 951; Bellon et al., 1997, Bioconjugate Chem. 8, 204).
  • nucleic acid molecules of the present invention are modified extensively to enhance stability by modification with nuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-flouro, 2′-O-methyl, 2′-H (for a review see Usman and Cedergren, 1992, TIBS 17, 34; Usman et al., 1994, Nucleic Acids Symp. Ser. 31, 163).
  • Ribozymes are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al., Supra, the totality of which is hereby incorporated herein by reference) and are re-suspended in water.
  • the sequences of the nucleic acid molecules, including enzymatic nucleic acid molecules and antisense, that are chemically synthesized, are shown in Table XIII.
  • the sequences of the enzymatic nucleic acid and antisense constructs that are chemically synthesized, are complementary to the Substrate sequences shown in Table XIII. Those in the art will recognize that these sequences are representative only of many more such sequences where the enzymatic portion of the ribozyme (all but the binding arms) is altered to affect activity.
  • the enzymatic nucleic acid and antisense construct sequences listed in Tables III to XIII can be formed of ribonucleotides or other nucleotides or non-nucleotides. Such enzymatic nucleic acid molecules with enzymatic activity are equivalent to the enzymatic nucleic acid molecules described specifically in the Tables.
  • oligonucleotides are modified to enhance stability and/or enhance biological activity by modification with nuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-flouro, 2′-O-methyl, 2′-H, nucleotide base modifications (for a review see Usman and Cedergren, 1992, TIBS. 17, 34; Usman et al., 1994, Nucleic Acids Symp. Ser. 31, 163; Burgin et al., 1996, Biochemistry, 35, 14090).
  • nuclease resistant groups for example, 2′-amino, 2′-C-allyl, 2′-flouro, 2′-O-methyl, 2′-H, nucleotide base modifications
  • Nucleic acid molecules having chemical modifications that maintain or enhance activity are provided. Such nucleic acid is also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity can not be significantly lowered.
  • Therapeutic nucleic acid molecules delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. Nucleic acid molecules are preferably resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA and DNA (Wincott et al., 1995 Nucleic Acids Res.
  • nucleic acid-based molecules of the invention can lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple antisense or enzymatic nucleic acid molecules targeted to different genes, nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of molecules (including different motifs) and/or other chemical or biological molecules).
  • combination therapies e.g., multiple antisense or enzymatic nucleic acid molecules targeted to different genes, nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of molecules (including different motifs) and/or other chemical or biological molecules).
  • the treatment of subjects with nucleic acid molecules can also include combinations of different types of nucleic acid molecules.
  • nucleic acid molecules e.g., enzymatic nucleic acid molecules and antisense nucleic acid molecules
  • delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state.
  • These nucleic acid molecules should be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of nucleic acid molecules described in the instant invention and in the art have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.
  • nucleic acid catalysts having chemical modifications that maintain or enhance enzymatic activity are provided.
  • Such nucleic acids are also generally more resistant to nucleases than unmodified nucleic acid.
  • the activity of the nucleic acid can not be significantly lowered.
  • enzymatic nucleic acids are useful in a cell and/or in vivo even if activity over all is reduced about 10 fold (Burgin et al., 1996, Biochemistry, 35, 14090).
  • Such enzymatic nucleic acids herein are said to “maintain” the enzymatic activity of an all RNA ribozyme or all DNA DNAzyme.
  • nucleic acid molecules comprise a 5′ and/or a 3′-cap structure.
  • cap structure is meant chemical modifications, which have been incorporated at either terminus of the oligonucleotide (see for example Wincott et al., WO 97/26270, incorporated by reference herein). These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and can help in delivery and/or localization within a cell.
  • the cap can be present at the 5′-terminus (5′-cap) or at the 3′-terminus (3′-cap) or can be present on both terminus.
  • the 5′-cap includes inverted abasic residue (moiety), 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide, 4′-thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha-nucleotides; modified base nucleotide; phosphorodithioate linkage; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide, 3′-3′-inverted nucleotide moiety; 3′-3′-inverted abasic moiety; 3′-2′-inverted nucleotide moiety; 3′-2′-inverted nu
  • the 3′-cap includes, for example 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4′-thio nucleotide, carbocyclic nucleotide; 5′-amino-alkyl phosphate; 1,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxyp
  • non-nucleotide any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity.
  • the group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine.
  • alkyl refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain “isoalkyl”, and cyclic alkyl groups.
  • alkyl also comprises alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C 1 -C 6 hydrocarbyl, aryl or substituted aryl groups.
  • the alkyl group has 1 to 12 carbons.
  • the alkyl group can be substituted or unsubstituted.
  • the substituted group(s) preferably comprise hydroxy, oxy, thio, amino, nitro, cyano, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, silyl, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C 1 -C 6 hydrocarbyl, aryl or substituted aryl groups.
  • alkyl also includes alkenyl groups containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups.
  • the alkenyl group has about 2 to 12 carbons. More preferably it is a lower alkenyl of from about 2 to 7 carbons, more preferably about 2 to 4 carbons.
  • the alkenyl group can be substituted or unsubstituted.
  • the substituted group(s) When substituted the substituted group(s) preferably comprise hydroxy, oxy, thio, amino, nitro, cyano, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, silyl, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C 1 -C 6 hydrocarbyl, aryl or substituted aryl groups.
  • alkyl also includes alkynyl groups containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups.
  • the alkynyl group has about 2 to 12 carbons. More preferably it is a lower alkynyl of from about 2 to 7 carbons, more preferably about 2 to 4 carbons.
  • the alkynyl group can be substituted or unsubstituted.
  • the substituted group(s) When substituted the substituted group(s) preferably comprise hydroxy, oxy, thio, amino, nitro, cyano, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, silyl, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C 1 -C 6 hydrocarbyl, aryl or substituted aryl groups.
  • Alkyl groups or moieties of the invention can also include aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide and ester groups.
  • aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups.
  • An “alkylaryl” group refers to an alkyl group (as described above) covalently joined to an aryl group (as described above).
  • Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted.
  • Heterocyclic aryl groups are groups having from about 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms.
  • Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted.
  • An “amide” refers to an —C(O)—NH—R, where R is either alkyl, aryl, alkylaryl or hydrogen.
  • An “ester” refers to an —C(O)—OR′, where R is either alkyl, aryl, alkylaryl or hydrogen.
  • alkoxyalkyl refers to an alkyl-O-alkyl ether, for example methoxyethyl or ethoxymethyl.
  • alkyl-thio-alkyl refers to an alkyl-S-alkyl thioether, for example methylthiomethyl or methylthioethyl.
  • amino refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic radicals.
  • aminoacyl and “aminoalkyl” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.
  • amino refers to a process in which an amino group or substituted amine is introduced into an organic molecule.
  • exocyclic amine protecting moiety refers to a nucleobase amino protecting group compatible with oligonucleotide synthesis, for example an acyl or amide group.
  • alkenyl refers to a straight or branched hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon double bond.
  • alkenyl include vinyl, allyl, and 2-methyl-3-heptene.
  • alkoxy refers to an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge.
  • alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.
  • alkynyl refers to a straight or branched hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond.
  • alkynyl include propargyl, propyne, and 3-hexyne.
  • aryl refers to an aromatic hydrocarbon ring system containing at least one aromatic ring.
  • the aromatic ring can optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings.
  • aryl groups include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl.
  • Preferred examples of aryl groups include phenyl and naphthyl.
  • cycloalkenyl refers to a C 3 -C 8 cyclic hydrocarbon containing at least one carbon-carbon double bond.
  • examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.
  • cycloalkyl refers to a C 3 -C 8 cyclic hydrocarbon.
  • examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkylalkyl refers to a C 3 -C 7 cycloalkyl group attached to the parent molecular moiety through an alkyl group, as defined above.
  • Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.
  • halogen or “halo” as used herein refers to indicate fluorine, chlorine, bromine, and iodine.
  • heterocycloalkyl refers to a non-aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl ring can be optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings.
  • Preferred heterocycloalkyl groups have from 3 to 7 members. Examples of heterocycloalkyl groups include, for example, piperazine, morpholine, piperidine, tetrahydrofuran, pyrrolidine, and pyrazole.
  • Preferred heterocycloalkyl groups include piperidinyl, piperazinyl, morpholinyl, and pyrolidinyl.
  • heteroaryl refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl ring can be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings.
  • heteroaryl groups include, for example, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline and pyrimidine.
  • heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.
  • C1-C6 hydrocarbyl refers to straight, branched, or cyclic alkyl groups having 1-6 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds.
  • hydrocarbyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, vinyl, 2-pentene, cyclopropylmethyl, cyclopropyl, cyclohexylmethyl, cyclohexyl and propargyl.
  • C1-C6 hydrocarbyl containing one or two double or triple bonds it is understood that at least two carbons are present in the alkyl for one double or triple bond, and at least four
  • nucleotide is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a phosphorylated sugar.
  • Nucleotides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1′ position of a nucleotide sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group.
  • the nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non-natural nucleotides, non-standard nucleotides and other; see for example, Usman and McSwiggen, supra; Eckstein et al., International PCT Publication No. WO 92/07065; Usman et al., International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra all are hereby incorporated by reference herein).
  • modified nucleic acid bases known in the art as summarized by Limbach et al., 1994, Nucleic Acids Res. 22, 2183.
  • nucleic acids include, for example, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2,4,6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g.
  • modified bases in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1′ position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions of the nucleic acid molecule.
  • nucleoside is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a sugar.
  • Nucleosides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1′ position of a nucleoside sugar moiety.
  • Nucleosides generally comprise a base and sugar group.
  • the nucleosides can be unmodified or modified at the sugar, and/or base moiety, (also referred to interchangeably as nucleoside analogs, modified nucleosides, non-natural nucleosides, non-standard nucleosides and other; see for example, Usman and McSwiggen, supra; Eckstein et al., International PCT Publication No.
  • nucleic acids Some of the non-limiting examples of chemically modified and other natural nucleic acid bases that can be introduced into nucleic acids include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2,4,6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g.
  • modified bases in this aspect is meant nucleoside bases other than adenine, guanine, cytosine and uracil at 1′ position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions of the nucleic acid molecule.
  • the invention features modified enzymatic nucleic acid molecules with phosphate backbone modifications comprising one or more phosphorothioate, phosphorodithioate, methylphosphonate, morpholino, amidate carbamate, carboxymethyl, acetamidate, polyamide, sulfonate, sulfonamide, sulfamate, formacetal, thioformacetal, and/or alkylsilyl, substitutions.
  • abasic sugar moieties lacking a base or having other chemical groups in place of a base at the 1′ position, for example a 3′,3′-linked or 5′,5′-linked deoxyabasic ribose derivative (for more details see Wincott et al., International PCT publication No. WO 97/26270).
  • unmodified nucleoside is meant one of the bases adenine, cytosine, guanine, thymine, uracil joined to the 1′ carbon of ⁇ -D-ribo-furanose.
  • modified nucleoside is meant any nucleotide base which contains a modification in the chemical structure of an unmodified nucleotide base, sugar and/or phosphate.
  • amino is meant 2′-NH 2 or 2′-O—NH 2 , which can be modified or unmodified.
  • modified groups are described, for example, in Eckstein et al., U.S. Pat. No. 5,672,695 and Matulic-Adamic et al., WO 98/28317, respectively, which are both incorporated by reference in their entireties.
  • nucleic acid e.g., antisense and ribozyme
  • modifications to nucleic acid can be made to enhance the utility of these molecules.
  • modifications can enhance shelf-life, half-life in vitro, stability, and ease of introduction of such oligonucleotides to the target site, including e.g., enhancing penetration of cellular membranes and conferring the ability to recognize and bind to targeted cells.
  • enzymatic nucleic acid molecules can lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs) and/or other chemical or biological molecules).
  • the treatment of subjects with nucleic acid molecules can also include combinations of different types of nucleic acid molecules.
  • Therapies can be devised which include a mixture of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs), antisense and/or 2-5A chimera molecules to one or more targets to alleviate symptoms of a disease.
  • nucleic acid molecules Methods for the delivery of nucleic acid molecules are described in Akhtar et al., 1992, Trends Cell Bio., 2, 139; and Delivery Strategies for Antisense Oligonucleotide Therapeutics , ed. Akhtar, 1995 which are both incorporated herein by reference.
  • Sullivan et al., PCT WO 94/02595 further describes the general methods for delivery of enzymatic RNA molecules. These protocols can be utilized for the delivery of virtually any nucleic acid molecule.
  • Nucleic acid molecules can be administered to cells by a variety of methods known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres.
  • the nucleic acid/vehicle combination is locally delivered by direct injection or by use of an infusion pump.
  • Other routes of delivery include, but are not limited to oral (tablet or pill form) and/or intrathecal delivery (Gold, 1997, Neuroscience, 76, 1153-1158).
  • Other approaches include the use of various transport and carrier systems, for example, through the use of conjugates and biodegradable polymers.
  • the molecules of the instant invention can be used as pharmaceutical agents.
  • Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state in a subject.
  • the negatively charged polynucleotides of the invention can be administered (e.g., RNA, DNA or protein) and introduced into a subject by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition.
  • RNA, DNA or protein e.g., RNA, DNA or protein
  • standard protocols for formation of liposomes can be followed.
  • the compositions of the present invention can also be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions; suspensions for injectable administration; and the other compositions known in the art.
  • the present invention also includes pharmaceutically acceptable formulations of the compounds described.
  • formulations include salts of the above compounds, e.g., acid addition salts, for example, salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonic acid.
  • a pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., systemic administration, into a cell or subject, preferably a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell (i.e., a cell to which the negatively charged polymer is desired to be delivered to). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms which prevent the composition or formulation from exerting its effect.
  • systemic administration in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body.
  • Administration routes which lead to systemic absorption include, without limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular.
  • Each of these administration routes expose the desired negatively charged polymers, e.g., nucleic acids, to an accessible diseased tissue.
  • the rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size.
  • the use of a liposome or other drug carrier comprising the compounds of the instant invention can potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES).
  • RES reticular endothelial system
  • a liposome formulation which can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach can provide enhanced delivery of the drug to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells, such as cancer cells.
  • compositions or formulation that allows for the effective distribution of the nucleic acid molecules of the instant invention in the physical location most suitable for their desired activity.
  • agents suitable for formulation with the nucleic acid molecules of the instant invention include: PEG conjugated nucleic acids, phospholipid conjugated nucleic acids, nucleic acids containing lipophilic moieties, phosphorothioates, P-glycoprotein inhibitors (such as Pluronic P85) which can enhance entry of drugs into various tissues, for example the CNS (Jolliet-Riant and Tillement, 1999, Fundam. Clin.
  • biodegradable polymers such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after implantation (Emerich, D F et al, 1999, Cell Transplant, 8, 47-58) Alkermes, Inc. Cambridge, Mass.; and loaded nanoparticles, such as those made of polybutylcyanoacrylate, which can deliver drugs across the blood brain barrier and can alter neuronal uptake mechanisms ( Prog Neuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999).
  • Other non-limiting examples of delivery strategies, including CNS delivery of the nucleic acid molecules of the instant invention include material described in Boado et al., 1998, J. Pharm.
  • the invention also features the use of the composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes).
  • Nucleic acid molecules of the invention can also comprise covalently attached PEG molecules of various molecular weights. These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug (Lasic et al. Chem. Rev. 1995, 95, 2601-2627; Ishiwata et al., Chem. Pharm. Bull.
  • MPS or RES mononuclear phagocytic system
  • liposomes have been shown to accumulate selectively in tumors, presumably by extravasation and capture in the neovascularized target tissues (Lasic et al., Science 1995, 267, 1275-1276; Oku et al., 1995, Biochim. Biophys. Acta, 1238, 86-90).
  • the long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes which are known to accumulate in tissues of the MPS (Liu et al., J. Biol. Chem. 1995, 42, 24864-24870; Choi et al., International PCT Publication No.
  • WO 96/10391 Ansell et al., International PCT Publication No. WO 96/10390; Holland et al., International PCT Publication No. WO 96/10392; all of which are incorporated by reference herein).
  • Long-circulating liposomes are also likely to protect drugs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive MPS tissues such as the liver and spleen. All of these references are incorporated by reference herein.
  • compositions prepared for storage or administration which include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences , Mack Publishing Co. (A. R. Gennaro edit. 1985) hereby incorporated by reference herein.
  • preservatives, stabilizers, dyes and flavoring agents can be provided. These include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • antioxidants and suspending agents can be used.
  • a pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state.
  • the pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer.
  • nucleic acid molecules of the invention and formulations thereof can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.
  • a pharmaceutical formulation comprising a nucleic acid molecule of the invention and a pharmaceutically acceptable carrier.
  • One or more nucleic acid molecules of the invention can be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients.
  • compositions containing nucleic acid molecules of the invention can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
  • the aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents and flavoring agents can be added to provide palatable oral preparations.
  • These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • compositions of the invention can also be in the form of oil-in-water emulsions.
  • the oily phase can be a vegetable oil or a mineral oil or mixtures of these.
  • Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions can also contain sweetening and flavoring agents.
  • Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the nucleic acid molecules of the invention can also be administered in the form of suppositories, e.g., for rectal administration of the drug.
  • suppositories e.g., for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • Nucleic acid molecules of the invention can be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient or subject per day).
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration.
  • Dosage unit forms generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient or subject depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the composition can also be added to the animal feed or drinking water. It can be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It can also be convenient to present the composition as a premix for addition to the feed or drinking water.
  • nucleic acid molecules of the present invention can also be administered to a subject in combination with other therapeutic compounds to increase the overall therapeutic effect.
  • the use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.
  • nucleic acid molecules of the instant invention can be expressed within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985, Science, 229, 345; McGarry and Lindquist, 1986, Proc. Natl. Acad. Sci., USA 83, 399; Scanlon et al., 1991, Proc. Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al., 1992, Antisense Res. Dev., 2, 3-15; Dropulic et al., 1992, J. Virol., 66, 1432-41; Weerasinghe et al., 1991, J.
  • eukaryotic promoters e.g., Izant and Weintraub, 1985, Science, 229, 345; McGarry and Lindquist, 1986, Proc. Natl. Acad. Sci., USA 83, 399; Scanlon e
  • nucleic acids can be augmented by their release from the primary transcript by a enzymatic nucleic acid (Draper et al., PCT WO 93/23569, and Sullivan et al., PCT WO 94/02595; Ohkawa et al., 1992, Nucleic Acids Symp. Ser., 27, 15-6; Taira et al., 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al., 1993, Nucleic Acids Res., 21, 3249-55; Chowrira et al., 1994, J. Biol. Chem., 269, 25856; all of these references are hereby incorporated in their totalities by reference herein).
  • a enzymatic nucleic acid Draper et al., PCT WO 93/23569, and Sullivan et al., PCT 94/02595; Ohkawa et al., 1992, Nucleic Acids Sy
  • RNA molecules of the present invention are preferably expressed from transcription units (see for example Couture et al., 1996, TIG., 12, 510) inserted into DNA or RNA vectors.
  • the recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus.
  • the recombinant vectors capable of expressing the nucleic acid molecules are delivered as described above, and persist in target cells.
  • viral vectors can be used that provide for transient expression of nucleic acid molecules. Such vectors can be repeatedly administered as necessary.
  • Delivery of nucleic acid molecule expressing vectors can be systemic, such as by intravenous or intra-muscular administration, by administration to target cells ex-planted from the patient or subject followed by reintroduction into the patient or subject, or by any other means that would allow for introduction into the desired target cell (for a review see Couture et al., 1996, TIG., 12, 510).
  • the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules of the instant invention is disclosed.
  • the nucleic acid sequence encoding the nucleic acid molecule of the instant invention is operably linked in a manner which allows expression of that nucleic acid molecule.
  • the invention features an expression vector comprising: a) a transcription initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription termination region (e.g., eukaryotic pol I, II or III termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
  • the vector can optionally include an open reading frame (ORF) for a protein operably linked on the 5′ side or the 3′-side of the sequence encoding the nucleic acid catalyst of the invention; and/or an intron (intervening sequences).
  • ORF open reading frame
  • RNA polymerase I RNA polymerase I
  • polymerase II RNA polymerase II
  • poly III RNA polymerase III
  • Transcripts from pol II or pol III promoters are expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby.
  • Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl. Acad. Sci.
  • nucleic acid molecules such as ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992, Antisense Res. Dev., 2, 3-15; Ojwang et al., 1992, Proc. Natl. Acad. Sci.
  • transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as ribozymes in cells (Thompson et al., supra; Couture and Stinchcomb, 1996, supra; Noonberg et al., 1994, Nucleic Acid Res., 22, 2830; Noonberg et al., U.S. Pat. No. 5,624,803; Good et al., 1997, Gene Ther., 4, 45; Beigelman et al., International PCT Publication No. WO 96/18736; all of these publications are incorporated by reference herein.
  • ribozyme transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review see Couture and Stinchcomb, 1996, supra).
  • plasmid DNA vectors such as adenovirus or adeno-associated virus vectors
  • viral RNA vectors such as retroviral or alphavirus vectors
  • the invention features an expression vector comprising nucleic acid sequence encoding at least one of the nucleic acid molecules of the invention, in a manner which allows expression of that nucleic acid molecule.
  • the expression vector comprises in one embodiment; a) a transcription initiation region; b) a transcription termination region; c) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
  • the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3′-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
  • the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
  • the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; e) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3′-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
  • the sequence of human IKK-gamma or PKR genes are screened for accessible sites using a computer-folding algorithm. Regions of the RNA that do not form secondary folding structures and contained potential enzymatic nucleic acid molecule and/or antisense binding/cleavage sites are identified. The sequences of these binding/cleavage sites are shown in Tables III-XIII.
  • Enzymatic nucleic acid molecule target sites are chosen by analyzing sequences of Human IKK-gamma (Genbank accession No: NM — 003639) and PKR (Genbank accession No: NM — 002759) and prioritizing the sites on the basis of folding. Enzymatic nucleic acid molecules are designed that can bind each target and are individually analyzed by computer folding (Christoffersen et al., 1994 J. Mol. Struc. Theochem, 311, 273; Jaeger et al., 1989, Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the enzymatic nucleic acid molecule sequences fold into the appropriate secondary structure.
  • binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA.
  • Enzymatic nucleic acid molecules and antisense constructs are designed to anneal to various sites in the RNA message.
  • the binding arms of the enzymatic nucleic acid molecules are complementary to the target site sequences described above, while the antisense constructs are fully complementary to the target site sequences described above.
  • the enzymatic nucleic acid molecules and antisense constructs were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al., (1987 J. Am. Chem.
  • Enzymatic nucleic acid molecules and antisense constructs are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51). Enzymatic nucleic acid molecules and antisense constructs are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al., supra; the totality of which is hereby incorporated herein by reference) and are resuspended in water. The sequences of the chemically synthesized enzymatic nucleic acid molecules used in this study are shown below in Table XIII. The sequences of the chemically synthesized antisense constructs used in this study are complementary sequences to the Substrate sequences shown below as in Tables III to XIII.
  • Enzymatic nucleic acid molecules targeted to the human IKK-gamma or PKR RNA are designed and synthesized as described above. These enzymatic nucleic acid molecules can be tested for cleavage activity in vitro, for example, using the following procedure.
  • the target sequences and the nucleotide location within the IKK-gamma or PKR RNA are given in Tables III-XIII.
  • Full-length or partially full-length, internally-labeled target RNA for enzymatic nucleic acid molecule cleavage assay is prepared by in vitro transcription in the presence of [a- 32 P] CTP, passed over a G 50 Sephadex column by spin chromatography and used as substrate RNA without further purification.
  • substrates are 5′- 32 P-end labeled using T4 polynucleotide kinase enzyme.
  • Assays are performed by pre-warming a 2 ⁇ concentration of purified enzymatic nucleic acid molecule in enzymatic nucleic acid molecule cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37° C., 10 mM MgCl 2 ) and the cleavage reaction was initiated by adding the 2 ⁇ enzymatic nucleic acid molecule mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. As an initial screen, assays are carried out for 1 hour at 37° C.
  • enzymatic nucleic acid molecule cleavage buffer 50 mM Tris-HCl, pH 7.5 at 37° C., 10 mM MgCl 2
  • enzymatic nucleic acid molecule excess a final concentration of either 40 nM or 1 mM enzymatic nucleic acid molecule, i.e., enzymatic nucleic acid molecule excess.
  • the reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which the sample is heated to 95° C. for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel.
  • Substrate RNA and the specific RNA cleavage products generated by enzymatic nucleic acid molecule cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.
  • Nucleic acid molecules targeted to the human IKK-gamma or PKR RNA are designed and synthesized as described above. These nucleic acid molecules can be tested for cleavage activity in vivo, for example using the procedures described below.
  • the target sequences and the nucleotide location within the IKK-gamma or PKR RNA are given in Tables III-XIII.
  • Phenotypic endpoints include inhibition of cell proliferation, apoptosis assays and reduction of IKK-gamma or PKR protein expression, or a decrease in NFKB expression. Since IKK-gamma and PKR are both involved in the induction of NFKB, NFKB can be used as a surrogate marker in cell culture, animal, and clinical studies. Because overexpression of NFKB is directly associated with increased proliferation of tumor cells, a proliferation endpoint for cell culture assays is preferably used as a primary screen. There are several methods by which this endpoint can be measured.
  • cells are allowed to grow (typically 5 days) after which either the cell viability, the incorporation of [ 3 H] thymidine into cellular DNA and/or the cell density can be measured.
  • the assay of cell density is very straightforward and can be performed in a 96-well format using commercially available fluorescent nucleic acid stains (such as Syto® 13 or CyQuant®). An assay using CyQuant® is described herein.
  • a nucleic acid-mediated decrease in the level of IKK-gamma or PKR RNA and/or IKK-gamma or PKR protein expression can be evaluated.
  • a decrease in the level of NFKB RNA can be evaluated.
  • Cell types that express/over-express NFKB include HeLa, macrophages, peripheral blood lymphocytes, hepatocytes, fibroblasts, endothelial cells and epithelial cells. In culture, these cells can be stimulated to express/over-express NFKB by addition of TNF-alpha PMA or IL-1-beta to the culture medium. Some of these cell types also can respond with a similar activation of NFKB following LPS treatment. Activation of NFKB in cultured cells can be evaluated by electrophoretic mobility shift assay (EMSA). Delineation of alterations in the subunits can be determined by Western blot.
  • EMSA electrophoretic mobility shift assay
  • a useful cell culture system in evaluating NFKB modulation is human colonic epithelial cells.
  • One suitable cell line is SW620 colon carcinoma cells (CCL227). These cells respond to stimulation with TNF-alpha, LPS and/or IL-1-beta with an increase in NFKB activation.
  • SW620 cells are grown in MEM supplemented with 10% heat-inactivated FBS and glutamine (2 mmol/L).
  • TNF-alpha dose-response curves in these cells are determined by incubating cells with various concentrations of recombinant human TNF-alpha (Sigma Chemical Co.). Maximal DNA binding activity induction can occur with 150 U/ml TNF-alpha in the culture medium. Induction is typically evident within 10 minutes of treatment with TNF-alpha reaches a peak at one hour post-treatment and persists for up to 4 hours post-treatment.
  • the primary readout can be NFKB DNA activity in nuclear extracts of SW620 cells as determined by electrophoretic mobility shift assays (EMSA).
  • TNF-alpha inhibition of IKK-gamma, PKR, or NFKB activation is evaluated using specific and non-specific inhibitors of activation, sulfasalazine and steroids, respectively.
  • Cells are incubated with inhibitors or control media for 30 minutes prior to stimulation with TNF-alpha
  • Nuclear extracts are prepared and evaluated for DNA binding activity by EMSA. Once the activity of positive controls has been established, enzymatic nucleic acids targeting the IKK-gamma or PKR are evaluated in this system.
  • Supershift assays using polyclonal antibodies against the NFKB or PKR protein subunits can be performed to confirm down-regulation of NFKB.
  • SW620 cells can be transfected with the 3 ⁇ Ig-kappa-B-Luc reporter construct 18 hours before challenge with TNF-alpha, LPS or PMA.
  • the readout for this assay is luciferase activity.
  • Test compounds are applied 17.5 hours after transfection (30 minutes before challenge).
  • Cells are harvested 24 hours after challenge and relative changes in luciferase activity is used as the endpoint.
  • the activation of NFKB can be visualized fluorescently.
  • Inactive NFKB heterodimers are held in the cytoplasm by inhibitory proteins. Once activated, the free heterodimers translocate to the nucleus.
  • the relative change in cytoplasmic versus nuclear fluorescence can indicate the degree of NFKB activation.
  • Cells can be grown on chamber slides, treated with TNF-alpha with and without test compounds), and the location of the NFKB subunit can be determined by immunofluorescence using a FITC-labeled antibody to NFKB.
  • Tumor cell lines are characterized to establish their growth curves in mice. These cell lines are implanted into both nude and SCID mice and primary tumor volumes are measured 3 times per week. Growth characteristics of these tumor lines using a Matrigel implantation format can also be established. The use of other cell lines that have been engineered to express high levels of NFKB can also be used in the described studies.
  • the tumor cell line(s) and implantation method that supports the most consistent and reliable tumor growth is used in animal studies testing the lead IKK-gamma or PKR nucleic acid(s). Nucleic acids are administered by daily subcutaneous injection or by continuous subcutaneous infusion from Alzet mini osmotic pumps beginning 3 days after tumor implantation and continuing for the duration of the study. Group sizes of at least 10 animals are employed.
  • Efficacy is determined by statistical comparison of tumor volume of nucleic acid-treated animals to a control group of animals treated with saline alone. Because the growth of these tumors is generally slow (45-60 days), an initial endpoint is the time in days it takes to establish an easily measurable primary tumor (i.e. 50-100 mm 3 ) in the presence or absence of nucleic acid treatment.
  • the 10 cm portion of gut from each animal is cut into five equal sections. Transverse and longitudinal sections of each portion are cut and stained with hematoxylin and eosin. All slides are read in a blinded fashion and each section is scored for necrosis (% area of involvement) and inflammatory response according to the following scale:
  • the scores for each of the five sections are averaged for necrosis and for inflammation.
  • cancer patients can be pre-screened for elevated NFKB prior to admission to initial clinical trials testing an anti-IKK-gamma or PKR nucleic acid.
  • Initial NFKB levels can be determined (by ELISA) from tumor biopsies or resected tumor samples. During clinical trials, it can be possible to monitor circulating NFKB protein by ELISA. Evaluation of serial blood/serum samples over the course of the anti-IKK-gamma or PKR nucleic acid treatment period could be useful in determining early indications of efficacy.
  • nucleic acid molecules targeted against IKK-gamma or PKR RNA have been designed and synthesized. These nucleic acid molecules can be tested in cell proliferation and RNA reduction assays described herein.
  • the model proliferation assay used in the study requires a cell-plating density of 2,000-10,000 cells/well in 96-well plates and at least 2 cell doublings over a 5-day treatment period.
  • Cells used in proliferation studies were either lung or ovarian cancer cells (A549 and SKOV-3 cells respectively).
  • FIPS fluoro-imaging processing system
  • This method allows for cell density measurements after nucleic acids are stained with CyQuant® dye, and has the advantage of accurately measuring cell densities over a very wide range 1,000-100,000 cells/well in 96-well format.
  • Enzymatic nucleic acid molecules (50-200 nM) are delivered in the presence of cationic lipid at 2.5-5.0 ⁇ g/mL and inhibition of proliferation was determined on day 5 post-treatment.
  • RNA is harvested 24 hours post-treatment using the Qiagen RNeasy® 96 procedure.
  • Real time RT-PCR (TaqMan® assay) is performed on purified RNA samples using separate primer/probe sets specific for target IKK-gamma or PKR RNA.
  • Particular degenerative and disease states that can be associated with IKK-gamma or PKR expression modulation include but are not limited to cancerous and/or inflammatory diseases and conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, incontinentia pigmenti and any other diseases or conditions that are related to or respond to the levels of IKK-gamma or PKR in a cell or tissue.
  • ischemia/reperfusion injury CNS and myocardial
  • nucleic acid molecules e.g. ribozymes and antisense molecules
  • chemotherapies that can be combined with nucleic acid molecules of the instant invention include various combinations of cytotoxic drugs to kill cancer cells. These drugs include but are not limited to paclitaxel (Taxol), docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, vinorelbine etc.
  • paclitaxel Taxol
  • docetaxel cisplatin
  • methotrexate cyclophosphamide
  • doxorubin fluorouracil carboplatin
  • edatrexate gemcitabine
  • vinorelbine vinorelbine
  • the nucleic acid molecules of this invention can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of IKK-gamma or PKR RNA in a cell.
  • the close relationship between enzymatic nucleic acid molecule activity and the structure of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three-dimensional structure of the target RNA.
  • Cleavage of target RNAs with enzymatic nucleic acid molecules can be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets can be defined as important mediators of the disease.
  • combinational therapies e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules and/or other chemical or biological molecules.
  • enzymatic nucleic acid molecules of this invention include detection of the presence of mRNAs associated with IKK-gamma or PKR-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with an enzymatic nucleic acid molecule using standard methodology.
  • enzymatic nucleic acid molecules which cleave only wild-type or mutant forms of the target RNA are used for the assay.
  • the first enzymatic nucleic acid molecule is used to identify wild-type RNA present in the sample and the second enzymatic nucleic acid molecule is used to identify mutant RNA in the sample.
  • synthetic substrates of both wild-type and mutant RNA are cleaved by both enzymatic nucleic acid molecules to demonstrate the relative enzymatic nucleic acid molecule efficiencies in the reactions and the absence of cleavage of the “non-targeted” RNA species.
  • the cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population.
  • each analysis requires two enzymatic nucleic acid molecules, two substrates and one unknown sample which is combined into six reactions.
  • the presence of cleavage products is determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells.
  • mRNA whose protein product is implicated in the development of the phenotype (i.e., IKK-gamma or PKR) is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost of the initial diagnosis. Higher mutant form to wild-type ratios are correlated with higher risk whether RNA levels are compared qualitatively or quantitatively.
  • enzymatic nucleic acid molecules in diagnostic applications contemplated by the instant invention is more fully described in George et al., U.S. Pat. Nos. 5,834,186 and 5,741,679, Shih et al., U.S. Pat. No.
  • sequence-specific enzymatic nucleic acid molecules of the instant invention can have many of the same applications for the study of RNA that DNA restriction endonucleases have for the study of DNA (Nathans et al., 1975 Ann. Rev. Biochem. 44:273).
  • the pattern of restriction fragments can be used to establish sequence relationships between two related RNAs, and large RNAs can be specifically cleaved to fragments of a size more useful for study.
  • the ability to engineer sequence specificity of the enzymatic nucleic acid molecule is ideal for cleavage of RNAs of unknown sequence.
  • Applicant has described the use of nucleic acid molecules to down-regulate gene expression of target genes in bacterial, microbial, fungal, viral, and eukaryotic systems including plant, or mammalian cells.
  • RNAse P RNA (M1 RNA) Size ⁇ 290 to 400 nucleotides. RNA portion of a ubiquitous ribonucleoprotein enzyme. Cleaves tRNA precursors to form mature tRNA[ xiii ].
  • RNAse P is found throughout the prokaryotes and eukaryotes. The RNA subunit has been sequenced from bacteria, yeast, rodents, and primates. Recruitment of endogenous RNAse P for therapeutic applications is possible through hybridization of an External Guide Sequence (EGS) to the target RNA[ xiv , xv ] Important phosphate and 2′ OH contacts recently identified[ xvi , xvii ] Group II Introns Size: >1000 nucleotides. Trans cleavage of target RNAs recently demonstrated[ xviii , xix ]. Sequence requirements not fully determined.
  • EGS External Guide Sequence
  • Reaction mechanism 2′-OH of an internal adenosine generates cleavage products with 3′-OH and a “lariat” RNA containing a 3′-5′ and a 2′-5′ branch point. Only natural ribozyme with demonstrated participation in DNA cleavage[ xx , xxi ] in addition to RNA cleavage and ligation. Major structural features largely established through phylogenetic comparisons[ xxii ]. Important 2′ OH contacts beginning to be identified[ xxiii ] Kinetic framework under development[ xxiv ] Neurospora VS RNA Size: ⁇ 144 nucleotides. Trans cleavage of hairpin target RNAs recently demonstrated[ xxv ].
  • Reaction mechanism attack by 2′-OH 5′ to the scissile bond to generate cleavage products with 2′,3′-cyclic phosphate and 5′-OH ends. 14 known members of this class. Found in a number of plant pathogens (virusoids) that use RNA as the infectious agent. Essential structural features largely defined, including 2 crystal structures[ xxvi , xxvii ] Minimal ligation activity demonstrated (for engineering through in vitro selection)[ xxviii ] Complete kinetic framework established for two or more ribozymes[ xxix ]. Chemical modification investigation of important residues well established[ xxx ]. Hairpin Ribozyme Size: ⁇ 50 nucleotides.
  • RNA pathogen satellite RNAs of the tobacco ringspot virus, arabis mosaic virus and chicory yellow mottle virus
  • Folded ribozyme contains a pseudoknot structure[ xl ]. Reaction mechanism: attack by 2′-OH 5′ to the scissile bond to generate cleavage products with 2′,3′-cyclic phosphate and 5′-OH ends. Only 2 known members of this class. Found in human HDV. Circular form of HDV is active and shows increased nuclease stability[ xli ] i Michel, Francois; Westhof, Eric. Slippery substrates. Nat. Struct. Biol. (1994), 1(1), 5-7. ii Lisacek, Frederique; Diaz, Yolade; Michel, Francois. Automatic identification of group I intron cores in genomic DNA sequences. J. Mol. Biol.
  • Thermodynamic and activation parameters for binding of a pyrene-labeled substrate by the Tetrahymena ribozyme docking is not diffusion-controlled and is driven by a favorable entropy change. Biochemistry (1995), 34(44), 14394-9. viii Banerjee, Aloke Raj; Turner, Douglas H.. The time dependence of chemical modification reveals slow steps in the folding of a group I ribozyme. Biochemistry (1995), 34(19), 6504-12. ix Zarrinkar, Patrick P.; Williamson, James R.. The P9.1-P9.2 peripheral extension helps guide folding of the Tetrahymena ribozyme. Nucleic Acids Res. (1996), 24(5), 854-8.
  • a group II intron RNA is a catalytic component of a DNA endonuclease involved in intron mobility.
  • Cell (Cambridge, Mass.) (1995), 83(4), 529-38.
  • Group II intron ribozymes that cleave DNA and RNA linkages with similar efficiency, and lack contacts with substrate 2′-hydroxyl groups.
  • Core Sequence CUGAUGAG GCCGUUAGGC CGAA NM_003639 ( Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), mRNA.; 1994 bp)
  • Underlined region can be any X sequence or linker, as described herein.
  • Core Sequence CUGAUGAG GCCGUUAGGC CGAA NM_003639 ( Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), mRNA.; 1994 bp)
  • Underlined region can be any X sequence or linker, as described herein. “I” stands for Inosine.
  • Core Sequence GCcgaaagGCGaGuCaaGGuCu NM_003639 ( Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), mRNA.; 1994 bp)
  • Core Sequence GGCTAGCTACAACGA NM_003639 ( Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), mRNA.; 1994 bp)
  • Core Sequence CUGAUGAG GCCGUUAGGC CGAA NM_002759 ( Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)
  • Underlined region can be any X sequence or linker, as described herein.
  • NM_002759 Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp
  • Underlined region can be any X sequence or linker, as described herein. “I” stands for Inosine.
  • Core Sequence GCcgaaagGCGaGuCaaGGuCu NM_002759 ( Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)
  • Core Sequence GGCTAGCTACAACGA NM_002759 ( Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)
  • Core Sequence GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG NM_002759 ( Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)

Abstract

The present invention relates to nucleic acid molecules, including antisense and enzymatic nucleic acid molecules, such as hammerhead ribozymes, DNAzymes, allozymes, aptamers, decoys and siRNA (RNAi), which modulate the expression or function of IKK genes, such as IKK-gamma, IKK-alpha, or IKK-beta, and PKR genes.

Description

  • This patent application is a continuation of U.S. Ser. No. 10/156,306, filed May 28, 2002, now allowed, which is a continuation in part of PCT/US02/10512, filed Apr. 3, 2002, and which claims the benefit of U.S. Ser. No. 60/294,412, filed May 29, 2001. These applications are hereby incorporated by reference herein in their entirety including the drawings.
    • FIELD OF THE INVENTION
  • The present invention relates to therapeutic compositions and methods for the treatment or diagnosis of diseases or conditions related to IKK gamma (IKKG) and PKR levels, such as cancer, inflammatory, and autoimmune diseases and/or disorders.
    • BACKGROUND OF THE INVENTION
  • The following is a brief description of the physiological role of nuclear factor kappa B (NFKB), IKK kinases, and protein kinase PKR. The discussion is provided only for understanding the invention that follows. This summary is not an admission that any of the work described below is prior art to the claimed invention.
  • Nuclear factor kappa B (NFKB) is a multiunit transcription factor which regulates the expression of genes involved in a number of physiologic and pathologic processes. NFKB is a key component of the TNF signaling pathway. These processes include, but are not limited to: apoptosis, immune, inflammatory and acute phase responses. The REL-A gene product (a.k.a. RelA or p65), and p50 subunits of NFKB, have been implicated in the induction of inflammatory responses and cellular transformation. NFKB exists in the cytoplasm as an inactive heterodimer of the p50 and p65 subunits. NFKB is complexed with an inhibitory protein complex, IkappaB (IKK complex), until activated by the appropriate stimuli. NFKB activation can occur following stimulation of a variety of cell types by inflammatory mediators, for example TNF and IL-1, and reactive oxygen intermediates. In response to induction, NFKB can stimulate production of pro-inflammatory cytokines such as TNF-alpha, IL-1-beta, IL-6 and iNOS, thereby perpetuating a positive feedback loop. NFKB appears to play a role in a number of disease processes including: ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, arthritis, and cancer.
  • The nuclear DNA-binding protein, NFKB, was first identified as a factor that binds and activates the immunoglobulin kappa light chain enhancer in B cells. NFKB now is known to activate transcription of a variety of other cellular genes (e.g., cytokines, adhesion proteins, oncogenes and viral proteins) in response to a variety of stimuli (e.g., phorbol esters, mitogens, cytokines and oxidative stress). In addition, molecular and biochemical characterization of NFKB has shown that the activity is due to a homodimer or heterodimer of a family of DNA binding subunits. Each subunit bears a stretch of 300 amino acids that is homologous to the oncogene, v-rel. The activity first described as NFKB is a heterodimer of p49 or p50 with p65. The p49 and p50 subunits of NFKB (encoded by the NF-kappa B2 or NF kappa B1 genes, respectively) are generated from the precursors NFKB1 (p105) or NFKB2 (p100). The p65 subunit of NFKB (now termed REL-A) is encoded by the rel-A locus.
  • The roles of each specific transcription-activating complex now are being elucidated in cells (Perkins, et al., 1992, Proc. Natl. Acad. Sci USA, 89, 1529-1533). For instance, the heterodimer of NFKB1 and Rel A (p50/p65) activates transcription of the promoter for the adhesion molecule, VCAM-1, while NFKB2/RelA heterodimers (p49/p65) actually inhibit transcription (Shu, et al., 1993, Mol. Cell. Biol., 13, 6283-6289). Conversely, heterodimers of NFKB2/RelA (p49/p65) act with Tat-I to activate transcription of the HIV genome, while NFKB1/RelA (p50/p65) heterodimers have little effect (Liu et al., 1992, J. Virol., 3883-3887). Similarly, blocking rel A gene expression with antisense oligonucleotides specifically blocks embryonic stem cell adhesion; blocking NFKB1 gene expression with antisense oligonucleotides had no effect on cellular adhesion (Narayanan et al., 1993, Mol. Cell. Biol., 13, 3802-3810). Thus, the promiscuous role initially assigned to NFKB in transcriptional activation (Lenardo, and Baltimore, 1989, Cell, 58, 227-229) represents the sum of the activities of the rel family of DNA-binding proteins. This conclusion is supported by recent transgenic “knock-out” mice of individual members of the rel family. Such “knock-outs” show few developmental defects, suggesting that essential transcriptional activation functions can be performed by more than one member of the rel family.
  • A number of specific inhibitors of NFKB function in cells exist, including treatment with phosphorothioate antisense oliogonucleotide, treatment with double-stranded NFKB binding sites, and over expression of the natural inhibitor MAD-3 (an Ikappa-B family member). These agents have been used to show that NFKB is required for induction of a number of molecules involved in cancer and/or inflammation, as described below.
  • NFkB is required for phorbol ester-mediated induction of IL-6 (Kitajima, et al., 1992, Science, 258, 1792-5) and IL-8 (Kunsch and Rosen, 1993, Mol. Cell. Biol., 13, 6137-46).
  • NFkB is required for induction of the adhesion molecules ICAM-1 (Eck, et al., 1993, Mol. Cell. Biol., 13, 6530-6536), VCAM-1 (Shu et al., supra), and E-selectin (Read, et al., 1994, J. Exp. Med., 179, 503-512) on endothelial cells.
  • NFkB is involved in the induction of the integrin subunit, CD18, and other adhesive properties of leukocytes (Eck et al., 1993 supra).
  • HER2/Neu overexpression induces NFKB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IKB-alpha. Breast cancer has been shown to typify the aberrant expression of NFKB/REL factors (Pianetti et al., 2001, Oncogene, 20, 1287-1299; Sovak et al., 1999, J. Clin. Invest., 100, 2952-2960).
  • Inhibition of NFKB activity has been shown to induce apoptosis in murine hepatocytes (Bellas et al., 1997, Am. J. Pathol., 151, 891-896).
  • NFKB has been shown to regulate cyclooxygenase-2 expression and cell proliferation in human gastric cancer cells (Joo Weon et al., 2001, Laboratory Investigation, 81, 349-360).
  • The above studies suggest that NFKB is integrally involved in the induction of cytokines and adhesion molecules by inflammatory mediators and is involved in the transformation of cancerous cells. Two reported studies point to another connection between NFKB and inflammation: glucocorticoids can exert their anti-inflammatory effects by inhibiting NFKB. The glucocorticoid receptor and p65 both act at NFKB binding sites in the ICAM-1 promoter (van de Stolpe, et al., 1994, J. Biol. Chem., 269, 6185-6192). Glucocorticoid receptor inhibits NFKB-mediated induction of IL-6 (Ray and Prefontaine, 1994 Proc. Natl. Acad. Sci USA, 91, 752-756). Conversely, overexpression of p65 inhibits glucocorticoid induction of the mouse mammary tumor virus promoter. Finally, protein cross-linking and co-immunoprecipitation experiments demonstrated direct physical interaction between p65 and the glucocorticoid receptor.
  • The IKK complex that sequesters NFKB in the cytoplasm comprises IkappaB (IκB) proteins (IκB-alpha, IκB-beta, IκB-epsilon, p105, and p100). The phosphorylation of IκB proteins results in the release of NFKB from the IκB complex which is transported to the nucleus via the unmasking of nuclear translocation signals. Phosphorylation marks IkB proteins for ubiquitination and degradation via the proteosome pathway. Most NFKB inducing stimuli initiate activation of an IκB kinase (IKK) complex that contains two catalytic subunits, IKK -alpha (IKK1) and IKK-beta (IKK2), that phosphorylate IκB-alpha and IκB-beta, with IKK-beta playing a predominant role in pro-inflammatory signaling. In addition to the two kinases, the IKK complex contains regulatory subunits, including IKK-gamma (NEMO/IKKAP1). IKK-gamma is a protein that is critical for the assembly of the IKK complex. IKK-gamma directly binds to IKK-beta and is required for activation of NFKB, for example by TNF-alpha, IL-1-beta, lipopolysaccharide, phorbol 12-myristate 13-acetate, the human T-cell lymphotrophic virus (HTLV-1), or double stranded RNA. Genomic rearrangements in IKK-gamma have been shown to impair NFKB activation and result in incontinentia pigmenti. Additional proteins that associate with the IKK complex include, MEK kinase (MEKK1), NFKB inducing kinase (NIK), receptor interacting protein (RIP), protein kinase CK2, and IKK-associated protein (IKAP), which appears to be associated with the IκB Kinase (IKK) complex, but does not appear to be an integral component of the tripartate IKK complex as does IKK-gamma (Krappmann et al., 2001, J. Biol. Chem., 275, 29779-87).
  • The RNA-dependent protein kinase PKR is a signal transducer for NFKB and IFN regulatory factor-1. PKR is required for activation of NFKB by IFN-gamma via a STAT-1 independent pathway (Amitabha et al., 2001, J. Immunol., 166, 6170-6180). The induction of NFKB by PKR takes place though phosphorylation of IκB-alpha, and appears not to require the catalytic activity of PKR, thereby proceeding independently of the dsRNA-binding properties of PKR (Ishii et al., 2001, Oncogene, 20, 1900-1912). PKR also plays an important role in the regulation of protein synthesis by modulating the activity of eukaryotic initiation factor 2 (eIF-2-alpha) through interferon induction.
  • Kamiya, JP 2000253884, describes specific antisense oligonucleotides for inhibiting IκB-kinase subunit expression. Krappmann et al., 2001, J. Biol. Chem., describe specific antisense oligonucleotides to IKK-gamma.
    • SUMMARY OF THE INVENTION
  • The present invention features a nucleic acid molecule, such as decoy RNA, dsRNA, siRNA, aptamers, antisense nucleic acid molecules, and enzymatic nucleic acid molecule which down regulates expression of a sequence encoding an IkappaB kinase (IKK) subunit. The invention also features an enzymatic nucleic acid molecule which down regulates expression of a sequence encoding protein kinase PKR.
  • In one embodiment, an enzymatic nucleic acid molecule of the invention comprises a sequence selected from the group consisting of SEQ ID NOs. 632-1261, 1762-2260, 2480-2698, 2904-3485, 3814-4360, 4555-4748, 5253-5756, 6034-6310, 6380-6789, 7142-7770, and 7884-8001.
  • In another embodiment, an enzymatic nucleic acid molecule of the invention comprises at least one binding arm wherein one or more of said binding arms comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1-631, 1263-1761, 2261-2479, 2699-2903, 3486-3813, 4361-4554, 4749-5252, 5757-6033, 6311-6379, 6790-7141, and 7771-7883.
  • In another embodiment, an antisense nucleic acid molecule of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1-631, 1263-1761, 2261-2479, 2699-2903, 3486-3813, 4361-4554, 4749-5252, 5757-6033, 6311-6379, 6790-7141, and 7771-7883.
  • In another embodiment, an nucleic acid molecule of the invention is adapted to treat cancer. In yet another embodiment, an enzymatic nucleic acid molecule of the invention has an endonuclease activity to cleave RNA having IKK-gamma or PKR nucleic acid sequence.
  • In one embodiment, an enzymatic nucleic acid molecule of the invention is in an Inozyme, Zinzyme, G-cleaver, Amberzyme, DNAzyme, or Hammerhead configuration.
  • In another embodiment, an Inozyme of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1263-1761, 4749-5252, 7781-7787, 7796-7800, 7822-7846, and 7866-7870.
  • In another embodiment, an Inozyme of the invention comprises a sequence selected from the group consisting of SEQ ID NOs. 1762-2260, 5253-5756, 7894-7900, 7909-7913, 7938-7962, and 7982-7986.
  • In another embodiment, a Zinzyme of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 2261-2479, 5757-6033, 7788-7790, 7847-7860, and 7871-7895.
  • In another embodiment, a Zinzyme of the invention comprises a sequence selected from the group consisting of SEQ ID NOs 2480-2698, 6034-6310, 7901-7903, 7963-7976, and 7987-7991.
  • In another embodiment, an Amberzyme of the invention comprises a sequence selected from the group consisting of SEQ ID NOs 3814-4360, 7142-7770, 7924-7928, and 7997-8001.
  • In another embodiment, a DNAzyme of the invention comprises a sequence selected from the group consisting of SEQ ID NOs 2904-3485, 6380-6789, 7919-7923, and 7992-7996.
  • In another embodiment, a Hammerhead of the invention comprises a sequence complementary to a sequence selected from the group consisting of SEQ ID NOs. 1-631, 4361-4554, 7771-7780, 7791-7795, 7813-7821, and 7861-7865.
  • In another embodiment, a Hammerhead of the invention comprises a sequence selected from the group consisting of SEQ ID NOs 632-1262, 4555-4748, 7884-7894, 7904-7908, 7929-7937, 7977-7981.
  • In one embodiment, a nucleic acid molecule of the invention comprises between 12 and 100 bases complementary to RNA having an IKK-gamma or PKR nucleic acid sequence. In another embodiment, a nucleic acid molecule of the invention comprises between 14 and 24 bases complementary to RNA having an IKK-gamma or PKR nucleic acid sequence.
  • In yet another embodiment, a nucleic acid molecule of the invention is chemically synthesized.
  • In another embodiment, a nucleic acid molecule or antisense nucleic acid molecule of the invention comprises at least one 2′-sugar modification, at least one nucleic acid base modification, or at least one phosphate backbone modification.
  • In one embodiment, a siRNA molecule of the invention comprises a double stranded RNA wherein one strand of the RNA is complimentary to the RNA of IKK-gamma or PKR gene.
  • In another embodiment, a siRNA molecule of the invention comprises a double stranded RNA wherein one strand of the RNA comprises a portion of a sequence of RNA having IKK-gamma or PKR gene sequence. In yet another embodiment, a siRNA molecule of the invention comprises a double stranded RNA wherein both strands of RNA are connected by a non-nucleotide linker. Alternately, a siRNA molecule of the invention comprises a double stranded RNA wherein both strands of RNA are connected by a nucleotide linker, such as a loop or stem loop structure.
  • In one embodiment, a single strand component of a siRNA molecule of the invention is from about 14 to about 50 nucleotides in length. In another embodiment, a single strand component of a siRNA molecule of the invention is about 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 nucleotides in length. In yet another embodiment, a single strand component of a siRNA molecule of the invention is about 23 nucleotides in length. In one embodiment, a siRNA molecule of the invention is from about 28 to about 56 nucleotides in length. In another embodiment, a siRNA molecule of the invention is about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 nucleotides in length. In yet another embodiment, a siRNA molecule of the invention is about 46 nucleotides in length.
  • In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, decoy RNA, dsRNA, siRNA, or aptamer molecules of the invention comprises at least one 2′-sugar modification.
  • In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, decoy RNA, dsRNA, siRNA, or aptamer, nucleic acids of the invention comprises at least one nucleic acid base modification.
  • In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, decoy RNA, dsRNA, siRNA, or aptamer, nucleic acids of the invention comprises at least one phosphate backbone modification.
  • In one embodiment, the invention features a mammalian cell, for example a human cell, including an nucleic acid molecule of the invention.
  • The present invention features method of down-regulating PKR activity in a cell, comprising contacting the cell with an enzymatic nucleic acid molecule or antisense nucleic acid molecule, or other nucleic acid molecule of the invention, under conditions suitable for down-regulating of PKR activity.
  • The present invention also features method of treatment of a subject having a condition associated with the level of PKR, comprising contacting cells of the subject with an enzymatic nucleic acid molecule or antisense nucleic acid molecule or other nucleic acid molecule of the invention under conditions suitable for the treatment.
  • The present invention features method of down-regulating IKK-gamma activity in a cell, comprising contacting the cell with an enzymatic nucleic acid molecule or antisense nucleic acid molecule or other nucleic acid molecule of the invention, under conditions suitable for down-regulating of IKK-gamma activity.
  • The present invention also features method of treatment of a subject having a condition associated with the level of IKK-gamma, comprising contacting cells of the subject with the enzymatic nucleic acid molecule or antisense nucleic acid molecule or other nucleic acid molecule of the invention, under conditions suitable for the treatment.
  • In one embodiment, a method of treatment of the invention comprises the use of one or more drug therapies under conditions suitable for said treatment.
  • The present invention features methods of cleaving RNA comprising a PKR nucleic acid sequence comprising contacting an enzymatic nucleic acid molecule of the invention with the RNA under conditions suitable for the cleavage.
  • The present invention also features methods of cleaving RNA comprising a IKK-gamma nucleic acid sequence comprising contacting an enzymatic nucleic acid molecule of the invention with the RNA under conditions suitable for the cleavage.
  • In one embodiment, a method of cleavage of the invention is carried out in the presence of a divalent cation, for example Mg2+.
  • In another embodiment, an enzymatic nucleic acid or antisense nucleic acid molecule or other nucleic acid molecule of the invention comprises a cap structure, wherein the cap structure is at the 5′-end, or 3′-end, or both the 5′-end and the 3′-end, for example a 3′,3′-linked or 5′,5′-linked deoxyabasic derivative.
  • The present invention also features an expression vector comprising a nucleic acid sequence encoding at least one enzymatic nucleic acid molecule, antisense, or other nucleic acid molecule of the invention in a manner which allows expression of the nucleic acid molecule.
  • In one embodiment, the invention features a mammalian cell, for example a human cell, including an expression vector contemplated by the invention.
  • In another embodiment, an expression vector of the invention further comprises an antisense nucleic acid molecule complementary to RNA of a subunit of IKK-gamma or PKR.
  • In yet another embodiment, an expression vector of the invention comprises a nucleic acid sequence encoding two or more enzymatic nucleic acid molecules, which can be the same or different.
  • The present invention also features a method for treatment of cancer, for example breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, esophageal cancer, stomach cancer, bladder cancer, pancreatic cancer, cervical cancer, head and neck cancer, ovarian cancer, melanoma, lymphoma, glioma, or multidrug resistant cancer, comprising administering to a subject an enzymatic nucleic acid molecule or antisense nucleic acid molecule or other nucleic acid molecule of the invention under conditions suitable for said treatment.
  • In one embodiment, a nucleic acid molecule of the invention comprises at least five ribose residues, at least ten 2′-O-methyl modifications, and a 3′-end modification such as a 3′-3′ inverted abasic moiety, and/or phosphorothioate linkages on at least three of the 5′ terminal nucleotides.
  • In another embodiment, other drug therapies contemplated by the invention include monoclonal antibodies, IKK-gamma or PKR-specific inhibitors, chemotherapy, or radiation therapy.
  • Specific chemotherapy contemplated by the invention include paclitaxel, docetaxel, cisplatin, methotrexate, cyclophosphamide, 5-fluoro uridine, Leucovorin, Irinotecan (CAMPTOSAR® or CPT-11 or Camptothecin-11 or Campto), Paclitaxel, Carboplatin doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, or vinorelbine or a combination thereof.
  • The invention also features a method for treatment of an inflammatory disease, for example rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury, glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, or infection, comprising the step of administering to a subject an enzymatic nucleic acid or antisense nucleic acid molecule of the invention under conditions suitable for the treatment.
  • The present invention features compositions comprising the enzymatic nucleic acid and/or antisense nucleic acid molecules of the invention in a pharmaceutically acceptable carrier.
  • The invention also features a method of administering to a cell, such as mammalian cell (e.g. human cell), where the cell can be in culture or in a mammal, such as a human, an enzymatic nucleic acid molecule or antisense molecule of the instant invention, comprising contacting the cell with the enzymatic nucleic acid molecule or antisense molecule or other nucleic acid molecule of the invention under conditions suitable for such administration. The method of administration can be in the presence of a delivery reagent, for example a lipid, cationic lipid, phospholipid, or liposome.
    • DETAILED DESCRIPTION OF THE INVENTION
  • First the drawings will be described briefly.
    • DRAWINGS
  • FIG. 1 shows examples of chemically stabilized ribozyme motifs. HH Rz, represents hammerhead ribozyme motif (Usman et al., 1996, Curr. Op. Struct. Bio., 1, 527); NCH Rz represents the NCH ribozyme motif (Ludwig & Sproat, International PCT Publication No. WO 98/58058); G-Cleaver, represents G-cleaver ribozyme motif (Kore et al., 1998, Nucleic Acids Research 26, 4116-4120, Eckstein et al., International PCT publication No. WO 99/16871). N or n, represent independently a nucleotide which can be same or different and have complementarity to each other; rI, represents ribo-Inosine nucleotide; arrow indicates the site of cleavage within the target. Position 4 of the HH Rz and the NCH Rz is shown as having 2′-C-allyl modification, but those skilled in the art will recognize that this position can be modified with other modifications well known in the art, so long as such modifications do not significantly inhibit the activity of the ribozyme.
  • FIG. 2 shows an example of the Amberzyme ribozyme motif that is chemically stabilized (see for example Beigelman et al., International PCT publication No. WO 99/55857).
  • FIG. 3 shows an example of the Zinzyme A ribozyme motif that is chemically stabilized (see for example Beigelman et al., Beigelman et al, International PCT publication No. WO 99/55857).
  • FIG. 4 shows an example of a DNAzyme motif described by Santoro et al., 1997, PNAS, 94, 4262.
  • The invention features nucleic acid molecules, for example enzymatic nucleic acid molecules, antisense nucleic acid molecules, 2,5-A chimeras, decoys, double stranded RNA, triplex oligonucleotides, and/or aptamers, and methods to modulate gene expression, for example, genes encoding a member of the IκB kinase IKK complex, such as IKK-alpha (IKK1), IKK-beta (IKK2), or IKK-gamma (IKKγ) and/or a protein kinase PKR protein. In particular, the instant invention features nucleic-acid based molecules and methods to modulate the expression of IKK-gamma (IKKγ) and protein kinase PKR.
  • The invention features one or more enzymatic nucleic acid-based molecules and methods that independently or in combination modulate the expression of gene(s) encoding a member of the IκB kinase IKK complex or PKR. In particular embodiments, the invention features nucleic acid-based molecules and methods that modulate the expression of a member of the IκB kinase IKK complex, for example IKK-alpha (IKK1), IKK-beta (IKK2), or IKK-gamma (IKKγ) and/or a protein kinase PKR protein, such as IKK-alpha (IKK1) gene (Genbank Accession No. NM—001278); IKK-beta (IKK2) gene, for example (Genbank Accession No.AF080158), IKK-gamma (IKKγ) gene, for example (Genbank Accession No. NM—003639), and protein kinase PKR gene, for example (Genbank Accession No. NM—002759).
  • The description below of the various aspects and embodiments is provided with reference to the exemplary IKK-gamma and PKR genes. IKK-gamma is also known as NEMO/IKKAP1. However, the various aspects and embodiments are also directed to other genes which encode other subunits of the IKK complex, such as IKK-alpha (IKK1) or IKK-beta (IKK2). Those additional genes can be analyzed for target sites using the methods described for IKK-gamma or PKR. Thus, the inhibition and the effects of such inhibition of the other genes can be performed as described herein.
  • In one embodiment, the invention features the use of an enzymatic nucleic acid molecule, preferably in the hammerhead, NCH, G-cleaver, amberzyme, zinzyme and/or DNAzyme motif, to down-regulate the expression of IKK-gamma or PKR genes.
  • By “inhibit” or “down-regulate” it is meant that the expression of the gene, or level of RNAs or equivalent RNAs encoding one or more protein subunits, or activity of one or more protein subunits, such as IKK-gamma or PKR subunit(s), is reduced below that observed in the absence of the nucleic acid molecules of the invention. In one embodiment, inhibition or down-regulation with enzymatic nucleic acid molecule preferably is below that level observed in the presence of an enzymatically inactive or attenuated molecule that is able to bind to the same site on the target RNA, but is unable to cleave that RNA. In another embodiment, inhibition or down-regulation with antisense oligonucleotides is preferably below that level observed in the presence of, for example, an oligonucleotide with scrambled sequence or with mismatches. In another embodiment, inhibition or down-regulation of IKK-gamma or PKR with the nucleic acid molecule of the instant invention is greater in the presence of the nucleic acid molecule than in its absence.
  • By “up-regulate” is meant that the expression of the gene, or level of RNAs or equivalent RNAs encoding one or more protein subunits, or activity of one or more protein subunits, such as IKK-gamma or PKR subunit(s), is greater than that observed in the absence of the nucleic acid molecules of the invention. For example, the expression of a gene, such as IKK-gamma or PKR gene, can be increased in order to treat, prevent, ameliorate, or modulate a pathological condition caused or exacerbated by an absence or low level of gene expression.
  • By “modulate” is meant that the expression of the gene, or level of RNAs or equivalent RNAs encoding one or more protein subunits, or activity of one or more protein subunit(s) is up-regulated or down-regulated, such that the expression, level, or activity is greater than or less than that observed in the absence of the nucleic acid molecules of the invention.
  • By “enzymatic nucleic acid molecule” it is meant a nucleic acid molecule which has complementarity in a substrate binding region to a specified gene target, and also has an enzymatic activity which is active to specifically cleave target RNA. That is, the enzymatic nucleic acid molecule is able to intermolecularly cleave RNA and thereby inactivate a target RNA molecule. These complementary regions allow sufficient hybridization of the enzymatic nucleic acid molecule to the target RNA and thus permit cleavage. One hundred percent complementarity is preferred, but complementarity as low as 50-75% can also be useful in this invention (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al., 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). The nucleic acids can be modified at the base, sugar, and/or phosphate groups. The term enzymatic nucleic acid is used interchangeably with phrases such as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA, aptazyme or aptamer-binding ribozyme, regulatable ribozyme, catalytic oligonucleotides, nucleozyme, DNAzyme, RNA enzyme, endoribonuclease, endonuclease, minizyme, leadzyme, oligozyme or DNA enzyme. All of these terminologies describe nucleic acid molecules with enzymatic activity. The specific enzymatic nucleic acid molecules described in the instant application are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site which is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving and/or ligation activity to the molecule (Cech et al., U.S. Pat. No. 4,987,071; Cech et al., 1988, 260 JAMA 3030).
  • Several varieties of enzymatic RNAs are known presently. Each can catalyze the hydrolysis of RNA phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological conditions. Table I summarizes some of the characteristics of these ribozymes. In general, enzymatic nucleic acids act by first binding to a target RNA. Such binding occurs through the target binding portion of a enzymatic nucleic acid which is held in close proximity to an enzymatic portion of the molecule that acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds a target RNA through complementary base-pairing, and once bound to the correct site, acts enzymatically to cut the target RNA. Strategic cleavage of such a target RNA will destroy its ability to direct synthesis of an encoded protein. After an enzymatic nucleic acid has bound and cleaved its RNA target, it is released from that RNA to search for another target and can repeatedly bind and cleave new targets. Thus, a single ribozyme molecule is able to cleave many molecules of target RNA. In addition, the ribozyme is a highly specific inhibitor of gene expression, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can completely eliminate catalytic activity of a ribozyme.
  • By “nucleic acid molecule” as used herein is meant a molecule having nucleotides. The nucleic acid can be single, double, or multiple stranded and can comprise modified or unmodified nucleotides or non-nucleotides or various mixtures and combinations thereof.
  • By “enzymatic portion” or “catalytic domain” is meant that portion/region of the enzymatic nucleic acid molecule essential for cleavage of a nucleic acid substrate (for example see FIGS. 1-4).
  • By “substrate binding arm” or “substrate binding domain” is meant that portion/region of a enzymatic nucleic acid which is able to interact, for example via complementarity (i.e., able to base-pair with), with a portion of its substrate. Preferably, such complementarity is 100%, but can be less if desired. For example, as few as 10 bases out of 14 can be base-paired (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al., 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). Examples of such arms are shown generally in FIGS. 1-4. That is, these arms contain sequences within a enzymatic nucleic acid which are intended to bring enzymatic nucleic acid and target RNA together through complementary base-pairing interactions. The enzymatic nucleic acid of the invention can have binding arms that are contiguous or non-contiguous and can be of varying lengths. The length of the binding arm(s) are preferably greater than or equal to three nucleotides and of sufficient length to stably interact with the target RNA; preferably 12-100 nucleotides; more preferably 14-24 nucleotides long (see for example Werner and Uhlenbeck, supra; Hamman et al., supra; Hampel et al., EP0360257; Berzal-Herranz et al., 1993, EMBO J., 12, 2567-73). If two binding arms are chosen, the design is such that the length of the binding arms are symmetrical (i.e., each of the binding arms is of the same length; e.g., five and five nucleotides, or six and six nucleotides, or seven and seven nucleotides long) or asymmetrical (i.e., the binding arms are of different length; e.g., six and three nucleotides; three and six nucleotides long; four and five nucleotides long; four and six nucleotides long; four and seven nucleotides long; and the like).
  • By “Inozyme” or “NCH” motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as NCH Rz in FIG. 1. Inozymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet NCH/, where N is a nucleotide, C is cytidine and H is adenosine, uridine or cytidine, and/represents the cleavage site. H is used interchangeably with X. Inozymes can also possess endonuclease activity to cleave RNA substrates having a cleavage triplet NCN/, where N is a nucleotide, C is cytidine, and/represents the cleavage site. “I” in FIG. 1 represents an Inosine nucleotide, preferably a ribo-Inosine or xylo-Inosine nucleoside.
  • By “G-cleaver” motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as G-cleaver Rz in FIG. 1. G-cleavers possess endonuclease activity to cleave RNA substrates having a cleavage triplet NYN/, where N is a nucleotide, Y is uridine or cytidine and/represents the cleavage site. G-cleavers can be chemically modified as is generally shown in FIG. 1.
  • By “amberzyme” motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described in FIG. 2. Amberzymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet NG/N, where N is a nucleotide, G is guanosine, and/represents the cleavage site. Amberzymes can be chemically modified to increase nuclease stability through substitutions as are generally shown in FIG. 2. In addition, differing nucleoside and/or non-nucleoside linkers can be used to substitute the 5′-gaaa-3′ loops shown in the figure. Amberzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2′-OH) group within its own nucleic acid sequence for activity.
  • By “zinzyme” motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described in FIG. 3. Zinzymes possess endonuclease activity to cleave RNA substrates having a cleavage triplet including but not limited to YG/Y, where Y is uridine or cytidine, and G is guanosine and/represents the cleavage site. Zinzymes can be chemically modified to increase nuclease stability through substitutions as are generally shown in FIG. 3, including substituting 2′-O-methyl guanosine nucleotides for guanosine nucleotides. In addition, differing nucleotide and/or non-nucleotide linkers can be used to substitute the 5′-gaaa-2′ loop shown in the figure. Zinzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2′-OH) group within its own nucleic acid sequence for activity.
  • By ‘DNAzyme’ is meant, an enzymatic nucleic acid molecule that does not require the presence of a 2′-OH group within its own nucleic acid sequence for activity. In particular embodiments the enzymatic nucleic acid molecule can have an attached linker(s) or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2′-OH groups. DNAzymes can be synthesized chemically or expressed endogenously in vivo, by means of a single stranded DNA vector or equivalent thereof. An example of a DNAzyme is shown in FIG. 4 and is generally reviewed in Usman et al., U.S. Pat. No. 6,159,714; Chartrand et al., 1995, NAR 23, 4092; Breaker et al., 1995, Chem. Bio. 2, 655; Santoro et al., 1997, PNAS 94, 4262; Breaker, 1999, Nature Biotechnology, 17, 422-423; and Santoro et. al., 2000, J. Am. Chem. Soc., 122, 2433-39. Additional DNAzyme motifs can be selected for using techniques similar to those described in these references, and hence, are within the scope of the present invention.
  • By “sufficient length” is meant an oligonucleotide of greater than or equal to 3 nucleotides that is of a length great enough to provide the intended function under the expected condition. For example, for binding arms of enzymatic nucleic acid “sufficient length” means that the binding arm sequence is long enough to provide stable binding to a target site under the expected binding conditions. Preferably, the binding arms are not so long as to prevent useful turnover of the nucleic acid molecule.
  • By “stably interact” is meant interaction of the oligonucleotides with target nucleic acid (e.g., by forming hydrogen bonds with complementary nucleotides in the target under physiological conditions) that is sufficient to the intended purpose (e.g., cleavage of target RNA by an enzyme).
  • By “equivalent” or “related” RNA to IKK-gamma is meant to include those naturally occurring RNA molecules having homology (partial or complete) to IKK-gamma proteins or encoding for proteins with similar function as IKK-gamma proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites. The equivalent RNA sequence also includes in addition to the coding region, regions such as 5′-untranslated region, 3′-untranslated region, introns, intron-exon junction and the like.
  • By “equivalent” or “related” RNA to PKR is meant to include those naturally occurring RNA molecules having homology (partial or complete) to PKR proteins or encoding for proteins with similar function as PKR proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites. The equivalent RNA sequence also includes in addition to the coding region, regions such as 5′-untranslated region, 3′-untranslated region, introns, intron-exon junction and the like.
  • By “homology” is meant the nucleotide sequence of two or more nucleic acid molecules is partially or completely identical.
  • By “antisense nucleic acid”, it is meant a non-enzymatic nucleic acid molecule that binds to target RNA by means of RNA-RNA or RNA-DNA or RNA-PNA (protein nucleic acid; Egholm et al., 1993 Nature 365, 566) interactions and alters the activity of the target RNA (for a review, see Stein and Cheng, 1993 Science 261, 1004 and Woolf et al., U.S. Pat. No. 5,849,902). Typically, antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop. Thus, the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both. For a review of current antisense strategies, see Schmajuk et al., 1999, J. Biol. Chem., 274, 21783-21789, Delihas et al., 1997, Nature, 15, 751-753, Stein et al., 1997, Antisense N. A. Drug Dev., 7, 151, Crooke, 2000, Methods Enzymol., 313, 3-45; Crooke, 1998, Biotech. Genet. Eng. Rev., 15, 121-157, Crooke, 1997, Ad. Pharmacol., 40, 1-49. In addition, antisense DNA can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex. The antisense oligonucleotides can comprise one or more RNAse H activating region, which is capable of activating RNAse H cleavage of a target RNA. Antisense DNA can be synthesized chemically or expressed via the use of a single stranded DNA expression vector or equivalent thereof.
  • By “RNase H activating region” is meant a region (generally greater than or equal to 4-25 nucleotides in length, preferably from 5-11 nucleotides in length) of a nucleic acid molecule capable of binding to a target RNA to form a non-covalent complex that is recognized by cellular RNase H enzyme (see for example Arrow et al., U.S. Pat. No. 5,849,902; Arrow et al., U.S. Pat. No. 5,989,912). The RNase H enzyme binds to the nucleic acid molecule-target RNA complex and cleaves the target RNA sequence. The RNase H activating region comprises, for example, phosphodiester, phosphorothioate (preferably at least four of the nucleotides are phosphorothiote substitutions; more specifically, 4-11 of the nucleotides are phosphorothiote substitutions); phosphorodithioate, 5′-thiophosphate, or methylphosphonate backbone chemistry or a combination thereof. In addition to one or more backbone chemistries described above, the RNase H activating region can also comprise a variety of sugar chemistries. For example, the RNase H activating region can comprise deoxyribose, arabino, fluoroarabino or a combination thereof, nucleotide sugar chemistry. Those skilled in the art will recognize that the foregoing are non-limiting examples and that any combination of phosphate, sugar and base chemistry of a nucleic acid that supports the activity of RNase H enzyme is within the scope of the definition of the RNase H activating region and the instant invention.
  • By “2-5A chimera” is meant an oligonucleotide, for example an antisense nucleic acid molecule or enzymatic nucleic acid molecule, containing a 5′-phosphorylated 2′-5′-linked adenylate residue. These chimeras bind to target RNA in a sequence-specific manner and activate a cellular 2-5A-dependent ribonuclease which, in turn, cleaves the target RNA (Torrence et al., 1993 Proc. Natl. Acad. Sci. USA 90, 1300; Silverman et al., 2000, Methods Enzymol., 313, 522-533; Player and Torrence, 1998, Pharmacol. Ther., 78, 55-113).
  • By “triplex forming oligonucleotides” or “triplex oligonucleotide” is meant an oligonucleotide that can bind to a double-stranded DNA in a sequence-specific manner to form a triple-strand helix. Formation of such triple helix structure has been shown to inhibit transcription of the targeted gene (Duval-Valentin et al., 1992 Proc. Natl. Acad. Sci. USA 89, 504; Fox, 2000, Curr. Med. Chem., 7, 17-37; Praseuth et. al., 2000, Biochim. Biophys. Acta, 1489, 181-206).
  • By “double stranded RNA” or “dsRNA” is meant a double stranded RNA that matches a predetermined gene sequence that is capable of activating cellular enzymes that degrade the corresponding messenger RNA transcripts of the gene. These dsRNAs are referred to as short intervening RNA (siRNA) and can be used to inhibit gene expression (see for example Elbashir et al., 2001, Nature, 411, 494-498; and Bass, 2001, Nature, 411, 428-429). The term “double stranded RNA” or “dsRNA” as used herein refers to a double stranded RNA molecule capable of RNA interference “RNAi”, including short interfering RNA “siRNA” see for example Bass, 2001, Nature, 411, 428-429; Elbashir et al., 2001, Nature, 411, 494-498; and Kreutzer et al., International PCT Publication No. WO 00/44895; Zernicka-Goetz et al., International PCT Publication No. WO 01/36646; Fire, International PCT Publication No. WO 99/32619; Plaetinck et al., International PCT Publication No. WO 00/01846; Mello and Fire, International PCT Publication No. WO 01/29058; Deschamps-Depaillette, International PCT Publication No. WO 99/07409; and Li et al., International PCT Publication No. WO 00/44914.
  • By “gene” it is meant a nucleic acid that encodes an RNA, for example, nucleic acid sequences including but not limited to structural genes encoding a polypeptide.
  • “Complementarity” refers to the ability of a nucleic acid to form hydrogen bond(s) with another RNA sequence by either traditional Watson-Crick or other non-traditional types. In reference to the nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its target or complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., enzymatic nucleic acid cleavage, antisense or triple helix inhibition. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al., 1987, CSH Symp. Quant. Biol. LII pp. 123-133; Frier et al., 1986, Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc. 109:3783-3785). A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementary). “Perfectly complementary” means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.
  • By “RNA” is meant a molecule comprising at least one ribonucleotide residue. By “ribonucleotide” or “2′-OH” is meant a nucleotide with a hydroxyl group at the 2′ position of a β-D-ribo-furanose moiety.
  • By “decoy” is meant a nucleic acid molecule, for example RNA or DNA, or aptamer that is designed to preferentially bind to a predetermined ligand. Such binding can result in the inhibition or activation of a target molecule. The decoy or aptamer can compete with a naturally occurring binding target for the binding of a specific ligand. For example, it has been shown that over-expression of HIV trans-activation response (TAR) RNA can act as a “decoy” and efficiently binds HIV tat protein, thereby preventing it from binding to TAR sequences encoded in the HIV RNA (Sullenger et al., 1990, Cell, 63, 601-608). This is but a specific example and those in the art will recognize that other embodiments can be readily generated using techniques generally known in the art, see for example Gold et al., 1995, Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000, J. Biotechnol., 74, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000, J. Biotechnol., 74, 27; Hermann and Patel, 2000, Science, 287, 820; and Jayasena, 1999, Clinical Chemistry, 45, 1628. Similarly, a decoys can be designed to bind to IKK-gamma or PKR and block the binding of IKK-gamma or PKR or a decoy can be designed to bind to IKK-gamma or PKR and prevent interaction with the IKK-gamma or PKR protein.
  • By “aptamer” or “nucleic acid aptamer” as used herein is meant a nucleic acid molecule that binds specifically to a target molecule wherein the nucleic acid molecule has sequence that is distinct from sequence recognized by the target molecule in its natural setting. Alternately, an aptamer can be a nucleic acid molecule that binds to a target molecule where the target molecule does not naturally bind to a nucleic acid. The target molecule can be any molecule of interest. For example, the aptamer can be used to bind to a ligand binding domain of a protein, thereby preventing interaction of the naturally occurring ligand with the protein. Similarly, the nucleic acid molecules of the instant invention can bind to IKK-gamma or PKR to block activity of the respective proteins. This is a non-limiting example and those in the art will recognize that other embodiments can be readily generated using techniques generally known in the art, see for example Gold et al., U.S. Pat. Nos. 5,475,096 and 5,270,163; Gold et al., 1995, Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000, J. Biotechnol., 74, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000, J. Biotechnol., 74, 27; Hermann and Patel, 2000, Science, 287, 820; and Jayasena, 1999, Clinical Chemistry, 45, 1628.
  • The enzymatic nucleic acid molecule, antisense nucleic acid or other nucleic acid molecules of the invention that down regulate IKK-gamma or PKR gene expression represent a therapeutic approach to treat a variety of inflammatory-related diseases and conditions, including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, incontinentia pigmenti, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other inflammatory disease or condition which respond to the modulation of IKK-gamma or PKR function.
  • The enzymatic nucleic acid molecule, antisense nucleic acid or other nucleic acid molecules of the invention that down regulate IKK-gamma or PKR gene expression also represent a therapeutic approach to treat a variety of cancers, including but not limited to breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, and/or other cancers which respond to the modulation of IKK-gamma or PKR function.
  • In one embodiment of the inventions described herein, the enzymatic nucleic acid molecule is formed in a hammerhead or hairpin motif, but can also be formed in the motif of a hepatitis delta virus, group I intron, group II intron or RNase P RNA (in association with an RNA guide sequence), Neurospora VS RNA, DNAzymes, NCH cleaving motifs, or G-cleavers. Examples of such hammerhead motifs are described by Dreyfus, supra, Rossi et al., 1992, AIDS Research and Human Retroviruses 8, 183; of hairpin motifs by Hampel et al., EP0360257, Hampel and Tritz, 1989 Biochemistry 28, 4929, Feldstein et al., 1989, Gene 82, 53, Haseloff and Gerlach, 1989, Gene, 82, 43, and Hampel et al., 1990 Nucleic Acids Res. 18, 299; Chowrira & McSwiggen, U.S. Pat. No. 5,631,359; of the hepatitis delta virus motif is described by Perrotta and Been, 1992 Biochemistry 31, 16; of the RNase P motif by Guerrier-Takada et al., 1983 Cell 35, 849; Forster and Altman, 1990, Science 249, 783; Li and Altman, 1996, Nucleic Acids Res. 24, 835; Neurospora VS RNA ribozyme motif is described by Collins (Saville and Collins, 1990 Cell 61, 685-696; Saville and Collins, 1991 Proc. Natl. Acad. Sci. USA 88, 8826-8830; Collins and Olive, 1993 Biochemistry 32, 2795-2799; Guo and Collins, 1995, EMBO. J. 14, 363); Group II introns are described by Griffin et al., 1995, Chem. Biol. 2, 761; Michels and Pyle, 1995, Biochemistry 34, 2965; Pyle et al., International PCT Publication No. WO 96/22689; of the Group I intron by Cech et al., U.S. Pat. No. 4,987,071 and of DNAzymes by Usman et al., International PCT Publication No. WO 95/11304; Chartrand et al., 1995, NAR 23, 4092; Breaker et al., 1995, Chem. Bio. 2, 655; Santoro et al., 1997, PNAS 94, 4262, and Beigelman et al., International PCT publication No. WO 99/55857. NCH cleaving motifs are described in Ludwig & Sproat, International PCT Publication No. WO 98/58058; and G-cleavers are described in Kore et al., 1998, Nucleic Acids Research 26, 4116-4120 and Eckstein et al., International PCT Publication No. WO 99/16871. Additional motifs such as the Aptazyme (Breaker et al., WO 98/43993), Amberzyme (Class I motif; FIG. 2; Beigelman et al., U.S. Ser. No. 09/301,511) and Zinzyme (FIG. 3) (Beigelman et al., U.S. Ser. No. 09/301,511), all included by reference herein including drawings, can also be used in the present invention. These specific motifs or configurations are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site which is complementary to one or more of the target gene RNA regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart an RNA cleaving activity to the molecule (Cech et al., U.S. Pat. No. 4,987,071).
  • In one embodiment of the present invention, a nucleic acid molecule of the instant invention can be between about 10 and 100 nucleotides in length. Exemplary enzymatic nucleic acid molecules of the invention are shown in Tables III to VII. For example, enzymatic nucleic acid molecules of the invention are preferably between about 15 and 50 nucleotides in length, more preferably between about 25 and 40 nucleotides in length, e.g., 34, 36, or 38 nucleotides in length (for example see Jarvis et al., 1996, J. Biol. Chem., 271, 29107-29112). Exemplary DNAzymes of the invention are preferably between about 15 and 40 nucleotides in length, more preferably between about 25 and 35 nucleotides in length, e.g., 29, 30, 31, or 32 nucleotides in length (see for example Santoro et al., 1998, Biochemistry, 37, 13330-13342; Chartrand et al., 1995, Nucleic Acids Research, 23, 4092-4096). Exemplary antisense molecules of the invention are preferably between about 15 and 75 nucleotides in length, more preferably between about 20 and 35 nucleotides in length, e.g., 25, 26, 27, or 28 nucleotides in length (see for example Woolf et al., 1992, PNAS, 89, 7305-7309; Milner et al., 1997, Nature Biotechnology, 15, 537-541). Exemplary triplex forming oligonucleotide molecules of the invention are preferably between about 10 and 40 nucleotides in length, more preferably between about 12 and 25 nucleotides in length, e.g., 18, 19, 20, or 21 nucleotides in length (see for example Maher et al., 1990, Biochemistry, 29, 8820-8826; Strobel and Dervan, 1990, Science, 249, 73-75). Those skilled in the art will recognize that all that is required is that the nucleic acid molecule be of sufficient length and suitable conformation for the nucleic acid molecule to interact with its target and/or catalyze a reaction contemplated herein. The length of the nucleic acid molecules of the instant invention are not limiting within the general limits stated.
  • Preferably, a nucleic acid molecule that modulates, for example, down-regulates IKK-gamma or PKR expression comprises between 12 and 100 bases complementary to a RNA molecule of IKK-gamma or PKR. Even more preferably, a nucleic acid molecule that modulates, for example IKK-gamma or PKR expression comprises between 14 and 24 bases complementary to a RNA molecule of IKK-gamma or PKR.
  • The invention provides a method for producing a class of nucleic acid-based gene modulating agents which exhibit a high degree of specificity for the RNA of a desired target. For example, the enzymatic nucleic acid molecule is preferably targeted to a highly conserved sequence region of target RNAs encoding IKK-gamma or PKR (specifically IKK-gamma or PKR genes) such that specific treatment of a disease or condition can be provided with either one or several nucleic acid molecules of the invention. Such nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required. Alternatively, the nucleic acid molecules (e.g., ribozymes and antisense) can be expressed from DNA and/or RNA vectors that are delivered to specific cells.
  • As used in herein “cell” is used in its usual biological sense, and does not refer to an entire multicellular organism. The cell can, for example, be in vitro, e.g., in cell culture, or present in a multicellular organism, including, e.g., birds, plants and mammals such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats. The cell can be prokaryotic (e.g., bacterial cell) or eukaryotic (e.g., mammalian or plant cell).
  • By “IKK-gamma proteins” is meant, a peptide or protein comprising a IKK-gamma or NEMO/IKKAP1 component of the IKK complex, for example a regulatory IKK subunit involved in the assembly of the high molecular weight IKK complex and/or induction of NFKB.
  • By “PKR proteins” is meant, a peptide or protein comprising a protein kinase PKR activity, for example the activation of NFKB.
  • By “highly conserved sequence region” is meant, a nucleotide sequence of one or more regions in a target gene does not vary significantly from one generation to the other or from one biological system to the other.
  • Nucleic acid-based inhibitors of IKK-gamma or PKR function are useful for the prevention and/or treatment of cancers and cancerous conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, and any other diseases or conditions that are related to or will respond to the levels of IKK-gamma or PKR in a cell or tissue, alone or in combination with other therapies.
  • Nucleic acid-based inhibitors of IKK-gamma or PKR function are also useful for the prevention and/or treatment of inflammatory related diseases and conditions, including but not limited to rheumatoid arthritis, restenosis, asthma, Crohn's disease, incontinentia pigmenti, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other inflammatory disease or condition which respond to the modulation of IKK-gamma or PKR function.
  • The nucleic acid-based inhibitors of the invention are added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues. The nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through injection or infusion pump, with or without their incorporation in biopolymers. In preferred embodiments, the enzymatic nucleic acid inhibitors comprise sequences, which are complementary to the substrate sequences in Tables III to XIII. Examples of such enzymatic nucleic acid molecules also are shown in Tables III to XIII. Examples of such enzymatic nucleic acid molecules consist essentially of sequences defined in these tables.
  • In another embodiment, the invention features antisense nucleic acid molecules and 2-5A chimera including sequences complementary to the substrate sequences shown in Tables III to XIII. Such nucleic acid molecules can include sequences as shown for the binding arms of the enzymatic nucleic acid molecules in Tables III to XIII. Similarly, triplex molecules can be provided targeted to the corresponding DNA target regions, and containing the DNA equivalent of a target sequence or a sequence complementary to the specified target (substrate) sequence. Typically, antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop. Thus, the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both.
  • By “consists essentially of” is meant that the active nucleic acid molecule of the invention, for example, an enzymatic nucleic acid molecule, contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind RNA such that cleavage at the target site occurs. Other sequences can be present which do not interfere with such cleavage. Thus, a core region can, for example, include one or more loop, stem-loop structure, or linker which does not prevent enzymatic activity. Thus, the underlined regions in the sequences in Tables III, IV, VIII, and IX can be such a loop, stem-loop, nucleotide linker, and/or non-nucleotide linker and can be represented generally as sequence “X”. For example, a core sequence for a hammerhead enzymatic nucleic acid can comprise a conserved sequence, such as 5′-CUGAUGAG-3′ and 5′-CGAA-3′ connected by “X”, where X is 5′-GCCGUUAGGC-3′ (SEQ ID NO 8002), or any other Stem II region known in the art, or a nucleotide and/or non-nucleotide linker. Similarly, for other nucleic acid molecules of the instant invention, such as Inozyme, G-cleaver, amberzyme, zinzyme, DNAzyme, antisense, 2-5A antisense, triplex forming nucleic acid, and decoy nucleic acids, other sequences or non-nucleotide linkers can be present that do not interfere with the function of the nucleic acid molecule.
  • Sequence X can be a linker of ≧2 nucleotides in length, preferably 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 26, 30, where the nucleotides can preferably be internally base-paired to form a stem of preferably ≧2 base pairs. In yet another embodiment, the nucleotide linker X can be a nucleic acid aptamer, such as an ATP aptamer, HIV Rev aptamer (RRE), HIV Tat aptamer (TAR) and others (for a review see Gold et al., 1995, Annu. Rev. Biochem., 64, 763; and Szostak & Ellington, 1993, in The RNA World, ed. Gesteland and Atkins, pp. 511, CSH Laboratory Press). A “nucleic acid aptamer” as used herein is meant to indicate a nucleic acid sequence capable of interacting with a ligand. The ligand can be any natural or a synthetic molecule, including but not limited to a resin, metabolites, nucleosides, nucleotides, drugs, toxins, transition state analogs, peptides, lipids, proteins, amino acids, nucleic acid molecules, hormones, carbohydrates, receptors, cells, viruses, bacteria and others.
  • In yet another embodiment, alternatively or in addition, sequence X can be a non-nucleotide linker. Non-nucleotides as can include abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, or polyhydrocarbon compounds. Specific examples include those described by Seela and Kaiser, Nucleic Acids Res. 1990, 18:6353 and Nucleic Acids Res. 1987, 15:3113; Cload and Schepartz, J. Am. Chem. Soc. 1991, 113:6324; Richardson and Schepartz, J. Am. Chem. Soc. 1991, 113:5109; Ma et al., Nucleic Acids Res. 1993, 21:2585 and Biochemistry 1993, 32:1751; Durand et al., Nucleic Acids Res. 1990, 18:6353; McCurdy et al., Nucleosides & Nucleotides 1991, 10:287; Jschke et al., Tetrahedron Lett. 1993, 34:301; Ono et al., Biochemistry 1991, 30:9914; Arnold et al., International Publication No. WO 89/02439; Usman et al., International Publication No. WO 95/06731; Dudycz et al., International Publication No. WO 95/11910 and Ferentz and Verdine, J. Am. Chem. Soc. 1991, 113:4000, all hereby incorporated by reference herein. A “non-nucleotide” further means any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound can be abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine. Thus, in a preferred embodiment, the invention features an enzymatic nucleic acid molecule having one or more non-nucleotide moieties, and having enzymatic activity to cleave an RNA or DNA molecule.
  • In another aspect of the invention, enzymatic nucleic acid molecules or antisense molecules that interact with target RNA molecules and down-regulate IKK-gamma or PKR (specifically IKK-gamma or PKR gene) activity are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Enzymatic nucleic acid molecule or antisense expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the enzymatic nucleic acid molecules or antisense are delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of enzymatic nucleic acid molecules or antisense. Such vectors can be repeatedly administered as necessary. Once expressed, the enzymatic nucleic acid molecules or antisense bind to the target RNA and down-regulate its function or expression. Delivery of enzymatic nucleic acid molecule or antisense expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient or subject followed by reintroduction into the patient or subject, or by any other means that would allow for introduction into the desired target cell. Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector.
  • By “vectors” is meant any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid.
  • By “subject” is meant an organism, which is a donor or recipient of explanted cells or the cells themselves. “subject” also refers to an organism to which the nucleic acid molecules of the invention can be administered. Preferably, a subject is a mammal or mammalian cells. More preferably, a subject is a human or human cells.
  • By “enhanced enzymatic activity” is meant to include activity measured in cells and/or in vivo where the activity is a reflection of both the catalytic activity and the stability of the nucleic acid molecules of the invention. In this invention, the product of these properties can be increased in vivo compared to an all RNA enzymatic nucleic acid or all DNA enzyme. In some cases, the activity or stability of the nucleic acid molecule can be decreased (i.e., less than ten-fold), but the overall activity of the nucleic acid molecule is enhanced, in vivo.
  • The nucleic acid molecules of the instant invention, individually, or in combination or in conjunction with other drugs, can be used to treat diseases or conditions discussed above. For example, to treat a disease or condition associated with the levels of IKK-gamma or PKR, the subject can be treated, or other appropriate cells can be treated, as is evident to those skilled in the art, individually or in combination with one or more drugs under conditions suitable for the treatment.
  • In a further embodiment, the described nucleic acid molecules, such as antisense or ribozymes, can be used in combination with other known treatments to treat conditions or diseases discussed above. For example, the described molecules can be used in combination with one or more known therapeutic agents to treat breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, incontinentia pigmenti, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, and any other cancerous disease or inflammatory disease or condition which respond to the modulation of IKK-gamma or PKR expression.
  • In another embodiment, the invention features nucleic acid-based inhibitors (e.g., enzymatic nucleic acid molecules (eg; ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, dsRNA, antisense nucleic acids containing RNA cleaving chemical groups) and methods for their use to down regulate or inhibit the expression of genes (e.g., IKK-gamma or PKR) capable of progression and/or maintenance of cancer, inflammatory diseases, and/or other disease states which respond to the modulation of IKK-gamma or PKR expression.
  • By “comprising” is meant including, but not limited to, whatever follows the word “comprising”. Thus, use of the term “comprising” indicates that the listed elements are required or mandatory, but that other elements are optional and can or can not be present. By “consisting of” is meant including, and limited to, whatever follows the phrase “consisting of”. Thus, the phrase “consisting of” indicates that the listed elements are required or mandatory, and that no other elements can be present.
  • Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.
  • Mechanism of Action of Nucleic Acid Molecules of the Invention as Proposed in the Art
  • Antisense: Antisense molecules can be modified or unmodified RNA, DNA, or mixed polymer oligonucleotides and primarily function by specifically binding to matching sequences resulting in inhibition of peptide synthesis (Wu-Pong, November 1994, BioPharm, 20-33). The antisense oligonucleotide binds to target RNA by Watson Crick base-pairing and blocks gene expression by preventing ribosomal translation of the bound sequences either by steric blocking or by activating RNase H enzyme. Antisense molecules can also alter protein synthesis by interfering with RNA processing or transport from the nucleus into the cytoplasm (Mukhopadhyay & Roth, 1996, Crit. Rev. in Oncogenesis 7, 151-190).
  • In addition, binding of single stranded DNA to RNA can result in nuclease degradation of the heteroduplex (Wu-Pong, supra; Crooke, supra). To date, the only backbone modified DNA chemistry which act as substrates for RNase H are phosphorothioates, phosphorodithioates, and borontrifluoridates. Recently it has been reported that 2′-arabino and 2′-fluoro arabino-containing oligos can also activate RNase H activity.
  • A number of antisense molecules have been described that utilize novel configurations of chemically modified nucleotides, secondary structure, and/or RNase H substrate domains (Woolf et al., International PCT Publication No. WO 98/13526; Thompson et al., International PCT Publication No. WO 99/54459; Hartmann et al., U.S. Ser. No. 60/101,174 which was filed on Sep. 21, 1998) all of these are incorporated by reference herein in their entirety.
  • In addition, antisense deoxyoligoribonucleotides can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex. Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector or equivalents and variations thereof.
  • Enzymatic Nucleic Acid: Several varieties of enzymatic RNAs are presently known. In addition, several in vitro selection (evolution) strategies (Orgel, 1979, Proc. R. Soc. London, B 205, 435) have been used to evolve new nucleic acid catalysts capable of catalyzing cleavage and ligation of phosphodiester linkages (Joyce, 1989, Gene, 82, 83-87; Beaudry et al., 1992, Science 257, 635-641; Joyce, 1992, Scientific American 267, 90-97; Breaker et al., 1994, TIBTECH 12, 268; Bartel et al., 1993, Science 261:1411-1418; Szostak, 1993, TIBS 17, 89-93; Kumar et al, 1995, FASEB J., 9, 1183; Breaker, 1996, Curr. Op. Biotech., 7, 442; Santoro et al., 1997, Proc. Natl. Acad. Sci., 94, 4262; Tang et al., 1997, RNA 3, 914; Nakacane & Eckstein, 1994, supra; Long & Uhlenbeck, 1994, supra; Ishizaka et al., 1995, supra; Vaish et al., 1997, Biochemistry 36, 6495; all of these are incorporated by reference herein). Each can catalyze a series of reactions including the hydrolysis of phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological conditions.
  • Nucleic acid molecules of this invention will block to some extent IKK-gamma or PKR and/or IKK-gamma or PKR protein expression and can be used to treat disease or diagnose disease associated with the levels of IKK-gamma or PKR and/or IKK-gamma or PKR. Enzymatic nucleic acid sequences targeting IKK-gamma or PKR RNA and sequences that can be targeted with nucleic acid molecules of the invention to down-regulate IKK-gamma or PKR expression are shown in Tables III to XIII.
  • The enzymatic nature of an enzymatic nucleic acid molecule can allow the concentration of enzymatic nucleic acid molecule necessary to affect a therapeutic treatment to be lower. This reflects the ability of the enzymatic nucleic acid molecule to act enzymatically. Thus, a single enzymatic nucleic acid molecule is able to cleave many molecules of target RNA. In addition, the enzymatic nucleic acid molecule is a highly specific inhibitor, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can be chosen to greatly attenuate the catalytic activity of a enzymatic nucleic acid molecule.
  • Nucleic acid molecules having an endonuclease enzymatic activity are able to repeatedly cleave other separate RNA molecules in a nucleotide base sequence-specific manner. Such enzymatic nucleic acid molecules can be targeted to virtually any RNA transcript, and achieve efficient cleavage in vitro (Zaug et al., 324, Nature 429 1986; Uhlenbeck, 1987 Nature 328, 596; Kim et al., 84 Proc. Natl. Acad. Sci. USA 8788, 1987; Dreyfus, 1988, Einstein Quart. J. Bio. Med., 6, 92; Haseloff and Gerlach, 334 Nature 585, 1988; Cech, 260 JAMA 3030, 1988; and Jefferies et al., 17 Nucleic Acids Research 1371, 1989; Santoro et al., 1997 supra).
  • Because of their sequence specificity, trans-cleaving enzymatic nucleic acid molecules can be used as therapeutic agents for human disease (Usman & McSwiggen, 1995 Ann. Rep. Med. Chem. 30, 285-294; Christoffersen and Marr, 1995 J. Med. Chem. 38, 2023-2037). Enzymatic nucleic acid molecules can be designed to cleave specific RNA targets within the background of cellular RNA. Such a cleavage event renders the RNA non-functional and abrogates protein expression from that RNA. In this manner, synthesis of a protein associated with a disease state can be selectively inhibited (Warashina et al., 1999, Chemistry and Biology, 6, 237-250).
  • Enzymatic nucleic acid molecules of the invention that are allosterically regulated (“allozymes”) can be used to modulate IKK-gamma or PKR expression. These allosteric enzymatic nucleic acids or allozymes (see for example George et al., U.S. Pat. Nos. 5,834,186 and 5,741,679, Shih et al., U.S. Pat. No. 5,589,332, Nathan et al., U.S. Pat. No. 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al., International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al., International PCT publication No. WO 99/29842) are designed to respond to a signaling agent, for example, mutant IKK-gamma protein, wild-type IKK-gamma protein, mutant IKK-gamma RNA, wild-type IKK-gamma RNA, other proteins and/or RNAs involved in IKK-gamma activity, compounds, metals, polymers, molecules and/or drugs that are targeted to IKK-gamma or an IKK subunit, such as IKK-alpha or IKK-beta, expressing cells etc., which in turn modulates the activity of the enzymatic nucleic acid molecule. In response to interaction with a predetermined signaling agent, the allosteric enzymatic nucleic acid molecule's activity is activated or inhibited such that the expression of a particular target is selectively down-regulated. The target can comprise wild-type IKK-gamma, mutant IKK-gamma, a component of IKK-gamma, and/or a predetermined cellular component that modulates IKK-gamma activity. In a specific example, allosteric enzymatic nucleic acid molecules that are activated by interaction with a RNA encoding a mutant IKK-gamma protein are used as therapeutic agents in vivo. The presence of RNA encoding the mutant IKK-gamma activates the allosteric enzymatic nucleic acid molecule that subsequently cleaves the RNA encoding a mutant IKK-gamma protein resulting in the inhibition of mutant IKK-gamma protein expression. In this manner, cells that express the mutant form of the IKK-gamma protein are selectively targeted. Such an approach, can be used to treat, for example, incontinentia pigmenti.
  • In another non-limiting example, an allozyme can be activated by a IKK-gamma or PKR protein, peptide, or mutant polypeptide that caused the allozyme to inhibit the expression of IKK-gamma or PKR gene, by, for example, cleaving RNA encoded by IKK-gamma or PKR gene. In this non-limiting example, the allozyme acts as a decoy to inhibit the function of IKK-gamma or PKR and also inhibit the expression of IKK-gamma or PKR once activated by the IKK-gamma or PKR protein.
  • The nucleic acid molecules of the instant invention are also referred to as GeneBloc reagents, which are essentially nucleic acid molecules (eg; ribozymes, antisense) capable of down-regulating gene expression.
  • Target Sites
  • Targets for useful enzymatic nucleic acid molecules and antisense nucleic acids can be determined as disclosed in Draper et al., WO 93/23569; Sullivan et al., WO 93/23057; Thompson et al., WO 94/02595; Draper et al., WO 95/04818; McSwiggen et al., U.S. Pat. No. 5,525,468, and hereby incorporated by reference herein in totality. Other examples include the following PCT applications, which concern inactivation of expression of disease-related genes: WO 95/23225, WO 95/13380, WO 94/02595, incorporated by reference herein. Rather than repeat the guidance provided in those documents here, below are provided specific examples of such methods, not limiting to those in the art. Enzymatic nucleic acid molecules and antisense to such targets are designed as described in those applications and synthesized to be tested in vitro and in vivo, as also described. The sequences of human IKK-gamma or PKR RNAs were screened for optimal enzymatic nucleic acid and antisense target sites using a computer-folding algorithm. Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme, or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified. These sites are shown in Tables III to XIII (all sequences are 5′ to 3′ in the tables; underlined regions can be any sequence “X” or linker X, the actual sequence is not relevant here). The nucleotide base position is noted in the Tables as that site to be cleaved by the designated type of enzymatic nucleic acid molecule. While human sequences can be screened and enzymatic nucleic acid molecule and/or antisense thereafter designed, as discussed in Stinchcomb et al., WO 95/23225, mouse targeted enzymatic nucleic acid molecules can be useful to test efficacy of action of the enzymatic nucleic acid molecule and/or antisense prior to testing in humans.
  • Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified. The nucleic acid molecules are individually analyzed by computer folding (Jaeger et al., 1989 Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the sequences fold into the appropriate secondary structure. Those nucleic acid molecules with unfavorable intramolecular interactions such as between the binding arms and the catalytic core are eliminated from consideration. Varying binding arm lengths can be chosen to optimize activity.
  • Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme or G-Cleaver enzymatic nucleic acid molecule binding/cleavage sites were identified and were designed to anneal to various sites in the RNA target. The binding arms are complementary to the target site sequences described above. The nucleic acid molecules were chemically synthesized. The method of synthesis used follows the procedure for normal DNA/RNA synthesis as described below and in Usman et al., 1987 J. Am. Chem. Soc., 109, 7845; Scaringe et al., 1990 Nucleic Acids Res., 18, 5433; and Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684; Caruthers et al., 1992, Methods in Enzymology 211,3-19.
  • Synthesis of Nucleic Acid Molecules
  • Synthesis of nucleic acids greater than 100 nucleotides in length can be difficult using automated methods, and the therapeutic cost of such molecules can be prohibitive. In this invention, small nucleic acid motifs (“small refers to nucleic acid motifs less than about 100 nucleotides in length, preferably less than about 80 nucleotides in length, and more preferably less than about 50 nucleotides in length; e.g., antisense oligonucleotides, hammerhead or the NCH ribozymes) are preferably used for exogenous delivery. The simple structure of these molecules increases the ability of the nucleic acid to invade targeted regions of RNA structure. Exemplary molecules of the instant invention are chemically synthesized, and others can similarly be synthesized.
  • Oligonucleotides (eg; antisense, GeneBlocs) are synthesized using protocols known in the art as described in Caruthers et al., 1992, Methods in Enzymology 211, 3-19, Thompson et al., International PCT Publication No. WO 99/54459, Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al., 1997, Methods Mol. Bio., 74, 59, Brennan et al., 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, U.S. Pat. No. 6,001,311. All of these references are incorporated herein by reference. The synthesis of oligonucleotides makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 2.5 min coupling step for 2′-O-methylated nucleotides and a 45 sec coupling step for 2′-deoxy nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be performed on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, Calif.) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M=6.6 μmol) of 2′-O-methyl phosphoramidite and a 105-fold excess of S-ethyl tetrazole (60 μL of 0.25 M=15 μmol) can be used in each coupling cycle of 2′-O-methyl residues relative to polymer-bound 5′-hydroxyl. A 22-fold excess (40 μL of 0.11 M=4.4 μmol) of deoxy phosphoramidite and a 70-fold excess of S-ethyl tetrazole (40 μL of 0.25 M=10 μmol) can be used in each coupling cycle of deoxy residues relative to polymer-bound 5′-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); and oxidation solution is 16.9 mM I2, 49 mM pyridine, 9% water in THF (PERSEPTIVE™). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-1,2-Benzodithiol-3-one 1,1-dioxide, 0.05 M in acetonitrile) is used.
  • Deprotection of the antisense oligonucleotides is performed as follows: the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65° C. for 10 min. After cooling to −20° C., the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCN:H2O/3:1:1, vortexed and the supernatant is then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, are dried to a white powder.
  • The method of synthesis used for RNA and chemically modified RNA including certain enzymatic nucleic acid molecules follows the procedure as described in Usman et al., 1987, J. Am. Chem. Soc., 109, 7845; Scaringe et al., 1990, Nucleic Acids Res., 18, 5433; and Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684 Wincott et al., 1997, Methods Mol. Bio., 74, 59, and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 7.5 min coupling step for alkylsilyl protected nucleotides and a 2.5 min coupling step for 2′-O-methylated nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be done on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, Calif.) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M=6.6 μmol) of 2′-O-methyl phosphoramidite and a 75-fold excess of S-ethyl tetrazole (60 μL of 0.25 M=15 μmol) can be used in each coupling cycle of 2′-O-methyl residues relative to polymer-bound 5′-hydroxyl. A 66-fold excess (120 μL of 0.11 M=13.2 μmol) of alkylsilyl (ribo) protected phosphoramidite and a 150-fold excess of S-ethyl tetrazole (120 μL of 0.25 M=30 μmol) can be used in each coupling cycle of ribo residues relative to polymer-bound 5′-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution is 16.9 mM I2, 49 mM pyridine, 9% water in THF (PERSEPTIVE™). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-1,2-Benzodithiol-3-one 1,1-dioxide 0.05 M in acetonitrile) is used.
  • Deprotection of the RNA is performed using either a two-pot or one-pot protocol. For the two-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65° C. for 10 min. After cooling to −20° C., the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCN:H2O/3:1:1, vortexed and the supernatant is then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, are dried to a white powder. The base deprotected oligoribonucleotide is resuspended in anhydrous TEA/HF/NMP solution (300 μl of a solution of 1.5 mL N-methylpyrrolidinone, 750 μL TEA and 1 mL TEA.3HF to provide a 1.4 M HF concentration) and heated to 65° C. After 1.5 h, the oligomer is quenched with 1.5 M NH4HCO3.
  • Alternatively, for the one-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO: 1/1 (0.8 mL) at 65° C. for 15 min. The vial is brought to r.t. TEA.3HF (0.1 mL) is added and the vial is heated at 65° C. for 15 min. The sample is cooled at −20° C. and then quenched with 1.5 M NH4HCO3.
  • For purification of the trityl-on oligomers, the quenched NH4HCO3 solution is loaded onto a C-18 containing cartridge that had been prewashed with acetonitrile followed by 50 mM TEAA. After washing the loaded cartridge with water, the RNA is detritylated with 0.5% TFA for 13 min. The cartridge is then washed again with water, salt exchanged with 1 M NaCl and washed with water again. The oligonucleotide is then eluted with 30% acetonitrile.
  • Inactive hammerhead ribozymes or binding attenuated control (BAC) oligonucleotides can be synthesized by substituting a U for G5 and a U for A14 (numbering from Hertel, K. J., et al., 1992, Nucleic Acids Res., 20, 3252). Similarly, one or more nucleotide substitutions can be introduced in other enzymatic nucleic acid molecules to inactivate the molecule and such molecules can serve as a negative control.
  • The average stepwise coupling yields are typically >98% (Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684). Those of ordinary skill in the art will recognize that the scale of synthesis can be adapted to be larger or smaller than the example described above including but not limited to 96 well format, with the ratio of chemicals being used in the reaction adjusted accordingly.
  • Alternatively, the nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example by ligation (Moore et al., 1992, Science 256, 9923; Draper et al., International PCT publication No. WO 93/23569; Shabarova et al., 1991, Nucleic Acids Research 19, 4247; Bellon et al., 1997, Nucleosides & Nucleotides, 16, 951; Bellon et al., 1997, Bioconjugate Chem. 8, 204).
  • The nucleic acid molecules of the present invention are modified extensively to enhance stability by modification with nuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-flouro, 2′-O-methyl, 2′-H (for a review see Usman and Cedergren, 1992, TIBS 17, 34; Usman et al., 1994, Nucleic Acids Symp. Ser. 31, 163). Ribozymes are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al., Supra, the totality of which is hereby incorporated herein by reference) and are re-suspended in water.
  • The sequences of the nucleic acid molecules, including enzymatic nucleic acid molecules and antisense, that are chemically synthesized, are shown in Table XIII. The sequences of the enzymatic nucleic acid and antisense constructs that are chemically synthesized, are complementary to the Substrate sequences shown in Table XIII. Those in the art will recognize that these sequences are representative only of many more such sequences where the enzymatic portion of the ribozyme (all but the binding arms) is altered to affect activity. The enzymatic nucleic acid and antisense construct sequences listed in Tables III to XIII can be formed of ribonucleotides or other nucleotides or non-nucleotides. Such enzymatic nucleic acid molecules with enzymatic activity are equivalent to the enzymatic nucleic acid molecules described specifically in the Tables.
  • Optimizing Activity of the Nucleic Acid Molecule of the Invention.
  • Chemically synthesizing nucleic acid molecules with modifications (base, sugar and/or phosphate) that prevent their degradation by serum ribonucleases can increase their potency (see e.g., Eckstein et al., International Publication No. WO 92/07065; Perrault et al., 1990 Nature 344, 565; Pieken et al., 1991, Science 253, 314; Usman and Cedergren, 1992, Trends in Biochem. Sci. 17, 334; Usman et al., International Publication No. WO 93/15187; and Rossi et al., International Publication No. WO 91/03162; Sproat, U.S. Pat. No. 5,334,711; and Burgin et al., supra; all of these describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of the nucleic acid molecules herein). Modifications which enhance their efficacy in cells, and removal of bases from nucleic acid molecules to shorten oligonucleotide synthesis times and reduce chemical requirements are desired. (All these publications are hereby incorporated by reference herein).
  • There are several examples in the art describing sugar, base and phosphate modifications that can be introduced into nucleic acid molecules with significant enhancement in their nuclease stability and efficacy. For example, oligonucleotides are modified to enhance stability and/or enhance biological activity by modification with nuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-flouro, 2′-O-methyl, 2′-H, nucleotide base modifications (for a review see Usman and Cedergren, 1992, TIBS. 17, 34; Usman et al., 1994, Nucleic Acids Symp. Ser. 31, 163; Burgin et al., 1996, Biochemistry, 35, 14090). Sugar modification of nucleic acid molecules have been extensively described in the art (see Eckstein et al., International Publication PCT No. WO 92/07065; Perrault et al. Nature, 1990, 344, 565-568; Pieken et al. Science, 1991, 253, 314-317; Usman and Cedergren, Trends in Biochem. Sci., 1992, 17, 334-339; Usman et al. International Publication PCT No. WO 93/15187; Sproat, U.S. Pat. No. 5,334,711 and Beigelman et al, 1995, J. Biol. Chem., 270, 25702; Beigelman et al., International PCT publication No. WO 97/26270; Beigelman et al., U.S. Pat. No. 5,716,824; Usman et al., U.S. Pat. No. 5,627,053; Woolf et al., International PCT Publication No. WO 98/13526; Thompson et al., U.S. Ser. No. 60/082,404 which was filed on Apr. 20, 1998; Karpeisky et al., 1998, Tetrahedron Lett., 39, 1131; Earnshaw and Gait, 1998, Biopolymers (Nucleic acid Sciences), 48, 39-55; Verma and Eckstein, 1998, Annu. Rev. Biochem., 67, 99-134; and Burlina et al., 1997, Bioorg. Med. Chem., 5, 1999-2010; all of the references are hereby incorporated in their totality by reference herein). Such publications describe general methods and strategies to determine the location of incorporation of sugar, base and/or phosphate modifications and the like into ribozymes without inhibiting catalysis, and are incorporated by reference herein. In view of such teachings, similar modifications can be used as described herein to modify the nucleic acid molecules of the instant invention.
  • While chemical modification of oligonucleotide internucleotide linkages with phosphorothioate, phosphorothioate, and/or 5′-methylphosphonate linkages improves stability, too many of these modifications can cause some toxicity. Therefore when designing nucleic acid molecules the amount of these internucleotide linkages should be minimized. The reduction in the concentration of these linkages should lower toxicity resulting in increased efficacy and higher specificity of these molecules.
  • Nucleic acid molecules having chemical modifications that maintain or enhance activity are provided. Such nucleic acid is also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity can not be significantly lowered. Therapeutic nucleic acid molecules delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. Nucleic acid molecules are preferably resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA and DNA (Wincott et al., 1995 Nucleic Acids Res. 23, 2677; Caruthers et al., 1992, Methods in Enzymology 211,3-19 (incorporated by reference herein) have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.
  • Use of the nucleic acid-based molecules of the invention can lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple antisense or enzymatic nucleic acid molecules targeted to different genes, nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of molecules (including different motifs) and/or other chemical or biological molecules). The treatment of subjects with nucleic acid molecules can also include combinations of different types of nucleic acid molecules.
  • Therapeutic nucleic acid molecules (e.g., enzymatic nucleic acid molecules and antisense nucleic acid molecules) delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. These nucleic acid molecules should be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of nucleic acid molecules described in the instant invention and in the art have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.
  • In one embodiment, nucleic acid catalysts having chemical modifications that maintain or enhance enzymatic activity are provided. Such nucleic acids are also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity of the nucleic acid can not be significantly lowered. As exemplified herein such enzymatic nucleic acids are useful in a cell and/or in vivo even if activity over all is reduced about 10 fold (Burgin et al., 1996, Biochemistry, 35, 14090). Such enzymatic nucleic acids herein are said to “maintain” the enzymatic activity of an all RNA ribozyme or all DNA DNAzyme.
  • In another aspect the nucleic acid molecules comprise a 5′ and/or a 3′-cap structure.
  • By “cap structure” is meant chemical modifications, which have been incorporated at either terminus of the oligonucleotide (see for example Wincott et al., WO 97/26270, incorporated by reference herein). These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5′-terminus (5′-cap) or at the 3′-terminus (3′-cap) or can be present on both terminus. In non-limiting examples, the 5′-cap includes inverted abasic residue (moiety), 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide, 4′-thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha-nucleotides; modified base nucleotide; phosphorodithioate linkage; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide, 3′-3′-inverted nucleotide moiety; 3′-3′-inverted abasic moiety; 3′-2′-inverted nucleotide moiety; 3′-2′-inverted abasic moiety; 1,4-butanediol phosphate; 3′-phosphoramidate; hexylphosphate; aminohexyl phosphate; 3′-phosphate; 3′-phosphorothioate; phosphorodithioate; or bridging or non-bridging methylphosphonate moiety (for more details see Wincott et al., International PCT publication No. WO 97/26270, incorporated by reference herein).
  • In another embodiment the 3′-cap includes, for example 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4′-thio nucleotide, carbocyclic nucleotide; 5′-amino-alkyl phosphate; 1,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5′-5′-inverted nucleotide moiety; 5′-5′-inverted abasic moiety; 5′-phosphoramidate; 5′-phosphorothioate; 1,4-butanediol phosphate; 5′-amino; bridging and/or non-bridging 5′-phosphoramidate, phosphorothioate and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5′-mercapto moieties (for more details see Beaucage and Iyer, 1993, Tetrahedron 49, 1925; incorporated by reference herein).
  • By the term “non-nucleotide” is meant any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine.
  • The term “alkyl” as used herein refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain “isoalkyl”, and cyclic alkyl groups. The term “alkyl” also comprises alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C1-C6 hydrocarbyl, aryl or substituted aryl groups. Preferably, the alkyl group has 1 to 12 carbons. More preferably it is a lower alkyl of from about 1 to 7 carbons, more preferably about 1 to 4 carbons. The alkyl group can be substituted or unsubstituted. When substituted the substituted group(s) preferably comprise hydroxy, oxy, thio, amino, nitro, cyano, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, silyl, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C1-C6 hydrocarbyl, aryl or substituted aryl groups. The term “alkyl” also includes alkenyl groups containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkenyl group has about 2 to 12 carbons. More preferably it is a lower alkenyl of from about 2 to 7 carbons, more preferably about 2 to 4 carbons. The alkenyl group can be substituted or unsubstituted. When substituted the substituted group(s) preferably comprise hydroxy, oxy, thio, amino, nitro, cyano, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, silyl, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C1-C6 hydrocarbyl, aryl or substituted aryl groups. The term “alkyl” also includes alkynyl groups containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkynyl group has about 2 to 12 carbons. More preferably it is a lower alkynyl of from about 2 to 7 carbons, more preferably about 2 to 4 carbons. The alkynyl group can be substituted or unsubstituted. When substituted the substituted group(s) preferably comprise hydroxy, oxy, thio, amino, nitro, cyano, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, silyl, alkenyl, alkynyl, alkoxy, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, C1-C6 hydrocarbyl, aryl or substituted aryl groups. Alkyl groups or moieties of the invention can also include aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide and ester groups. The preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups. An “alkylaryl” group refers to an alkyl group (as described above) covalently joined to an aryl group (as described above). Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted. Heterocyclic aryl groups are groups having from about 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted. An “amide” refers to an —C(O)—NH—R, where R is either alkyl, aryl, alkylaryl or hydrogen. An “ester” refers to an —C(O)—OR′, where R is either alkyl, aryl, alkylaryl or hydrogen.
  • The term “alkoxyalkyl” as used herein refers to an alkyl-O-alkyl ether, for example methoxyethyl or ethoxymethyl.
  • The term “alkyl-thio-alkyl” as used herein refers to an alkyl-S-alkyl thioether, for example methylthiomethyl or methylthioethyl.
  • The term “amino” as used herein refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic radicals. For example, the terms “aminoacyl” and “aminoalkyl” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.
  • The term “amination” as used herein refers to a process in which an amino group or substituted amine is introduced into an organic molecule.
  • The term “exocyclic amine protecting moiety” as used herein refers to a nucleobase amino protecting group compatible with oligonucleotide synthesis, for example an acyl or amide group.
  • The term “alkenyl” as used herein refers to a straight or branched hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon double bond. Examples of “alkenyl” include vinyl, allyl, and 2-methyl-3-heptene.
  • The term “alkoxy” as used herein refers to an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.
  • The term “alkynyl” as used herein refers to a straight or branched hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond. Examples of “alkynyl” include propargyl, propyne, and 3-hexyne.
  • The term “aryl” as used herein refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring can optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examples of aryl groups include phenyl and naphthyl.
  • The term “cycloalkenyl” as used herein refers to a C3-C8 cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.
  • The term “cycloalkyl” as used herein refers to a C3-C8 cyclic hydrocarbon. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • The term “cycloalkylalkyl,” as used herein, refers to a C3-C7 cycloalkyl group attached to the parent molecular moiety through an alkyl group, as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.
  • The terms “halogen” or “halo” as used herein refers to indicate fluorine, chlorine, bromine, and iodine.
  • The term “heterocycloalkyl,” as used herein refers to a non-aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring can be optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings. Preferred heterocycloalkyl groups have from 3 to 7 members. Examples of heterocycloalkyl groups include, for example, piperazine, morpholine, piperidine, tetrahydrofuran, pyrrolidine, and pyrazole. Preferred heterocycloalkyl groups include piperidinyl, piperazinyl, morpholinyl, and pyrolidinyl.
  • The term “heteroaryl” as used herein refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring can be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline and pyrimidine. Preferred examples of heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.
  • The term “C1-C6 hydrocarbyl” as used herein refers to straight, branched, or cyclic alkyl groups having 1-6 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds. Examples of hydrocarbyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, vinyl, 2-pentene, cyclopropylmethyl, cyclopropyl, cyclohexylmethyl, cyclohexyl and propargyl. When reference is made herein to C1-C6 hydrocarbyl containing one or two double or triple bonds it is understood that at least two carbons are present in the alkyl for one double or triple bond, and at least four carbons for two double or triple bonds.
  • By “nucleotide” is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a phosphorylated sugar. Nucleotides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1′ position of a nucleotide sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group. The nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non-natural nucleotides, non-standard nucleotides and other; see for example, Usman and McSwiggen, supra; Eckstein et al., International PCT Publication No. WO 92/07065; Usman et al., International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra all are hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al., 1994, Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of chemically modified and other natural nucleic acid bases that can be introduced into nucleic acids include, for example, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2,4,6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, quesosine, 2-thiouridine, 4-thiouridine, wybutosine, wybutoxosine, 4-acetylcytidine, 5-(carboxyhydroxymethyl)uridine, 5′-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluridine, beta-D-galactosylqueosine, 1-methyladenosine, 1-methylinosine, 2,2-dimethylguanosine, 3-methylcytidine, 2-methyladenosine, 2-methylguanosine, N6-methyladenosine, 7-methylguanosine, 5-methoxyaminomethyl-2-thiouridine, 5-methylaminomethyluridine, 5-methylcarbonylmethyluridine, 5-methyloxyuridine, 5-methyl-2-thiouridine, 2-methylthio-N-6-isopentenyladenosine, beta-D-mannosylqueosine, uridine-5-oxyacetic acid, 2-thiocytidine, threonine derivatives and others (Burgin et al., 1996, Biochemistry, 35, 14090; Uhlman & Peyman, supra). By “modified bases” in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1′ position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions of the nucleic acid molecule.
  • By “nucleoside” is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a sugar. Nucleosides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1′ position of a nucleoside sugar moiety. Nucleosides generally comprise a base and sugar group. The nucleosides can be unmodified or modified at the sugar, and/or base moiety, (also referred to interchangeably as nucleoside analogs, modified nucleosides, non-natural nucleosides, non-standard nucleosides and other; see for example, Usman and McSwiggen, supra; Eckstein et al., International PCT Publication No. WO 92/07065; Usman et al., International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra all are hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al., 1994, Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of chemically modified and other natural nucleic acid bases that can be introduced into nucleic acids include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2,4,6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, quesosine, 2-thiouridine, 4-thiouridine, wybutosine, wybutoxosine, 4-acetylcytidine, 5-(carboxyhydroxymethyl)uridine, 5′-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluridine, beta-D-galactosylqueosine, 1-methyladenosine, 1-methylinosine, 2,2-dimethylguanosine, 3-methylcytidine, 2-methyladenosine, 2-methylguanosine, N6-methyladenosine, 7-methylguanosine, 5-methoxyaminomethyl-2-thiouridine, 5-methylaminomethyluridine, 5-methylcarbonylmethyluridine, 5-methyloxyuridine, 5-methyl-2-thiouridine, 2-methylthio-N6-isopentenyladenosine, beta-D-mannosylqueosine, uridine-5-oxyacetic acid, 2-thiocytidine, threonine derivatives and others (Burgin et al., 1996, Biochemistry, 35, 14090; Uhlman & Peyman, supra). By “modified bases” in this aspect is meant nucleoside bases other than adenine, guanine, cytosine and uracil at 1′ position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions of the nucleic acid molecule.
  • In one embodiment, the invention features modified enzymatic nucleic acid molecules with phosphate backbone modifications comprising one or more phosphorothioate, phosphorodithioate, methylphosphonate, morpholino, amidate carbamate, carboxymethyl, acetamidate, polyamide, sulfonate, sulfonamide, sulfamate, formacetal, thioformacetal, and/or alkylsilyl, substitutions. For a review of oligonucleotide backbone modifications see Hunziker and Leumann, 1995, Nucleic Acid Analogues: Synthesis and Properties, in Modern Synthetic Methods, VCH, 331-417, and Mesmaeker et al., 1994, Novel Backbone Replacements for Oligonucleotides, in Carbohydrate Modifications in Antisense Research, ACS, 24-39. These references are hereby incorporated by reference herein.
  • By “abasic” is meant sugar moieties lacking a base or having other chemical groups in place of a base at the 1′ position, for example a 3′,3′-linked or 5′,5′-linked deoxyabasic ribose derivative (for more details see Wincott et al., International PCT publication No. WO 97/26270).
  • By “unmodified nucleoside” is meant one of the bases adenine, cytosine, guanine, thymine, uracil joined to the 1′ carbon of β-D-ribo-furanose.
  • By “modified nucleoside” is meant any nucleotide base which contains a modification in the chemical structure of an unmodified nucleotide base, sugar and/or phosphate.
  • In connection with 2′-modified nucleotides as described for the present invention, by “amino” is meant 2′-NH2 or 2′-O—NH2, which can be modified or unmodified. Such modified groups are described, for example, in Eckstein et al., U.S. Pat. No. 5,672,695 and Matulic-Adamic et al., WO 98/28317, respectively, which are both incorporated by reference in their entireties.
  • Various modifications to nucleic acid (e.g., antisense and ribozyme) structure can be made to enhance the utility of these molecules. For example, such modifications can enhance shelf-life, half-life in vitro, stability, and ease of introduction of such oligonucleotides to the target site, including e.g., enhancing penetration of cellular membranes and conferring the ability to recognize and bind to targeted cells.
  • Use of these molecules can lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs) and/or other chemical or biological molecules). The treatment of subjects with nucleic acid molecules can also include combinations of different types of nucleic acid molecules. Therapies can be devised which include a mixture of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs), antisense and/or 2-5A chimera molecules to one or more targets to alleviate symptoms of a disease.
  • Administration of Nucleic Acid Molecules
  • Methods for the delivery of nucleic acid molecules are described in Akhtar et al., 1992, Trends Cell Bio., 2, 139; and Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995 which are both incorporated herein by reference. Sullivan et al., PCT WO 94/02595, further describes the general methods for delivery of enzymatic RNA molecules. These protocols can be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules can be administered to cells by a variety of methods known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres. Alternatively, the nucleic acid/vehicle combination is locally delivered by direct injection or by use of an infusion pump. Other routes of delivery include, but are not limited to oral (tablet or pill form) and/or intrathecal delivery (Gold, 1997, Neuroscience, 76, 1153-1158). Other approaches include the use of various transport and carrier systems, for example, through the use of conjugates and biodegradable polymers. For a comprehensive review on drug delivery strategies including CNS delivery, see Ho et al., 1999, Curr. Opin. Mol. Ther., 1, 336-343 and Jain, Drug Delivery Systems: Technologies and Commercial Opportunities, Decision Resources, 1998 and Groothuis et al., 1997, J. NeuroVirol., 3, 387-400. More detailed descriptions of nucleic acid delivery and administration are provided in Sullivan et al., supra, Draper et al., PCT WO93/23569, Beigelman et al., PCT WO99/05094, and Klimuk et al., PCT WO99/04819 all of which have been incorporated by reference herein.
  • The molecules of the instant invention can be used as pharmaceutical agents. Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state in a subject.
  • The negatively charged polynucleotides of the invention can be administered (e.g., RNA, DNA or protein) and introduced into a subject by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition. When it is desired to use a liposome delivery mechanism, standard protocols for formation of liposomes can be followed. The compositions of the present invention can also be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions; suspensions for injectable administration; and the other compositions known in the art.
  • The present invention also includes pharmaceutically acceptable formulations of the compounds described. These formulations include salts of the above compounds, e.g., acid addition salts, for example, salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonic acid.
  • A pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., systemic administration, into a cell or subject, preferably a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell (i.e., a cell to which the negatively charged polymer is desired to be delivered to). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms which prevent the composition or formulation from exerting its effect.
  • By “systemic administration” is meant in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body. Administration routes which lead to systemic absorption include, without limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes expose the desired negatively charged polymers, e.g., nucleic acids, to an accessible diseased tissue. The rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier comprising the compounds of the instant invention can potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A liposome formulation which can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach can provide enhanced delivery of the drug to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells, such as cancer cells.
  • By pharmaceutically acceptable formulation is meant, a composition or formulation that allows for the effective distribution of the nucleic acid molecules of the instant invention in the physical location most suitable for their desired activity. Non-limiting examples of agents suitable for formulation with the nucleic acid molecules of the instant invention include: PEG conjugated nucleic acids, phospholipid conjugated nucleic acids, nucleic acids containing lipophilic moieties, phosphorothioates, P-glycoprotein inhibitors (such as Pluronic P85) which can enhance entry of drugs into various tissues, for example the CNS (Jolliet-Riant and Tillement, 1999, Fundam. Clin. Pharmacol., 13, 16-26); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after implantation (Emerich, D F et al, 1999, Cell Transplant, 8, 47-58) Alkermes, Inc. Cambridge, Mass.; and loaded nanoparticles, such as those made of polybutylcyanoacrylate, which can deliver drugs across the blood brain barrier and can alter neuronal uptake mechanisms (Prog Neuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999). Other non-limiting examples of delivery strategies, including CNS delivery of the nucleic acid molecules of the instant invention include material described in Boado et al., 1998, J. Pharm. Sci., 87, 1308-1315; Tyler et al., 1999, FEBS Lett., 421, 280-284; Pardridge et al., 1995, PNAS USA., 92, 5592-5596; Boado, 1995, Adv. Drug Delivery Rev., 15, 73-107; Aldrian-Herrada et al., 1998, Nucleic Acids Res., 26, 4910-4916; and Tyler et al., 1999, PNAS USA., 96, 7053-7058. All these references are hereby incorporated herein by reference.
  • The invention also features the use of the composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). Nucleic acid molecules of the invention can also comprise covalently attached PEG molecules of various molecular weights. These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug (Lasic et al. Chem. Rev. 1995, 95, 2601-2627; Ishiwata et al., Chem. Pharm. Bull. 1995, 43, 1005-1011). Such liposomes have been shown to accumulate selectively in tumors, presumably by extravasation and capture in the neovascularized target tissues (Lasic et al., Science 1995, 267, 1275-1276; Oku et al., 1995, Biochim. Biophys. Acta, 1238, 86-90). The long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes which are known to accumulate in tissues of the MPS (Liu et al., J. Biol. Chem. 1995, 42, 24864-24870; Choi et al., International PCT Publication No. WO 96/10391; Ansell et al., International PCT Publication No. WO 96/10390; Holland et al., International PCT Publication No. WO 96/10392; all of which are incorporated by reference herein). Long-circulating liposomes are also likely to protect drugs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive MPS tissues such as the liver and spleen. All of these references are incorporated by reference herein.
  • The present invention also includes compositions prepared for storage or administration which include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985) hereby incorporated by reference herein. For example, preservatives, stabilizers, dyes and flavoring agents can be provided. These include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. In addition, antioxidants and suspending agents can be used.
  • A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state. The pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer.
  • The nucleic acid molecules of the invention and formulations thereof can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a nucleic acid molecule of the invention and a pharmaceutically acceptable carrier. One or more nucleic acid molecules of the invention can be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing nucleic acid molecules of the invention can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.
  • Pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.
  • Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
  • The nucleic acid molecules of the invention can also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
  • Nucleic acid molecules of the invention can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient or subject per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Dosage unit forms generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • It is understood that the specific dose level for any particular patient or subject depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • For administration to non-human animals, the composition can also be added to the animal feed or drinking water. It can be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It can also be convenient to present the composition as a premix for addition to the feed or drinking water.
  • The nucleic acid molecules of the present invention can also be administered to a subject in combination with other therapeutic compounds to increase the overall therapeutic effect. The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.
  • Alternatively, certain of the nucleic acid molecules of the instant invention can be expressed within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985, Science, 229, 345; McGarry and Lindquist, 1986, Proc. Natl. Acad. Sci., USA 83, 399; Scanlon et al., 1991, Proc. Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al., 1992, Antisense Res. Dev., 2, 3-15; Dropulic et al., 1992, J. Virol., 66, 1432-41; Weerasinghe et al., 1991, J. Virol., 65, 5531-4; Ojwang et al., 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res., 20, 4581-9; Sarver et al., 1990 Science, 247, 1222-1225; Thompson et al., 1995, Nucleic Acids Res., 23, 2259; Good et al., 1997, Gene Therapy, 4, 45; all of these references are hereby incorporated in their totalities by reference herein). Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a enzymatic nucleic acid (Draper et al., PCT WO 93/23569, and Sullivan et al., PCT WO 94/02595; Ohkawa et al., 1992, Nucleic Acids Symp. Ser., 27, 15-6; Taira et al., 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al., 1993, Nucleic Acids Res., 21, 3249-55; Chowrira et al., 1994, J. Biol. Chem., 269, 25856; all of these references are hereby incorporated in their totalities by reference herein). Gene therapy approaches specific to the CNS are described by Blesch et al., 2000, Drug News Perspect., 13, 269-280; Peterson et al., 2000, Cent. Nerv. Syst. Dis., 485-508; Peel and Klein, 2000, J. Neurosci. Methods, 98, 95-104; Hagihara et al., 2000, Gene Ther., 7, 759-763; and Herrlinger et al., 2000, Methods Mol. Med., 35, 287-312. AAV-mediated delivery of nucleic acid to cells of the nervous system is further described by Kaplitt et al., U.S. Pat. No. 6,180,613.
  • In another aspect of the invention, RNA molecules of the present invention are preferably expressed from transcription units (see for example Couture et al., 1996, TIG., 12, 510) inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the nucleic acid molecules are delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of nucleic acid molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the nucleic acid molecule binds to the target mRNA. Delivery of nucleic acid molecule expressing vectors can be systemic, such as by intravenous or intra-muscular administration, by administration to target cells ex-planted from the patient or subject followed by reintroduction into the patient or subject, or by any other means that would allow for introduction into the desired target cell (for a review see Couture et al., 1996, TIG., 12, 510).
  • In one aspect the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules of the instant invention is disclosed. The nucleic acid sequence encoding the nucleic acid molecule of the instant invention is operably linked in a manner which allows expression of that nucleic acid molecule.
  • In another aspect the invention features an expression vector comprising: a) a transcription initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription termination region (e.g., eukaryotic pol I, II or III termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. The vector can optionally include an open reading frame (ORF) for a protein operably linked on the 5′ side or the 3′-side of the sequence encoding the nucleic acid catalyst of the invention; and/or an intron (intervening sequences).
  • Transcription of the nucleic acid molecule sequences are driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters are expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl. Acad. Sci. USA, 87, 6743-7; Gao and Huang 1993, Nucleic Acids Res., 21, 2867-72; Lieber et al., 1993, Methods Enzymol., 217, 47-66; Zhou et al., 1990, Mol. Cell. Biol., 10, 4529-37). All of these references are incorporated by reference herein. Several investigators have demonstrated that nucleic acid molecules, such as ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992, Antisense Res. Dev., 2, 3-15; Ojwang et al., 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res., 20, 4581-9; Yu et al., 1993, Proc. Natl. Acad. Sci. USA, 90, 6340-4; L'Huillier et al., 1992, EMBO J, 11, 4411-8; Lisziewicz et al., 1993, Proc. Natl. Acad. Sci. U.S.A, 90, 8000-4; Thompson et al., 1995, Nucleic Acids Res., 23, 2259; Sullenger & Cech, 1993, Science, 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as ribozymes in cells (Thompson et al., supra; Couture and Stinchcomb, 1996, supra; Noonberg et al., 1994, Nucleic Acid Res., 22, 2830; Noonberg et al., U.S. Pat. No. 5,624,803; Good et al., 1997, Gene Ther., 4, 45; Beigelman et al., International PCT Publication No. WO 96/18736; all of these publications are incorporated by reference herein. The above ribozyme transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review see Couture and Stinchcomb, 1996, supra).
  • In another aspect the invention features an expression vector comprising nucleic acid sequence encoding at least one of the nucleic acid molecules of the invention, in a manner which allows expression of that nucleic acid molecule. The expression vector comprises in one embodiment; a) a transcription initiation region; b) a transcription termination region; c) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
  • In another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3′-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In yet another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
  • In another embodiment, the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; e) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3′-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.
    • EXAMPLES
  • The following are non-limiting examples showing the selection, isolation, synthesis and activity of nucleic acids of the instant invention.
  • The following examples demonstrate the selection and design of Antisense, hammerhead, DNAzyme, NCH, Amberzyme, Zinzyme, or G-Cleaver ribozyme molecules and binding/cleavage sites within IKK-gamma or PKR RNA.
    • Example 1 Identification of Potential Target Sites in Human IKK-Gamma and PKR RNA
  • The sequence of human IKK-gamma or PKR genes are screened for accessible sites using a computer-folding algorithm. Regions of the RNA that do not form secondary folding structures and contained potential enzymatic nucleic acid molecule and/or antisense binding/cleavage sites are identified. The sequences of these binding/cleavage sites are shown in Tables III-XIII.
    • Example 2 Selection of Enzymatic Nucleic Acid Cleavage Sites in Human IKK-Gamma and PKR RNA
  • Enzymatic nucleic acid molecule target sites are chosen by analyzing sequences of Human IKK-gamma (Genbank accession No: NM—003639) and PKR (Genbank accession No: NM—002759) and prioritizing the sites on the basis of folding. Enzymatic nucleic acid molecules are designed that can bind each target and are individually analyzed by computer folding (Christoffersen et al., 1994 J. Mol. Struc. Theochem, 311, 273; Jaeger et al., 1989, Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the enzymatic nucleic acid molecule sequences fold into the appropriate secondary structure. Those enzymatic nucleic acid molecules with unfavorable intramolecular interactions between the binding arms and the catalytic core were eliminated from consideration. As noted below, varying binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA.
    • Example 3 Chemical Synthesis and Purification of Ribozymes and Antisense for Efficient Cleavage and/or Blocking of IKK-Gamma and PKR RNA
  • Enzymatic nucleic acid molecules and antisense constructs are designed to anneal to various sites in the RNA message. The binding arms of the enzymatic nucleic acid molecules are complementary to the target site sequences described above, while the antisense constructs are fully complementary to the target site sequences described above. The enzymatic nucleic acid molecules and antisense constructs were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al., (1987 J. Am. Chem. Soc., 109, 7845), Scaringe et al., (1990 Nucleic Acids Res., 18, 5433) and Wincott et al., supra, and made use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. The average stepwise coupling yields were typically >98%.
  • Enzymatic nucleic acid molecules and antisense constructs are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51). Enzymatic nucleic acid molecules and antisense constructs are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al., supra; the totality of which is hereby incorporated herein by reference) and are resuspended in water. The sequences of the chemically synthesized enzymatic nucleic acid molecules used in this study are shown below in Table XIII. The sequences of the chemically synthesized antisense constructs used in this study are complementary sequences to the Substrate sequences shown below as in Tables III to XIII.
    • Example 4 Enzymatic Nucleic Acid Molecule Cleavage of IKK-Gamma and PKR RNA Target In Vitro
  • Enzymatic nucleic acid molecules targeted to the human IKK-gamma or PKR RNA are designed and synthesized as described above. These enzymatic nucleic acid molecules can be tested for cleavage activity in vitro, for example, using the following procedure. The target sequences and the nucleotide location within the IKK-gamma or PKR RNA are given in Tables III-XIII.
  • Cleavage Reactions: Full-length or partially full-length, internally-labeled target RNA for enzymatic nucleic acid molecule cleavage assay is prepared by in vitro transcription in the presence of [a-32P] CTP, passed over a G 50 Sephadex column by spin chromatography and used as substrate RNA without further purification. Alternately, substrates are 5′-32P-end labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2× concentration of purified enzymatic nucleic acid molecule in enzymatic nucleic acid molecule cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37° C., 10 mM MgCl2) and the cleavage reaction was initiated by adding the 2× enzymatic nucleic acid molecule mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. As an initial screen, assays are carried out for 1 hour at 37° C. using a final concentration of either 40 nM or 1 mM enzymatic nucleic acid molecule, i.e., enzymatic nucleic acid molecule excess. The reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which the sample is heated to 95° C. for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel. Substrate RNA and the specific RNA cleavage products generated by enzymatic nucleic acid molecule cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.
    • Example 5 Nucleic Acid Down-Regulation of IKK-Gamma and PKR Target RNA In Vivo
  • Nucleic acid molecules targeted to the human IKK-gamma or PKR RNA are designed and synthesized as described above. These nucleic acid molecules can be tested for cleavage activity in vivo, for example using the procedures described below. The target sequences and the nucleotide location within the IKK-gamma or PKR RNA are given in Tables III-XIII.
    • Example 6 In Vivo Models Used to Evaluate the Down-Regulation of IKK-Gamma or PKR Gene Expression
  • A variety of endpoints have been used in cell culture models to evaluate IKK-gamma or PKR-mediated effects after treatment with anti-IKK-gamma or PKR agents. Phenotypic endpoints include inhibition of cell proliferation, apoptosis assays and reduction of IKK-gamma or PKR protein expression, or a decrease in NFKB expression. Since IKK-gamma and PKR are both involved in the induction of NFKB, NFKB can be used as a surrogate marker in cell culture, animal, and clinical studies. Because overexpression of NFKB is directly associated with increased proliferation of tumor cells, a proliferation endpoint for cell culture assays is preferably used as a primary screen. There are several methods by which this endpoint can be measured. Following treatment of cells with nucleic acid molecules, cells are allowed to grow (typically 5 days) after which either the cell viability, the incorporation of [3H] thymidine into cellular DNA and/or the cell density can be measured. The assay of cell density is very straightforward and can be performed in a 96-well format using commercially available fluorescent nucleic acid stains (such as Syto® 13 or CyQuant®). An assay using CyQuant® is described herein.
  • As a secondary, confirmatory endpoint a nucleic acid-mediated decrease in the level of IKK-gamma or PKR RNA and/or IKK-gamma or PKR protein expression can be evaluated. Alternately, a decrease in the level of NFKB RNA can be evaluated.
  • Cell Culture
  • Cell types that express/over-express NFKB include HeLa, macrophages, peripheral blood lymphocytes, hepatocytes, fibroblasts, endothelial cells and epithelial cells. In culture, these cells can be stimulated to express/over-express NFKB by addition of TNF-alpha PMA or IL-1-beta to the culture medium. Some of these cell types also can respond with a similar activation of NFKB following LPS treatment. Activation of NFKB in cultured cells can be evaluated by electrophoretic mobility shift assay (EMSA). Delineation of alterations in the subunits can be determined by Western blot.
  • Primary Screen
  • A useful cell culture system in evaluating NFKB modulation is human colonic epithelial cells. One suitable cell line is SW620 colon carcinoma cells (CCL227). These cells respond to stimulation with TNF-alpha, LPS and/or IL-1-beta with an increase in NFKB activation. SW620 cells are grown in MEM supplemented with 10% heat-inactivated FBS and glutamine (2 mmol/L).
  • TNF-alpha dose-response curves in these cells are determined by incubating cells with various concentrations of recombinant human TNF-alpha (Sigma Chemical Co.). Maximal DNA binding activity induction can occur with 150 U/ml TNF-alpha in the culture medium. Induction is typically evident within 10 minutes of treatment with TNF-alpha reaches a peak at one hour post-treatment and persists for up to 4 hours post-treatment. The primary readout can be NFKB DNA activity in nuclear extracts of SW620 cells as determined by electrophoretic mobility shift assays (EMSA). Once the appropriate TNF-alpha dose/response profile has been determined, inhibition of IKK-gamma, PKR, or NFKB activation is evaluated using specific and non-specific inhibitors of activation, sulfasalazine and steroids, respectively. Cells are incubated with inhibitors or control media for 30 minutes prior to stimulation with TNF-alpha Nuclear extracts are prepared and evaluated for DNA binding activity by EMSA. Once the activity of positive controls has been established, enzymatic nucleic acids targeting the IKK-gamma or PKR are evaluated in this system. Supershift assays using polyclonal antibodies against the NFKB or PKR protein subunits can be performed to confirm down-regulation of NFKB.
  • Secondary Screens
  • SW620 cells can be transfected with the 3×Ig-kappa-B-Luc reporter construct 18 hours before challenge with TNF-alpha, LPS or PMA. The readout for this assay is luciferase activity. Test compounds are applied 17.5 hours after transfection (30 minutes before challenge). Cells are harvested 24 hours after challenge and relative changes in luciferase activity is used as the endpoint. Lastly, the activation of NFKB can be visualized fluorescently. Inactive NFKB heterodimers are held in the cytoplasm by inhibitory proteins. Once activated, the free heterodimers translocate to the nucleus. Thus, the relative change in cytoplasmic versus nuclear fluorescence can indicate the degree of NFKB activation. Cells can be grown on chamber slides, treated with TNF-alpha with and without test compounds), and the location of the NFKB subunit can be determined by immunofluorescence using a FITC-labeled antibody to NFKB.
  • Animal Models
  • Evaluating the efficacy of anti-IKK-gamma or PKR agents in animal models is an important prerequisite to human clinical trials. Studies have shown that human breast carcinoma cell lines express high levels of NFKB (Sovak et al., 1997, J. Clin. Invest., 100, 2952-2960). High levels of NFKB have also been observed in carcinogen-induced primary rat mammary tumors and in human breast cancer specimins. Additionally, HER2/neu overexpression has been shown to activate NFKB (Pianetti et al., 2001, Oncogene, 20, 1287-1299). As such, xenografts of cell lines that over-express NFKB can be used in animal models of tumorigenesis and/or inflammation to study the inhibition of NFKB.
  • Oncology Animal Model Development
  • Tumor cell lines are characterized to establish their growth curves in mice. These cell lines are implanted into both nude and SCID mice and primary tumor volumes are measured 3 times per week. Growth characteristics of these tumor lines using a Matrigel implantation format can also be established. The use of other cell lines that have been engineered to express high levels of NFKB can also be used in the described studies. The tumor cell line(s) and implantation method that supports the most consistent and reliable tumor growth is used in animal studies testing the lead IKK-gamma or PKR nucleic acid(s). Nucleic acids are administered by daily subcutaneous injection or by continuous subcutaneous infusion from Alzet mini osmotic pumps beginning 3 days after tumor implantation and continuing for the duration of the study. Group sizes of at least 10 animals are employed. Efficacy is determined by statistical comparison of tumor volume of nucleic acid-treated animals to a control group of animals treated with saline alone. Because the growth of these tumors is generally slow (45-60 days), an initial endpoint is the time in days it takes to establish an easily measurable primary tumor (i.e. 50-100 mm3) in the presence or absence of nucleic acid treatment.
  • Inflammation Animal Model Development
  • Chronic, sublethal administration of indomethacin to outbred rats produces an enteropathy characterized by thickening of the small intestine and mesentery, ulcerations, granulomatous inflammation, crypt abcesses and adhesions. These lesions are similar to those that are characteristic findings in human patients with Crohn's disease (CD). Thus, any beneficial therapeutic effects revealed using this model can be extrapolated to potential benefit for patients with CD.
  • Male Sprague-Dawley rats (200-275 g) are utilized for these studies. Chronic intestinal inflammation is induced by two subcutaneous injections of indomethacin (7.5 mg/kg in 5% NaHCO3) administered on subsequent days (Day-0 and Day-1). Animals are followed for four days following the first indomethacin injection. The mortality rate associated with this model is typically less than 10%. On the last day of the study, animals are euthanized by CO2 asphyxiation, small intestines excised and gross pathologic findings ranked according to the following criteria: 0, normal; 1, minimal abnormalities, slight thickening of the small intestine, no adhesions; 2, obvious thickening of small intestine with 1 adhesion; 3, obvious thickening of small intestine with 2 or 3 adhesions; 4, massive adhesions to the extent that the intestine cannot be separated, contents primarily fluid; 5, severe peritonitis resulting in death. A 10-cm portion of the most affected region of the small intestine is weighed, placed in 10% neutral buffered formalin and submitted for histopathologic evaluation.
  • The 10 cm portion of gut from each animal is cut into five equal sections. Transverse and longitudinal sections of each portion are cut and stained with hematoxylin and eosin. All slides are read in a blinded fashion and each section is scored for necrosis (% area of involvement) and inflammatory response according to the following scale:
      • Necrosis—1, 10%; 2, 10-25%; 3, 25-50%; 4, 50-75%; 5, 75-100%;
      • Inflammation—
        • 1=minimal in mesentery and muscle or lesion
        • 2=mild in mesentery and muscle or lesion
        • 3=moderate in mesentery and muscle or lesion
        • 4=marked in lesion
        • 5=severe in lesion
  • The scores for each of the five sections are averaged for necrosis and for inflammation.
  • NFKB Levels for Patient Screening and as a Potential Endpoint
  • Because elevated NFKB levels can be detected in cancers, cancer patients can be pre-screened for elevated NFKB prior to admission to initial clinical trials testing an anti-IKK-gamma or PKR nucleic acid. Initial NFKB levels can be determined (by ELISA) from tumor biopsies or resected tumor samples. During clinical trials, it can be possible to monitor circulating NFKB protein by ELISA. Evaluation of serial blood/serum samples over the course of the anti-IKK-gamma or PKR nucleic acid treatment period could be useful in determining early indications of efficacy.
    • Example 7 Activity of Nucleic Acid Molecules Used to Down-Regulate IKK-Gamma and PKR Gene Expression
  • Several nucleic acid molecules targeted against IKK-gamma or PKR RNA have been designed and synthesized. These nucleic acid molecules can be tested in cell proliferation and RNA reduction assays described herein.
  • Proliferation Assay
  • The model proliferation assay used in the study requires a cell-plating density of 2,000-10,000 cells/well in 96-well plates and at least 2 cell doublings over a 5-day treatment period. Cells used in proliferation studies were either lung or ovarian cancer cells (A549 and SKOV-3 cells respectively). To calculate cell density for proliferation assays, the FIPS (fluoro-imaging processing system) method known in the art was used. This method allows for cell density measurements after nucleic acids are stained with CyQuant® dye, and has the advantage of accurately measuring cell densities over a very wide range 1,000-100,000 cells/well in 96-well format. Enzymatic nucleic acid molecules (50-200 nM) are delivered in the presence of cationic lipid at 2.5-5.0 μg/mL and inhibition of proliferation was determined on day 5 post-treatment.
  • RNA Assay
  • RNA is harvested 24 hours post-treatment using the Qiagen RNeasy® 96 procedure. Real time RT-PCR (TaqMan® assay) is performed on purified RNA samples using separate primer/probe sets specific for target IKK-gamma or PKR RNA.
  • Indications
  • Particular degenerative and disease states that can be associated with IKK-gamma or PKR expression modulation include but are not limited to cancerous and/or inflammatory diseases and conditions such as breast, lung, prostate, colorectal, brain, esophageal, bladder, pancreatic, cervical, head and neck, and ovarian cancer, melanoma, lymphoma, glioma, multidrug resistant cancers, rheumatoid arthritis, restenosis, asthma, Crohn's disease, diabetes, obesity, autoimmune disease, lupus, multiple sclerosis, transplant/graft rejection, gene therapy applications, ischemia/reperfusion injury (CNS and myocardial), glomerulonephritis, sepsis, allergic airway inflammation, inflammatory bowel disease, infection, incontinentia pigmenti and any other diseases or conditions that are related to or respond to the levels of IKK-gamma or PKR in a cell or tissue. The present body of knowledge in IKK-gamma and PKR research indicates the need for methods to assay IKK-gamma and PKR activity and for compounds that can regulate IKK-gamma and PKR expression for research, diagnostic, and therapeutic use.
  • The use of monoclonal antibodies, chemotherapy, radiation therapy, analgesics, and/or anti-inflammatory compounds, are all non-limiting examples of a methods that can be combined with or used in conjunction with the nucleic acid molecules (e.g. ribozymes and antisense molecules) of the instant invention. Common chemotherapies that can be combined with nucleic acid molecules of the instant invention include various combinations of cytotoxic drugs to kill cancer cells. These drugs include but are not limited to paclitaxel (Taxol), docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, vinorelbine etc. Those skilled in the art will recognize that other drug compounds and therapies can be similarly be readily combined with the nucleic acid molecules of the instant invention (e.g. ribozymes and antisense molecules) are hence within the scope of the instant invention.
  • Diagnostic Uses
  • The nucleic acid molecules of this invention (e.g., enzymatic nucleic acid molecules) can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of IKK-gamma or PKR RNA in a cell. The close relationship between enzymatic nucleic acid molecule activity and the structure of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three-dimensional structure of the target RNA. By using multiple enzymatic nucleic acid molecules described in this invention, one can map nucleotide changes which are important to RNA structure and function in vitro, as well as in cells and tissues. Cleavage of target RNAs with enzymatic nucleic acid molecules can be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets can be defined as important mediators of the disease. These experiments can lead to better treatment of the disease progression by affording the possibility of combinational therapies (e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules and/or other chemical or biological molecules). Other in vitro uses of enzymatic nucleic acid molecules of this invention are well known in the art, and include detection of the presence of mRNAs associated with IKK-gamma or PKR-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with an enzymatic nucleic acid molecule using standard methodology.
  • In a specific example, enzymatic nucleic acid molecules which cleave only wild-type or mutant forms of the target RNA are used for the assay. The first enzymatic nucleic acid molecule is used to identify wild-type RNA present in the sample and the second enzymatic nucleic acid molecule is used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA are cleaved by both enzymatic nucleic acid molecules to demonstrate the relative enzymatic nucleic acid molecule efficiencies in the reactions and the absence of cleavage of the “non-targeted” RNA species. The cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus each analysis requires two enzymatic nucleic acid molecules, two substrates and one unknown sample which is combined into six reactions. The presence of cleavage products is determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells. The expression of mRNA whose protein product is implicated in the development of the phenotype (i.e., IKK-gamma or PKR) is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost of the initial diagnosis. Higher mutant form to wild-type ratios are correlated with higher risk whether RNA levels are compared qualitatively or quantitatively. The use of enzymatic nucleic acid molecules in diagnostic applications contemplated by the instant invention is more fully described in George et al., U.S. Pat. Nos. 5,834,186 and 5,741,679, Shih et al., U.S. Pat. No. 5,589,332, Nathan et al., U.S. Pat. No. 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al., International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al., International PCT publication No. WO 99/29842.
  • Additional Uses
  • Potential uses of sequence-specific enzymatic nucleic acid molecules of the instant invention can have many of the same applications for the study of RNA that DNA restriction endonucleases have for the study of DNA (Nathans et al., 1975 Ann. Rev. Biochem. 44:273). For example, the pattern of restriction fragments can be used to establish sequence relationships between two related RNAs, and large RNAs can be specifically cleaved to fragments of a size more useful for study. The ability to engineer sequence specificity of the enzymatic nucleic acid molecule is ideal for cleavage of RNAs of unknown sequence. Applicant has described the use of nucleic acid molecules to down-regulate gene expression of target genes in bacterial, microbial, fungal, viral, and eukaryotic systems including plant, or mammalian cells.
  • All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. All references cited in this disclosure are incorporated by reference to the same extent as if each reference had been incorporated by reference in its entirety individually.
  • One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.
  • It will be readily apparent to one skilled in the art that varying substitutions and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims.
  • The invention illustratively described herein suitably can be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting essentially of” and “consisting of” can be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, optional features, modification and variation of the concepts herein disclosed can be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims.
  • In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.
  • Other embodiments are within the claims that follow.
    TABLE I
    Characteristics of naturally occurring ribozymes
    Group I Introns
    Size: ˜150 to >1000 nucleotides.
    Requires a U in the target sequence immediately 5′ of the cleavage site.
    Binds 4-6 nucleotides at the 5′-side of the cleavage site.
    Reaction mechanism: attack by the 3′-OH of guanosine to generate cleavage
    products with 3′-OH and 5′-guanosine.
    Additional protein cofactors required in some cases to help folding and
    maintenance of the active structure.
    Over 300 known members of this class. Found as an intervening sequence in
    Tetrahymena thermophila rRNA, fungal mitochondria, chloroplasts, phage T4, blue-
    green algae, and others.
    Major structural features largely established through phylogenetic comparisons,
    mutagenesis, and biochemical studies[i,ii].
    Complete kinetic framework established for one ribozyme[iii,iv,v,vi].
    Studies of ribozyme folding and substrate docking underway[vii,viii,ix].
    Chemical modification investigation of important residues well established[x,xi].
    The small (4-6 nt) binding site can make this ribozyme too non-specific for
    targeted RNA cleavage, however, the Tetrahymena group I intron has been used
    to repair a “defective” β-galactosidase message by the ligation of new β-
    galactosidase sequences onto the defective message[xii].
    RNAse P RNA (M1 RNA)
    Size: ˜290 to 400 nucleotides.
    RNA portion of a ubiquitous ribonucleoprotein enzyme.
    Cleaves tRNA precursors to form mature tRNA[xiii].
    Reaction mechanism: possible attack by M2+-OH to generate cleavage products
    with 3′-OH and 5′-phosphate.
    RNAse P is found throughout the prokaryotes and eukaryotes. The RNA subunit
    has been sequenced from bacteria, yeast, rodents, and primates.
    Recruitment of endogenous RNAse P for therapeutic applications is possible
    through hybridization of an External Guide Sequence (EGS) to the target RNA[xiv,xv]
    Important phosphate and 2′ OH contacts recently identified[xvi,xvii]
    Group II Introns
    Size: >1000 nucleotides.
    Trans cleavage of target RNAs recently demonstrated[xviii,xix].
    Sequence requirements not fully determined.
    Reaction mechanism: 2′-OH of an internal adenosine generates cleavage products
    with 3′-OH and a “lariat” RNA containing a 3′-5′ and a 2′-5′ branch point.
    Only natural ribozyme with demonstrated participation in DNA cleavage[xx,xxi] in
    addition to RNA cleavage and ligation.
    Major structural features largely established through phylogenetic comparisons[xxii].
    Important 2′ OH contacts beginning to be identified[xxiii]
    Kinetic framework under development[xxiv]
    Neurospora VS RNA
    Size: ˜144 nucleotides.
    Trans cleavage of hairpin target RNAs recently demonstrated[xxv].
    Sequence requirements not fully determined.
    Reaction mechanism: attack by 2′-OH 5′ to the scissile bond to generate cleavage
    products with 2′,3′-cyclic phosphate and 5′-OH ends.
    Binding sites and structural requirements not fully determined.
    Only 1 known member of this class. Found in Neurospora VS RNA.
    Hammerhead Ribozyme
    (see text for references)
    Size: ˜13 to 40 nucleotides.
    Requires the target sequence UH immediately 5′ of the cleavage site.
    Binds a variable number nucleotides on both sides of the cleavage site.
    Reaction mechanism: attack by 2′-OH 5′ to the scissile bond to generate cleavage
    products with 2′,3′-cyclic phosphate and 5′-OH ends.
    14 known members of this class. Found in a number of plant pathogens
    (virusoids) that use RNA as the infectious agent.
    Essential structural features largely defined, including 2 crystal structures[xxvi,xxvii]
    Minimal ligation activity demonstrated (for engineering through in vitro selection)[xxviii]
    Complete kinetic framework established for two or more ribozymes[xxix].
    Chemical modification investigation of important residues well established[xxx].
    Hairpin Ribozyme
    Size: ˜50 nucleotides.
    Requires the target sequence GUC immediately 3′ of the cleavage site.
    Binds 4-6 nucleotides at the 5′-side of the cleavage site and a variable number to
    the 3′-side of the cleavage site.
    Reaction mechanism: attack by 2′-OH 5′ to the scissile bond to generate cleavage
    products with 2′,3′-cyclic phosphate and 5′-OH ends.
    3 known members of this class. Found in three plant pathogen (satellite RNAs of
    the tobacco ringspot virus, arabis mosaic virus and chicory yellow mottle virus)
    which uses RNA as the infectious agent.
    Essential structural features largely defined[xxxi,xxxii,xxxiii,xxxiv]
    Ligation activity (in addition to cleavage activity) makes ribozyme amenable to
    engineering through in vitro selection[xxxv]
    Complete kinetic framework established for one ribozyme[xxxvi].
    Chemical modification investigation of important residues begun[xxxvii,xxxviii].
    Hepatitis Delta Virus (HDV) Ribozyme
    Size: ˜60 nucleotides.
    Trans cleavage of target RNAs demonstrated[xxxix].
    Binding sites and structural requirements not fully determined, although no
    sequences 5′ of cleavage site are required. Folded ribozyme contains a pseudoknot
    structure[xl].
    Reaction mechanism: attack by 2′-OH 5′ to the scissile bond to generate cleavage
    products with 2′,3′-cyclic phosphate and 5′-OH ends.
    Only 2 known members of this class. Found in human HDV.
    Circular form of HDV is active and shows increased nuclease stability[xli]

    iMichel, Francois; Westhof, Eric. Slippery substrates. Nat. Struct. Biol. (1994), 1(1), 5-7.

    iiLisacek, Frederique; Diaz, Yolande; Michel, Francois. Automatic identification of group I intron cores in genomic DNA sequences. J. Mol. Biol. (1994), 235(4), 1206-17.

    iiiHerschlag, Daniel; Cech, Thomas R.. Catalysis of RNA cleavage by the Tetrahymena thermophila ribozyme. 1. Kinetic description of the reaction of an RNA substrate complementary to the active site. Biochemistry (1990), 29(44), 10159-71.

    ivHerschlag, Daniel; Cech, Thomas R.. Catalysis of RNA cleavage by the Tetrahymena thermophila ribozyme. 2. Kinetic description of the reaction of an RNA substrate that forms a mismatch at the active site. Biochemistry (1990), 29(44), 10172-80.

    vKnitt, Deborah S.; Herschlag, Daniel. pH Dependencies of the Tetrahymena Ribozyme Reveal an Unconventional Origin of an Apparent pKa. Biochemistry (1996), 35(5), 1560-70.

    viBevilacqua, Philip C.; Sugimoto, Naoki; Turner, Douglas H.. A mechanistic framework for the second step of splicing catalyzed by the Tetrahymena ribozyme. Biochemistry (1996), 35(2), 648-58.

    viiLi, Yi; Bevilacqua, Philip C.; Mathews, David; Turner, Douglas H.. Thermodynamic and activation parameters for binding of a pyrene-labeled substrate by the Tetrahymena ribozyme: docking is not diffusion-controlled and is driven by a favorable entropy change. Biochemistry (1995), 34(44), 14394-9.

    viiiBanerjee, Aloke Raj; Turner, Douglas H.. The time dependence of chemical modification reveals slow steps in the folding of a group I ribozyme. Biochemistry (1995), 34(19), 6504-12.

    ixZarrinkar, Patrick P.; Williamson, James R.. The P9.1-P9.2 peripheral extension helps guide folding of the Tetrahymena ribozyme. Nucleic Acids Res. (1996), 24(5), 854-8.

    xStrobel, Scott A.; Cech, Thomas R.. Minor groove recognition of the conserved G.cntdot.U pair at the Tetrahymena ribozyme reaction site. Science (Washington, D. C.) (1995), 267(5198), 675-9.

    xiStrobel, Scott A.; Cech, Thomas R.. Exocyclic Amine of the Conserved G.cntdot.U Pair at the Cleavage Site of the Tetrahymena Ribozyme Contributes to 5′-Splice Site Selection and Transition State Stabilization. Biochemistry (1996), 35(4), 1201-11.

    xiiSullenger, Bruce A.; Cech, Thomas R.. Ribozyme-mediated repair of defective mRNA by targeted trans-splicing. Nature (London) (1994), 371(6498), 619-22.

    xiiiRobertson, H. D.; Altman, S.; Smith, J. D. J. Biol. Chem., 247, 5243-5251 (1972)

    xivForster, Anthony C.; Altman, Sidney. External guide sequences for an RNA enzyme. Science (Washington, D. C., 1883-) (1990), 249(4970), 783-6.

    xvYuan, Y.; Hwang, E. S.; Altman, S. Targeted cleavage of mRNA by human RNase P. Proc. Natl. Acad. Sci. USA (1992) 89, 8006-10.

    xviHarris, Michael E.; Pace, Norman R.. Identification of phosphates involved in catalysis by the ribozyme RNase P RNA. RNA (1995), 1(2), 210-18.

    xviiPan, Tao; Loria, Andrew; Zhong, Kun. Probing of tertiary interactions in RNA: 2′-hydroxyl-base contacts between the RNase P RNA and pre-tRNA. Proc. Natl. Acad. Sci. U.S.A. (1995), 92(26), 12510-14.

    xviiiPyle, Anna Marie; Green, Justin B.. Building a Kinetic Framework for Group II Intron Ribozyme Activity: Quantitation of Interdomain Binding and Reaction Rate. Biochemistry (1994), 33(9), 2716-25.

    xixMichels, William J. Jr.; Pyle, Anna Marie. Conversion of a Group II Intron into a New Multiple-Turnover Ribozyme that Selectively Cleaves Oligonucleotides: Elucidation of Reaction Mechanism and Structure/Function Relationships. Biochemistry (1995), 34(9), 2965-77.

    xxZimmerly, Steven; Guo, Huatao; Eskes, Robert; Yang, Jian; Perlman, Philip S.; Lambowitz, Alan M.. A group II intron RNA is a catalytic component of a DNA endonuclease involved in intron mobility. Cell (Cambridge, Mass.) (1995), 83(4), 529-38.

    xxiGriffin, Edmund A., Jr.; Qin, Zhifeng; Michels, Williams J., Jr.; Pyle, Anna Marie. Group II intron ribozymes that cleave DNA and RNA linkages with similar efficiency, and lack contacts with substrate 2′-hydroxyl groups. Chem. Biol. (1995), 2(11), 761-70.

    xxiiMichel, Francois; Ferat, Jean Luc. Structure and activities of group II introns. Annu. Rev. Biochem. (1995), 64, 435-61.

    xxiiiAbramovitz, Dana L.; Friedman, Richard A.; Pyle, Anna Marie. Catalytic role of 2′-hydroxyl groups within a group II intron active site. Science (Washington, D. C.) (1996), 271(5254), 1410-13.

    xxivDaniels, Danette L.; Michels, William J., Jr.; Pyle, Anna Marie. Two competing pathways for self-splicing by group II introns: a quantitative analysis of in vitro reaction rates and products. J. Mol. Biol. (1996), 256(1), 31-49.

    xxvGuo, Hans C. T.; Collins, Richard A.. Efficient trans-cleavage of a stem-loop RNA substrate by a ribozyme derived from Neurospora VS RNA. EMBO J. (1995), 14(2), 368-76.

    xxviScott, W. G., Finch, J. T., Aaron, K. The crystal structure of an all RNA hammerhead ribozyme:Aproposed mechanism for RNA catalytic cleavage. Cell, (1995), 81, 991-1002.

    xxviiMcKay, Structure and function of the hammerhead ribozyme: an unfinished story. RNA, (1996), 2, 395-403.

    xxviiiLong, D., UhIenbeck, O., Hertel, K. Ligation with hammerhead ribozymes. U.S. Pat. No. 5,633,133.

    xxixHertel, K. J., Herschlag, D., Uhlenbeck, O. A kinetic and thermodynamic framework for the hammerhead ribozyme reaction. Biochemistry, (1994) 33, 3374-3385. Beigelman, L., et al., Chemical modifications of hammerhead ribozymes. J. Biol. Chem., (1995) 270, 25702-25708.

    xxxBeigelman, L., et al., Chemical modifications of hammerhead ribozymes. J. Biol. Chem., (1995) 270, 25702-25708.

    xxxiHampel, Arnold; Tritz, Richard; Hicks, Margaret; Cruz, Philip. ‘Hairpin’ catalytic RNA model: evidence for helixes and sequence requirement for substrate RNA. Nucleic Acids Res. (1990), 18(2), 299-304.

    xxxiiChowrira, Bharat M.; Berzal-Herranz, Alfredo; Burke, John M.. Novel guanosine requirement for catalysis by the hairpin ribozyme. Nature (London) (1991), 354(6351), 320-2.

    xxxiiiBerzal-Herranz, Alfredo; Joseph, Simpson; Chowrira, Bharat M.; Butcher, Samuel E.; Burke, John M.. Essential nucleotide sequences and secondary structure elements of the hairpin ribozyme. EMBO J. (1993), 12(6), 2567-73.

    xxxivJoseph, Simpson; Berzal-Herranz, Alfredo; Chowrira, Bharat M.; Butcher, Samuel E.. Substrate selection rules for the hairpin ribozyme determined by in vitro selection, mutation, and analysis of mismatched substrates. Genes Dev. (1993), 7(1), 130-8.

    xxxvBerzal-Herranz, Alfredo; Joseph, Simpson; Burke, John M.. In vitro selection of active hairpin ribozymes by sequential RNA-catalyzed cleavage and ligation reactions. Genes Dev. (1992), 6(1), 129-34.

    xxxviHegg, Lisa A.; Fedor, Martha J.. Kinetics and Thermodynamics of Intermolecular Catalysis by Hairpin Ribozymes. Biochemistry (1995), 34(48), 15813-28.

    xxxviiGrasby, Jane A.; Mersmann, Karin; Singh, Mohinder; Gait, Michael J.. Purine Functional Groups in Essential Residues of the Hairpin Ribozyme Required for Catalytic Cleavage of RNA. Biochemistry (1995), 34(12), 4068-76.

    xxxviiiSchmidt, Sabine; Beigelman, Leonid; Karpeisky, Alexander; Usman, Nassim; Sorensen, Ulrik S.; Gait, Michael J.. Base and sugar requirements for RNA cleavage of essential nucleoside residues in internal loop B of the hairpin ribozyme: implications for secondary structure. Nucleic Acids Res. (1996), 24(4), 573-81.

    xxxixPerrotta, Anne T.; Been, Michael D.. Cleavage of oligoribonucleotides by a ribozyme derived from the hepatitis delta. virus RNA sequence. Biochemistry (1992), 31(1), 16-21.

    xlPerrotta, Anne T.; Been, Michael D.. A pseudoknot-like structure required for efficient self-cleavage of hepatitis delta virus RNA. Nature (London) (1991), 350(6317), 434-6.

    xliPuttaraju, M.; Perrotta, Anne T.; Been, Michael D.. A circular trans-acting hepatitis delta virus ribozyme. Nucleic Acids Res. (1993), 21(18), 4253-8.
  • TABLE II
    Reagent Equivalents Amount Wait Time* DNA Wait Time* 2′-O-methyl Wait Time*RNA
    A. 2.5 μmol Synthesis Cycle ABI 394 Instrument
    Phosphoramidites 6.5 163 μL 45 sec 2.5 min 7.5 min
    S-Ethyl Tetrazole 23.8 238 μL 45 sec 2.5 min 7.5 min
    Acetic Anhydride 100 233 μL 5 sec 5 sec 5 sec
    N-Methyl 186 233 μL 5 sec 5 sec 5 sec
    Imidazole
    TCA 176 2.3 mL 21 sec 21 sec 21 sec
    Iodine 11.2 1.7 mL 45 sec 45 sec 45 sec
    Beaucage 12.9 645 μL 100 sec 300 sec 300 sec
    Acetonitrile NA 6.67 mL NA NA NA
    B. 0.2 μmol Synthesis Cycle ABI 394 Instrument
    Phosphoramidites 15 31 μL 45 sec 233 sec 465 sec
    S-Ethyl Tetrazole 38.7 31 μL 45 sec 233 min 465 sec
    Acetic Anhydride 655 124 μL 5 sec 5 sec 5 sec
    N-Methyl 1245 124 μL 5 sec 5 sec 5 sec
    Imidazole
    TCA 700 732 μL 10 sec 10 sec 10 sec
    Iodine 20.6 244 μL 15 sec 15 sec 15 sec
    Beaucage 7.7 232 μL 100 sec 300 sec 300 sec
    Acetonitrile NA 2.64 mL NA NA NA
    C. 0.2 μmol Synthesis Cycle 96 well Instrument
    Equivalents: DNA/ Amount: DNA/2′-O- Wait Time* 2′-O-
    Reagent 2′-O-methyl/Ribo methyl/Ribo Wait Time* DNA methyl Wait Time* Ribo
    Phosphoramidites   22/33/66 40/60/120 μL 60 sec 180 sec 360 sec
    S-Ethyl Tetrazole   70/105/210 40/60/120 μL 60 sec 180 min 360 sec
    Acetic Anhydride  265/265/265 50/50/50 μL 10 sec 10 sec 10 sec
    N-Methyl  502/502/502 50/50/50 μL 10 sec 10 sec 10 sec
    Imidazole
    TCA  238/475/475 250/500/500 μL 15 sec 15 sec 15 sec
    Iodine  6.8/6.8/6.8 80/80/80 μL 30 sec 30 sec 30 sec
    Beaucage   34/51/51 80/120/120 100 sec 200 sec 200 sec
    Acetonitrile NA 1150/1150/1150 μL NA NA NA

    *Wait time does not include contact time during delivery.
  • TABLE III
    Human IKK-gamma Hammerhead and Substrate Sequence
    Seq Seq
    Pos Substrate ID Hammerhead ID
    18 AUGGCCCU U GUGAUCCA 4361 UGGAUCAC CUGAUGAGGCCGUUAGGCCGAA AGGGCCAU 4555
    24 CUUGUGAU C CAGGUGGG 4362 CCCACCUG CUGAUGAGGCCGUUAGGCCGAA AUCACAAG 4556
    39 GGGAAACU A AGGCCCAG 4363 CUGGGCCU CUGAUGAGGCCGUUAGGCCGAA AGUUUCCC 4557
    70 CGCAGACU A UCAAUCCC 4364 GGGAUUGA CUGAUGAGGCCGUUAGGCCGAA AGUCUGCG 4558
    72 CAGACUAU C AAUCCCAG 4365 CUGGGAUU CUGAUGAGGCCGUUAGGCCGAA AUAGUCUG 4559
    76 CUAUCAAU C CCAGUCUC 4366 GAGACUGG CUGAUGAGGCCGUUAGGCCGAA AUUGAUAG 4560
    82 AUCCCAGU C UCUUCCCC 4367 GGGGAAGA CUGAUGAGGCCGUUAGGCCGAA ACUGGGAU 4561
    84 CCCAGUCU C UUCCCCUC 4368 GAGGGGAA CUGAUGAGGCCGUUAGGCCGAA AGACUGGG 4562
    86 CAGUCUCU U CCCCUCAC 4369 GUGAGGGG CUGAUGAGGCCGUUAGGCCGAA AGAGACUG 4563
    87 AGUCUCUU C CCCUCACU 4370 AGUGAGGG CUGAUGAGGCCGUUAGGCCGAA AAGAGACU 4564
    92 CUUCCCCU C ACUCCCUG 4371 CAGGGAGU CUGAUGAGGCCGUUAGGCCGAA AGGGGAAG 4565
    96 CCCUCACU C CCUGUGAA 4372 UUCACAGG CUGAUGAGGCCGUUAGGCCGAA AGUGAGGG 4566
    108 GUGAAGCU C UCCAGCAU 4373 AUGCUGGA CUGAUGAGGCCGUUAGGCCGAA AGCUUCAC 4567
    110 GAAGCUCU C CAGCAUCA 4374 UGAUGCUG CUGAUGAGGCCGUUAGGCCGAA AGAGCUUC 4568
    117 UCCAGCAU C AUCGAGGU 4375 ACCUCGAU CUGAUGAGGCCGUUAGGCCGAA AUGCUGGA 4569
    120 AGCAUCAU C GAGGUCCC 4376 GGGACCUC CUGAUGAGGCCGUUAGGCCGAA AUGAUGCU 4570
    126 AUCGAGGU C CCAUCAGC 4377 GCUGAUGG CUGAUGAGGCCGUUAGGCCGAA ACCUCGAU 4571
    131 GGUCCCAU C AGCCCUUG 4378 CAAGGGCU CUGAUGAGGCCGUUAGGCCGAA AUGGGACC 4572
    138 UCAGCCCU U GCCCUGUU 4379 AACAGGGC CUGAUGAGGCCGUUAGGCCGAA AGGGCUGA 4573
    146 UGCCCUGU U GGAUGAAU 4380 AUUCAUCC CUGAUGAGGCCGUUAGGCCGAA ACAGGGCA 4574
    155 GGAUGAAU A GGCACCUC 4381 GAGGUGCC CUGAUGAGGCCGUUAGGCCGAA AUUCAUCC 4575
    163 AGGCACCU C UGGAAGAG 4382 CUCUUCCA CUGAUGAGGCCGUUAGGCCGAA AGCUGCCU 4576
    218 CAGCAGAU C AGGACGUA 4383 UACGUCCU CUGAUGAGGCCGUUAGGCCGAA AUCUGCUG 4577
    226 CAGGACGU A CUGGGCGA 4384 UCGCCCAG CUGAUGAGGCCGUUAGGCCGAA ACGUCCUG 4578
    240 CGAAGAGU C UCCUCUGG 4385 CCAGAGGA CUGAUGAGGCCGUUAGGCCGAA ACUCUUCG 4579
    242 AAGAGUCU C CUCUGGGG 4386 CCCCAGAG CUGAUGAGGCCGUUAGGCCGAA AGACUCUU 4580
    245 AGUCUCCU C UGGGGAAG 4387 CUUCCCCA CUGAUGAGGCCGUUAGGCCGAA AGGAGACU 4581
    275 ACCUGCCU U CAGAACAG 4388 CUGUUCUG CUGAUGAGGCCGUUAGGCCGAA AGGCAGGU 4582
    276 CCUGCCUU C AGAACAGG 4389 CCUGUUCU CUGAUGAGGCCGUUAGGCCGAA AAGGCAGG 4583
    290 AGGGCGCU C CUGAGACC 4390 GGUCUCAG CUGAUGAGGCCGUUAGGCCGAA AGCGCCCU 4584
    301 GAGACCCU C CAGCGCUG 4391 CAGCGCUG CUGAUGAGGCCGUUAGGCCGAA AGGGUCUC 4585
    323 AGGAGAAU C AAGAGCUC 4392 GAGCUCUU CUGAUGAGGCCGUUAGGCCGAA AUUCUCCU 4586
    331 CAAGAGCU C CGAGAUGC 4393 GCAUCUCG CUGAUGAGGCCGUUAGGCCGAA AGCUCUUG 4587
    343 GAUGCCAU C CGGCAGAG 4394 CUCUGCCG CUGAUGAGGCCGUUAGGCCGAA AUGGCAUC 4588
    361 AACCAGAU U CUGCGGGA 4395 UCCCGCAG CUGAUGAGGCCGUUAGGCCGAA AUCUGGUU 4589
    362 ACCAGAUU C UGCGGGAG 4396 CUCCCGCA CUGAUGAGGCCGUUAGGCCGAA AAUCUGGU 4590
    385 GAGGAGCU U CUGCAUUU 4397 AAAUGCAG CUGAUGAGGCCGUUAGGCCGAA AGCUCCUC 4591
    386 AGGAGCUU C UGCAUUUC 4398 GAAAUGCA CUGAUGAGGCCGUUAGGCCGAA AAGCUCCU 4592
    392 UUCUGCAU U UCCAAGCC 4399 GGCUUGGA CUGAUGAGGCCGUUAGGCCGAA AUGCAGAA 4593
    393 UCUGCAUU U CCAAGCCA 4400 UGGCUUGG CUGAUGAGGCCGUUAGGCCGAA AAUGCAGA 4594
    394 CUGCAUUU C CAAGCCAG 4401 CUGGCUUG CUGAUGAGGCCGUUAGGCCGAA AAAUGCAG 4595
    423 GAAGGAGU U CCUCAUGU 4402 ACAUGAGG CUGAUGAGGCCGUUAGGCCGAA ACUCCUUC 4596
    424 AAGGAGUU C CUCAUGUG 4403 CACAUGAG CUGAUGAGGCCGUUAGGCCGAA AACUCCUU 4597
    427 GAGUUCCU C AUGUGCAA 4404 UUGCACAU CUGAUGAGGCCGUUAGGCCGAA AGGAACUC 4598
    438 GUGCAAGU U CCAGGAGG 4405 CCUCCUGG CUGAUGAGGCCGUUAGGCCGAA ACUUGCAC 4599
    439 UGCAAGUU C CAGGAGGC 4406 GCCUCCUG CUGAUGAGGCCGUUAGGCCGAA AACUUGCA 4600
    469 GAGAGACU C GGCCUGGA 4407 UCCAGGCC CUGAUGAGGCCGUUAGGCCGAA AGUCUCUC 4601
    484 GAGAAGCU C GAUCUGAA 4408 UUCAGAUC CUGAUGAGGCCGUUAGGCCGAA AGCUUCUC 4602
    488 AGCUCGAU C UGAAGAGG 4409 CCUCUUCA CUGAUGAGGCCGUUAGGCCGAA AUCGAGCU 4603
    512 AGCAGGCU C UGCGGGAG 4410 CUCCCGCA CUGAUGAGGCCGUUAGGCCGAA AGCCUGCU 4604
    570 CAAGGCCU C UGUGAAAG 4411 CUUUCACA CUGAUGAGGCCGUUAGGCCGAA AGGCCUUG 4605
    591 GGUGACGU C CUUGCUCG 4412 CGAGCAAG CUGAUGAGGCCGUUAGGCCGAA ACGUCACC 4606
    594 GACGUCCU U GCUCGGGG 4413 CCCCGAGC CUGAUGAGGCCGUUAGGCCGAA AGGACGUC 4607
    598 UCCUUGCU C GGGGAGCU 4414 AGCUCCCC CUGAUGAGGCCGUUAGGCCGAA AGCAAGGA 4608
    623 GCCAGAGU C GCUUGGAG 4415 CUCCAAGC CUGAUGAGGCCGUUAGGCCGAA ACUCUGGC 4609
    627 GAGUCGCU U GGAGGCUG 4416 CAGCCUCC CUGAUGAGGCCGUUAGGCCGAA AGCGACUC 4610
    641 CUGCCACU A AGGAAUGC 4417 GCAUUCCU CUGAUGAGGCCGUUAGGCCGAA AGUGGCAG 4611
    656 GCCAGGCU C UGGAGGGU 4418 ACCCUCCA CUGAUGAGGCCGUUAGGCCGAA AGCCUGGC 4612
    665 UGGAGGGU C GGGCCCGG 4419 CCGGGCCC CUGAUGAGGCCGUUAGGCCGAA ACCCUCCA 4613
    787 GCCGCGCU C CGCAUGGA 4420 UCCAUGCG CUGAUGAGGCCGUUAGGCCGAA AGCGCGGC 4614
    810 GGCCGCCU C GGAGGAGA 4421 UCUCCUCC CUGAUGAGGCCGUUAGGCCGAA AGGCGGCC 4615
    837 GGCCCAGU U GCAGGUGG 4422 CCACCUGC CUGAUGAGGCCGUUAGGCCGAA ACUGGGCC 4616
    849 GGUGGCCU A UCACCAGC 4423 GCUGGUGA CUGAUGAGGCCGUUAGGCCGAA AGGCCACC 4617
    851 UGGCCUAU C ACCAGCUC 4424 GAGCUGGU CUGAUGAGGCCGUUAGGCCGAA AUAGGCCA 4618
    859 CACCAGCU C UUCCAAGA 4425 UCUUGGAA CUGAUGAGGCCGUUAGGCCGAA AGCUGGUG 4619
    861 CCAGCUCU U CCAAGAAU 4426 AUUCUUGG CUGAUGAGGCCGUUAGGCCGAA AGAGCUGG 4620
    862 CAGCUCUU C CAAGAAUA 4427 UAUUCUUG CUGAUGAGGCCGUUAGGCCGAA AAGAGCUG 4621
    870 CCAAGAAU A CGACAACC 4428 GGUUGUCG CUGAUGAGGCCGUUAGGCCGAA AUUCUUGG 4622
    883 AACCACAU C AAGAGCAG 4429 CUGCUCUU CUGAUGAGGCCGUUAGGCCGAA AUGUGGUU 4623
    935 UGGAAGAU C UCAAACAG 4430 CUGUUUGA CUGAUGAGGCCGUUAGGCCGAA AUCUUCCA 4624
    937 GAAGAUCU C AAACAGCA 4431 UGCUGUUU CUGAUGAGGCCGUUAGGCCGAA AGAUCUUC 4625
    949 CAGCAGCU C CAGCAGGC 4432 GCCUGCUG CUGAUGAGGCCGUUAGGCCGAA AGCUGCUG 4626
    991 GAGGUGAU C GAUAAGCU 4433 AGCUUAUC CUGAUGAGGCCGUUAGGCCGAA AUCACCUC 4627
    995 UGAUCGAU A AGCUGAAG 4434 CUUCAGCU CUGAUGAGGCCGUUAGGCCGAA AUCGAUCA 4628
    1027 CACAAGAU U GUGAUGGA 4435 UCCAUCAC CUGAUGAGGCCGUUAGGCCGAA AUCUUGUG 4629
    1042 GAGACCGU U CCGGUGCU 4436 AGCACCGG CUGAUGAGGCCGUUAGGCCGAA ACGGUCUC 4630
    1043 AGACCGUU C CGGUGCUG 4437 CAGCACCG CUGAUGAGGCCGUUAGGCCGAA AACGGUCU 4631
    1067 AGGCGGAU A UCUACAAG 4438 CUUGUAGA CUGAUGAGGCCGUUAGGCCGAA AUCCGCCU 4632
    1069 GCGGAUAU C UACAAGGC 4439 GCCUUGUA CUGAUGAGGCCGUUAGGCCGAA AUAUCCGC 4633
    1071 GGAUAUCU A CAAGGCGG 4440 CCGCCUUG CUGAUGAGGCCGUUAGGCCGAA AGAUAUCC 4634
    1083 GGCGGACU U CCAGGCUG 4441 CAGCCUGG CUGAUGAGGCCGUUAGGCCGAA AGUCCGCC 4635
    1084 GCGGACUU C CAGGCUGA 4442 UCAGCCUG CUGAUGAGGCCGUUAGGCCGAA AAGUCCGC 4636
    1132 AAGGAGCU C CUGCAGGA 4443 UCCUGCAG CUGAUGAGGCCGUUAGGCCGAA AGCUCCUU 4637
    1167 GAGGGAGU A CAGCAAAC 4444 GUUUGCUG CUGAUGAGGCCGUUAGGCCGAA ACUCCCUC 4638
    1190 CCAGCUGU C AGGAGUCG 4445 CGACUCCU CUGAUGAGGCCGUUAGGCCGAA ACAGCUGG 4639
    1197 UCAGGAGU C GGCCAGGA 4446 UCCUGGCC CUGAUGAGGCCGUUAGGCCGAA ACUCCUGA 4640
    1207 GCCAGGAU C GAGGACAU 4447 AUGUCCUC CUGAUGAGGCCGUUAGGCCGAA AUCCUGGC 4641
    1231 CGGCAUGU C GAGGUCUC 4448 GAGACCUC CUGAUGAGGCCGUUAGGCCGAA ACAUGCCG 4642
    1237 GUCGAGGU C UCCCAGGC 4449 GCCUGGGA CUGAUGAGGCCGUUAGGCCGAA ACCUCGAC 4643
    1239 CGAGGUCU C CCAGGCCC 4450 GGGCCUGG CUGAUGAGGCCGUUAGGCCGAA AGACCUCG 4644
    1251 GGCCCCCU U GCCCCCCG 4451 CGGGGGGC CUGAUGAGGCCGUUAGGCCGAA AGGGGGCC 4645
    1269 CCCUGCCU A CCUCUCCU 4452 AGGAGAGG CUGAUGAGGCCGUUAGGCCGAA AGGCAGGG 4646
    1273 GCCUACCU C UCCUCUCC 4453 GGAGAGGA CUGAUGAGGCCGUUAGGCCGAA AGGUAGGC 4647
    1275 CUACCUCU C CUCUCCCC 4454 GGGGAGAG CUGAUGAGGCCGUUAGGCCGAA AGAGGUAG 4648
    1278 CCUCUCCU C UCCCCUGG 4455 CCAGGGGA CUGAUGAGGCCGUUAGGCCGAA AGGAGAGG 4649
    1280 UCUCCUCU C CCCUGGCC 4456 GGCCAGGG CUGAUGAGGCCGUUAGGCCGAA AGAGGAGA 4650
    1332 ACCUGACU U CUGCUGUC 4457 GACAGCAG CUGAUGAGGCCGUUAGGCCGAA AGUCAGGU 4651
    1333 CCUGACUU C UGCUGUCC 4458 GGACAGCA CUGAUGAGGCCGUUAGGCCGAA AAGUCAGG 4652
    1340 UCUGCUGU C CCAAGUGC 4459 GCACUUGG CUGAUGAGGCCGUUAGGCCGAA ACAGCAGA 4653
    1353 GUGCCAGU A UCAGGCCC 4460 GGGCCUGA CUGAUGAGGCCGUUAGGCCGAA ACUGGCAC 4654
    1355 GCCAGUAU C AGGCCCCU 4461 AGGGGCCU CUGAUGAGGCCGUUAGGCCGAA AUACUGGC 4655
    1367 CCCCUGAU A UGGACACC 4462 GGUGUCCA CUGAUGAGGCCGUUAGGCCGAA AUCAGGGG 4656
    1384 CUGCAGAU A CAUGUCAU 4463 AUGACAUG CUGAUGAGGCCGUUAGGCCGAA AUCUGCAG 4657
    1390 AUACAUGU C AUGGAGUG 4464 CACUCCAU CUGAUGAGGCCGUUAGGCCGAA ACAUGUAU 4658
    1402 GAGUGCAU U GAGUAGGG 4465 CCCUACUC CUGAUGAGGCCGUUAGGCCGAA AUGCACUC 4659
    1407 CAUUGAGU A GGGCCGGC 4466 GCCGGCCC CUGAUGAGGCCGUUAGGCCGAA ACUCAAUG 4660
    1464 CGUGCAGU C UGCGCUUU 4467 AAAGCGCA CUGAUGAGGCCGUUAGGCCGAA ACUGCACG 4661
    1471 UCUGCGCU U UCCUCUCC 4468 GGAGAGGA CUGAUGAGGCCGUUAGGCCGAA AGCGCAGA 4662
    1472 CUGCGCUU U CCUCUCCC 4469 GGGAGAGG CUGAUGAGGCCGUUAGGCCGAA AAGCGCAG 4663
    1473 UGCGCUUU C CUCUCCCG 4470 CGGGAGAG CUGAUGAGGCCGUUAGGCCGAA AAAGCGCA 4664
    1476 GCUUUCCU C UCCCGCCU 4471 AGGCGGGA CUGAUGAGGCCGUUAGGCCGAA AGGAAAGC 4665
    1478 UUUCCUCU C CCGCCUGC 4472 GCAGGCGG CUGAUGAGGCCGUUAGGCCGAA AGAGGAAA 4666
    1489 GCCUGCCU A GCCCAGGA 4473 UCCUGGGC CUGAUGAGGCCGUUAGGCCGAA AGGCAGGC 4667
    1565 CGGCACCU U ACGCUUCA 4474 UGAAGCGU CUGAUGAGGCCGUUAGGCCGAA AGGUGCCG 4668
    1566 GGCACCUU A CGCUUCAG 4475 CUGAAGCG CUGAUGAGGCCGUUAGGCCGAA AAGGUGCC 4669
    1571 CUUACGCU U CAGCUGUU 4476 AACAGCUG CUGAUGAGGCCGUUAGGCCGAA AGCGUAAG 4670
    1572 UUACGCUU C AGCUGUUG 4477 CAACAGCU CUGAUGAGGCCGUUAGGCCGAA AAGCGUAA 4671
    1579 UCAGCUGU U GAUCCGCU 4478 AGCGGAUC CUGAUGAGGCCGUUAGGCCGAA ACAGCUGA 4672
    1583 CUGUUGAU C CGCUGGUC 4479 GACCAGCG CUGAUGAGGCCGUUAGGCCGAA AUCAACAG 4673
    1591 CCGCUGGU C CCCUCUUU 4480 AAAGAGGG CUGAUGAGGCCGUUAGGCCGAA ACCAGCGG 4674
    1596 GGUCCCCU C UUUUGGGG 4481 CCCCAAAA CUGAUGAGGCCGUUAGGCCGAA AGGGGACC 4675
    1598 UCCCCUCU U UUGGGGUA 4482 UACCCCAA CUGAUGAGGCCGUUAGGCCGAA AGAGGGGA 4676
    1599 CCCCUCUU U UGGGGUAG 4483 CUACCCCA CUGAUGAGGCCGUUAGGCCGAA AAGAGGGG 4677
    1600 CCCUCUUU U GGGGUAGA 4484 UCUACCCC CUGAUGAGGCCGUUAGGCCGAA AAAGAGGG 4678
    1606 UUUGGGGU A GAUGCGGC 4485 GCCGCAUC CUGAUGAGGCCGUUAGGCCGAA ACCCCAAA 4679
    1621 GCCCCGAU C AGGCCUGA 4486 UCAGGCCU CUGAUGAGGCCGUUAGGCCGAA AUCGGGGC 4680
    1632 GCCUGACU C GCUGCUCU 4487 AGAGCAGC CUGAUGAGGCCGUUAGGCCGAA AGUCAGGC 4681
    1639 UCGCUGCU C UUUUUGUU 4488 AACAAAAA CUGAUGAGGCCGUUAGGCCGAA AGCAGCGA 4682
    1641 GCUGCUCU U UUUGUUCC 4489 GGAACAAA CUGAUGAGGCCGUUAGGCCGAA AGAGCAGC 4683
    1642 CUGCUCUU U UUGUUCCC 4490 GGGAACAA CUGAUGAGGCCGUUAGGCCGAA AAGAGCAG 4684
    1643 UGCUCUUU U UGUUCCCU 4491 AGGGAACA CUGAUGAGGCCGUUAGGCCGAA AAAGAGCA 4685
    1644 GCUCUUUU U GUUCCCUU 4492 AAGGGAAC CUGAUGAGGCCGUUAGGCCGAA AAAAGAGC 4686
    1647 CUUUUUGU U CCCUUCUG 4493 CAGAAGGG CUGAUGAGGCCGUUAGGCCGAA ACAAAAAG 4687
    1648 UUUUUGUU C CCUUCUGU 4494 ACAGAAGG CUGAUGAGGCCGUUAGGCCGAA AACAAAAA 4688
    1652 UGUUCCCU U CUGUCUGC 4495 GCAGACAG CUGAUGAGGCCGUUAGGCCGAA AGGGAACA 4689
    1653 GUUCCCUU C UGUCUGCU 4496 AGCAGACA CUGAUGAGGCCGUUAGGCCGAA AAGGGAAC 4690
    1657 CCUUCUGU C UGCUCGAA 4497 UUCGAGCA CUGAUGAGGCCGUUAGGCCGAA ACAGAAGG 4691
    1662 UGUCUGCU C GAACCACU 4498 AGUGGUUC CUGAUGAGGCCGUUAGGCCGAA AGCAGACA 4692
    1671 GAACCACU U GCCUCGGG 4499 CCCGAGGC CUGAUGAGGCCGUUAGGCCGAA AGUGGUUC 4693
    1676 ACUUGCCU C GGGCUAAU 4500 AUUAGCCC CUGAUGAGGCCGUUAGGCCGAA AGGCAAGU 4694
    1682 CUCGGGCU A AUCCCUCC 4501 GGAGGGAU CUGAUGAGGCCGUUAGGCCGAA AGCCCGAG 4695
    1685 GGGCUAAU C CCUCCCUC 4502 GAGGGAGG CUGAUGAGGCCGUUAGGCCGAA AUUAGCCC 4696
    1689 UAAUCCCU C CCUCUUCC 4503 GGAAGAGG CUGAUGAGGCCGUUAGGCCGAA AGGGAUUA 4697
    1693 CCCUCCCU C UUCCUCCA 4504 UGGAGGAA CUGAUGAGGCCGUUAGGCCGAA AGGGAGGG 4698
    1695 CUCCCUCU U CCUCCACC 4505 GGUGGAGG CUGAUGAGGCCGUUAGGCCGAA AGAGGGAG 4699
    1696 UCCCUCUU C CUCCACCC 4506 GGGUGGAG CUGAUGAGGCCGUUAGGCCGAA AAGAGGGA 4700
    1699 CUCUUCCU C CACCCGGC 4507 GCCGGGUG CUGAUGAGGCCGUUAGGCCGAA AGGAAGAG 4701
    1719 GGGGAAGU C AAGAAUGG 4508 CCAUUCUU CUGAUGAGGCCGUUAGGCCGAA ACUUCCCC 4702
    1739 CUGGGGCU C UCAGGGAG 4509 CUCCCUGA CUGAUGAGGCCGUUAGGCCGAA AGCCCCAG 4703
    1741 GGGGCUCU C AGGGAGAA 4510 UUCUCCCU CUGAUGAGGCCGUUAGGCCGAA AGAGCCCC 4704
    1755 GAACUGCU U CCCCUGGC 4511 GCCAGGGG CUGAUGAGGCCGUUAGGCCGAA AGCAGUUC 4705
    1756 AACUGCUU C CCCUGGCA 4512 UGCCAGGG CUGAUGAGGCCGUUAGGCCGAA AAGCAGUU 4706
    1781 UGGCAGCU C UUCCUCCC 4513 GGGAGGAA CUGAUGAGGCCGUUAGGCCGAA AGCUGCCA 4707
    1783 GCAGCUCU U CCUCCCAC 4514 GUGGGAGG CUGAUGAGGCCGUUAGGCCGAA AGAGCUGC 4708
    1784 CAGCUCUU C CUCCCACC 4515 GGUGGGAG CUGAUGAGGCCGUUAGGCCGAA AAGAGCUG 4709
    1787 CUCUUCCU C CCACCGGA 4516 UCCGGUGG CUGAUGAGGCCGUUAGGCCGAA AGGAAGAG 4710
    1836 GCUGCCCU C UUACCAUG 4517 CAUGGUAA CUGAUGAGGCCGUUAGGCCGAA AGGGCAGC 4711
    1838 UGCCCUCU U ACCAUGCA 4518 UGCAUGGU CUGAUGAGGCCGUUAGGCCGAA AGAGGGCA 4712
    1839 GCCCUCUU A CCAUGCAC 4519 GUGCAUGG CUGAUGAGGCCGUUAGGCCGAA AAGAGGGC 4713
    1857 CGGGUGCU C UCCUUUUG 4520 CAAAAGGA CUGAUGAGGCCGUUAGGCCGAA AGCACCCG 4714
    1859 GGUGCUCU C CUUUUGGG 4521 CCCAAAAG CUGAUGAGGCCGUUAGGCCGAA AGAGCACC 4715
    1862 GCUCUCCU U UUGGGCUG 4522 CAGCCCAA CUGAUGAGGCCGUUAGGCCGAA AGGAGAGC 4716
    1863 CUCUCCUU U UGGGCUGC 4523 GCAGCCCA CUGAUGAGGCCGUUAGGCCGAA AAGGAGAG 4717
    1864 UCUCCUUU U GGGCUGCA 4524 UGCAGCCC CUGAUGAGGCCGUUAGGCCGAA AAAGGAGA 4718
    1877 UGCAUGCU A UUCCAUUU 4525 AAAUGGAA CUGAUGAGGCCGUUAGGCCGAA AGCAUGCA 4719
    1879 CAUGCUAU U CCAUUUUG 4526 CAAAAUGG CUGAUGAGGCCGUUAGGCCGAA AUAGCAUG 4720
    1880 AUGCUAUU C CAUUUUGC 4527 GCAAAAUG CUGAUGAGGCCGUUAGGCCGAA AAUAGCAU 4721
    1884 UAUUCCAU U UUGCAGCC 4528 GGCUGCAA CUGAUGAGGCCGUUAGGCCGAA AUGGAAUA 4722
    1885 AUUCCAUU U UGCAGCCA 4529 UGGCUGCA CUGAUGAGGCCGUUAGGCCGAA AAUGGAAU 4723
    1886 UUCCAUUU U GCAGCCAG 4530 CUGGCUGC CUGAUGAGGCCGUUAGGCCGAA AAAUGGAA 4724
    1905 CGAUGUGU A UUUAACCA 4531 UGGUUAAA CUGAUGAGGCCGUUAGGCCGAA ACACAUCG 4725
    1907 AUGUGUAU U UAACCAGU 4532 ACUGGUUA CUGAUGAGGCCGUUAGGCCGAA AUACACAU 4726
    1908 UGUGUAUU U AACCAGUC 4533 GACUGGUU CUGAUGAGGCCGUUAGGCCGAA AAUACACA 4727
    1909 GUGUAUUU A ACCAGUCA 4534 UGACUGGU CUGAUGAGGCCGUUAGGCCGAA AAAUACAC 4728
    1916 UAACCAGU C ACUAUUGA 4535 UCAAUAGU CUGAUGAGGCCGUUAGGCCGAA ACUGGUUA 4729
    1920 CAGUCACU A UUGAUGGA 4536 UCCAUCAA CUGAUGAGGCCGUUAGGCCGAA AGUGACUG 4730
    1922 GUCACUAU U GAUGGACA 4537 UGUCCAUC CUGAUGAGGCCGUUAGGCCGAA AUAGUGAC 4731
    1932 AUGGACAU U UGGGUUGU 4538 ACAACCCA CUGAUGAGGCCGUUAGGCCGAA AUGUCCAU 4732
    1933 UGGACAUU U GGGUUGUU 4539 AACAACCC CUGAUGAGGCCGUUAGGCCGAA AAUGUCCA 4733
    1938 AUUUGGGU U GUUUCCCA 4540 UGGGAAAC CUGAUGAGGCCGUUAGGCCGAA ACCCAAAU 4734
    1941 UGGGUUGU U UCCCAUCU 4541 AGAUGGGA CUGAUGAGGCCGUUAGGCCGAA ACAACCCA 4735
    1942 GGGUUGUU U CCCAUCUU 4542 AAGAUGGG CUGAUGAGGCCGUUAGGCCGAA AACAACCC 4736
    1943 GGUUGUUU C CCAUCUUU 4543 AAAGAUGG CUGAUGAGGCCGUUAGGCCGAA AAACAACC 4737
    1948 UUUCCCAU C UUUUUGUU 4544 AACAAAAA CUGAUGAGGCCGUUAGGCCGAA AUGGGAAA 4738
    1950 UCCCAUCU U UUUGUUAC 4545 GUAACAAA CUGAUGAGGCCGUUAGGCCGAA AGAUGGGA 4739
    1951 CCCAUCUU U UUGUUACC 4546 GGUAACAA CUGAUGAGGCCGUUAGGCCGAA AAGAUGGG 4740
    1952 CCAUCUUU U UGUUACCA 4547 UGGUAACA CUGAUGAGGCCGUUAGGCCGAA AAAGAUGG 4741
    1953 CAUCUUUU U GUUACCAU 4548 AUGGUAAC CUGAUGAGGCCGUUAGGCCGAA AAAAGAUG 4742
    1956 CUUUUUGU U ACCAUAAA 4549 UUUAUGGU CUGAUGAGGCCGUUAGGCCGAA ACAAAAAG 4743
    1957 UUUUUGUU A CCAUAAAU 4550 AUUUAUGG CUGAUGAGGCCGUUAGGCCGAA AACAAAAA 4744
    1962 GUUACCAU A AAUAAUGG 4551 CCAUUAUU CUGAUGAGGCCGUUAGGCCGAA AUGGUAAC 4745
    1966 CCAUAAAU A AUGGCAUA 4552 UAUGCCAU CUGAUGAGGCCGUUAGGCCGAA AUUUAUGG 4746
    1974 AAUGGCAU A GUAAAAAA 4553 UUUUUUAC CUGAUGAGGCCGUUAGGCCGAA AUGCCAUU 4747
    1977 GGCAUAGU A AAAAAAAA 4554 UUUUUUUU CUGAUGAGGCCGUUAGGCCGAA ACUAUGCC 4748

    Input Sequence = NM_003639. Cut Site = UH/.

    Arm Length = 8. Core Sequence = CUGAUGAG GCCGUUAGGC CGAA

    NM_003639 (Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), mRNA.; 1994 bp)

    Underlined region can be any X sequence or linker, as described herein.
  • TABLE IV
    Human IKK-gamma Inozyme and Substrate Sequence
    Seq Seq
    Pos Substrate ID Inozyme ID
    10 GCACGAGC A UGGCCCUU 4749 AAGGGCCA CUGAUGAGGCCGUUAGGCCGAA ICUCGUGC 5253
    15 AGCAUGGC C CUUGUGAU 4750 AUCACAAG CUGAUGAGGCCGUUAGGCCGAA ICCAUGCU 5254
    16 GCAUGGCC C UUGUGAUC 4751 GAUCACAA CUGAUGAGGCCGUUAGGCCGAA IGCCAUGC 5255
    17 CAUGGCCC U UGUGAUCC 4752 GGAUCACA CUGAUGAGGCCGUUAGGCCGAA IGGCCAUG 5256
    25 UUGUGAUC C AGGUGGGG 4753 CCCCACCU CUGAUGAGGCCGUUAGGCCGAA IAUCACAA 5257
    26 UGUGAUCC A GGUGGGGA 4754 UCCCCACC CUGAUGAGGCCGUUAGGCCGAA IGAUCACA 5258
    38 GGGGAAAC U AAGGCCCA 4755 UGGGCCUU CUGAUGAGGCCGUUAGGCCGAA IUUUCCCC 5259
    44 ACUAAGGC C CAGAGAAG 4756 CUUCUCUG CUGAUGAGGCCGUUAGGCCGAA ICCUUAGU 5260
    45 CUAAGGCC C AGAGAAGU 4757 ACUUCUCU CUGAUGAGGCCGUUAGGCCGAA IGCCUUAG 5261
    46 UAAGGCCC A GAGAAGUG 4758 CACUUCUC CUGAUGAGGCCGUUAGGCCGAA IGGCCUUA 5262
    60 GUGAGGAC C CCGCAGAC 4759 GUCUGCGG CUGAUGAGGCCGUUAGGCCGAA IUCCUCAC 5263
    61 UGAGGACC C CGCAGACU 4760 AGUCUGCG CUGAUGAGGCCGUUAGGCCGAA IGUCCUCA 5264
    62 GAGGACCC C GCAGACUA 4761 UAGUCUGC CUGAUGAGGCCGUUAGGCCGAA IGGUCCUC 5265
    65 GACCCCGC A GACUAUCA 4762 UGAUAGUC CUGAUGAGGCCGUUAGGCCGAA ICGGGGUC 5266
    69 CCGCAGAC U AUCAAUCC 4763 GGAUUGAU CUGAUGAGGCCGUUAGGCCGAA IUCUGCGG 5267
    73 AGACUAUC A AUCCCAGU 4764 ACUGGGAU CUGAUGAGGCCGUUAGGCCGAA IAUAGUCU 5268
    77 UAUCAAUC C CAGUCUCU 4765 AGAGACUG CUGAUGAGGCCGUUAGGCCGAA IAUUGAUA 5269
    78 AUCAAUCC C AGUCUCUU 4766 AAGAGACU CUGAUGAGGCCGUUAGGCCGAA IGAUUGAU 5270
    79 UCAAUCCC A GUCUCUUC 4767 GAAGAGAC CUGAUGAGGCCGUUAGGCCGAA IGGAUUGA 5271
    83 UCCCAGUC U CUUCCCCU 4768 AGGGGAAG CUGAUGAGGCCGUUAGGCCGAA IACUGGGA 5272
    85 CCAGUCUC U UCCCCUCA 4769 UGAGGGGA CUGAUGAGGCCGUUAGGCCGAA IAGACUGG 5273
    88 GUCUCUUC C CCUCACUC 4770 GAGUGAGG CUGAUGAGGCCGUUAGGCCGAA IAAGAGAC 5274
    89 UCUCUUCC C CUCACUCC 4771 GGAGUGAG CUGAUGAGGCCGUUAGGCCGAA IGAAGAGA 5275
    90 CUCUUCCC C UCACUCCC 4772 GGGAGUGA CUGAUGAGGCCGUUAGGCCGAA IGGAAGAG 5276
    91 UCUUCCCC U CACUCCCU 4773 AGGGAGUG CUGAUGAGGCCGUUAGGCCGAA IGGGAAGA 5277
    93 UUCCCCUC A CUCCCUGU 4774 ACAGGGAG CUGAUGAGGCCGUUAGGCCGAA IAGGGGAA 5278
    95 CCCCUCAC U CCCUGUGA 4775 UCACAGGG CUGAUGAGGCCGUUAGGCCGAA IUGAGGGG 5279
    97 CCUCACUC C CUGUGAAG 4776 CUUCACAG CUGAUGAGGCCGUUAGGCCGAA IAGUGAGG 5280
    98 CUCACUCC C UGUGAAGC 4777 GCUUCACA CUGAUGAGGCCGUUAGGCCGAA IGAGUGAG 5281
    99 UCACUCCC U GUGAAGCU 4778 AGCUUCAC CUGAUGAGGCCGUUAGGCCGAA IGGAGUGA 5282
    107 UGUGAAGC U CUCCAGCA 4779 UGCUGGAG CUGAUGAGGCCGUUAGGCCGAA ICUUCACA 5283
    109 UGAAGCUC U CCAGCAUC 4780 GAUGCUGG CUGAUGAGGCCGUUAGGCCGAA IAGCUUCA 5284
    111 AAGCUCUC C AGCAUCAU 4781 AUGAUGCU CUGAUGAGGCCGUUAGGCCGAA IAGAGCUU 5285
    112 AGCUCUCC A GCAUCAUC 4782 GAUGAUGC CUGAUGAGGCCGUUAGGCCGAA IGAGAGCU 5286
    115 UCUCCAGC A UCAUCGAG 4783 CUCGAUGA CUGAUGAGGCCGUUAGGCCGAA ICUGGAGA 5287
    118 CCAGCAUC A UCGAGGUC 4784 GACCUCGA CUGAUGAGGCCGUUAGGCCGAA IAUGCUGG 5288
    127 UCGAGGUC C CAUCAGCC 4785 GGCUGAUG CUGAUGAGGCCGUUAGGCCGAA IACCUCGA 5289
    128 CGAGGUCC C AUCAGCCC 4786 GGGCUGAU CUGAUGAGGCCGUUAGGCCGAA IGACCUCG 5290
    129 GAGGUCCC A UCAGCCCU 4787 AGGGCUGA CUGAUGAGGCCGUUAGGCCGAA IGGACCUC 5291
    132 GUCCCAUC A GCCCUUGC 4788 GCAAGGGC CUGAUGAGGCCGUUAGGCCGAA IAUGGGAC 5292
    135 CCAUCAGC C CUUGCCCU 4789 AGGGCAAG CUGAUGAGGCCGUUAGGCCGAA ICUGAUGG 5293
    136 CAUCAGCC C UUGCCCUG 4790 CAGGGCAA CUGAUGAGGCCGUUAGGCCGAA IGCUGAUG 5294
    137 AUCAGCCC U UGCCCUGU 4791 ACAGGGCA CUGAUGAGGCCGUUAGGCCGAA IGGCUGAU 5295
    141 GCCCUUGC C CUGUUGGA 4792 UCCAACAG CUGAUGAGGCCGUUAGGCCGAA ICAAGGGC 5296
    142 CCCUUGCC C UGUUGGAU 4793 AUCCAACA CUGAUGAGGCCGUUAGGCCGAA IGCAAGGG 5297
    143 CCUUGCCC U GUUGGAUG 4794 CAUCCAAC CUGAUGAGGCCGUUAGGCCGAA IGGCAAGG 5298
    159 GAAUAGGC A CCUCUGGA 4795 UCCAGAGG CUGAUGAGGCCGUUAGGCCGAA ICCUAUUC 5299
    161 AUAGGCAC C UCUGGAAG 4796 CUUCCAGA CUGAUGAGGCCGUUAGGCCGAA IUGCCUAU 5300
    162 UAGGCACC U CUGGAAGA 4797 UCUUCCAG CUGAUGAGGCCGUUAGGCCGAA IGUGCCUA 5301
    164 GGCACCUC U GGAAGAGC 4798 GCUCUUCC CUGAUGAGGCCGUUAGGCCGAA IAGGUGCC 5302
    173 GGAAGAGC C AACUGUGU 4799 ACACAGUU CUGAUGAGGCCGUUAGGCCGAA ICUCUUCC 5303
    174 GAAGAGCC A ACUGUGUG 4800 CACACAGU CUGAUGAGGCCGUUAGGCCGAA IGCUCUUC 5304
    177 GAGCCAAC U GUGUGAGA 4801 UCUCACAC CUGAUGAGGCCGUUAGGCCGAA IUUGGCUC 5305
    192 GAUGGUGC A GCCCAGUG 4802 CACUGGGC CUGAUGAGGCCGUUAGGCCGAA ICACCAUC 5306
    195 GGUGCAGC C CAGUGGUG 4803 CACCACUG CUGAUGAGGCCGUUAGGCCGAA ICUGCACC 5307
    196 GUGCAGCC C AGUGGUGG 4804 CCACCACU CUGAUGAGGCCGUUAGGCCGAA IGCUGCAC 5308
    197 UGCAGCCC A GUGGUGGC 4805 GCCACCAC CUGAUGAGGCCGUUAGGCCGAA IGGCUGCA 5309
    206 GUGGUGGC C CGGCAGCA 4806 UGCUGCCG CUGAUGAGGCCGUUAGGCCGAA ICCACCAC 5310
    207 UGGUGGCC C GGCAGCAG 4807 CUGCUGCC CUGAUGAGGCCGUUAGGCCGAA IGCCACCA 5311
    211 GGCCCGGC A GCAGAUCA 4808 UGAUCUGC CUGAUGAGGCCGUUAGGCCGAA ICCGGGCC 5312
    214 CCGGCAGC A GAUCAGGA 4809 UCCUGAUC CUGAUGAGGCCGUUAGGCCGAA ICUGCCGG 5313
    219 AGCAGAUC A GGACGUAC 4810 GUACGUCC CUGAUGAGGCCGUUAGGCCGAA IAUCUGCU 5314
    228 GGACGUAC U GGGCGAAG 4811 CUUCGCCC CUGAUGAGGCCGUUAGGCCGAA IUACGUCC 5315
    241 GAAGAGUC U CCUCUGGG 4812 CCCAGAGG CUGAUGAGGCCGUUAGGCCGAA IACUCUUC 5316
    243 AGAGUCUC C UCUGGGGA 4813 UCCCCAGA CUGAUGAGGCCGUUAGGCCGAA IAGACUCU 5317
    244 GAGUCUCC U CUGGGGAA 4814 UUCCCCAG CUGAUGAGGCCGUUAGGCCGAA IGAGACUC 5318
    246 GUCUCCUC U GGGGAAGC 4815 GCUUCCCC CUGAUGAGGCCGUUAGGCCGAA IAGGAGAC 5319
    255 GGGGAAGC C AGCCAUGC 4816 GCAUGGCU CUGAUGAGGCCGUUAGGCCGAA ICUUCCCC 5320
    256 GGGAAGCC A GCCAUGCU 4817 AGCAUGGC CUGAUGAGGCCGUUAGGCCGAA IGCUUCCC 5321
    259 AAGCCAGC C AUGCUGCA 4818 UGCAGCAU CUGAUGAGGCCGUUAGGCCGAA ICUGGCUU 5322
    260 AGCCAGCC A UGCUGCAC 4819 GUGCAGCA CUGAUGAGGCCGUUAGGCCGAA IGCUGGCU 5323
    264 AGCCAUGC U GCACCUGC 4820 GCAGGUGC CUGAUGAGGCCGUUAGGCCGAA ICAUGGCU 5324
    267 CAUGCUGC A CCUGCCUU 4821 AAGGCAGG CUGAUGAGGCCGUUAGGCCGAA ICAGCAUG 5325
    269 UGCUGCAC C UGCCUUCA 4822 UGAAGGCA CUGAUGAGGCCGUUAGGCCGAA IUGCAGCA 5326
    270 GCUGCACC U GCCUUCAG 4823 CUGAAGGC CUGAUGAGGCCGUUAGGCCGAA IGUGCAGC 5327
    273 GCACCUGC C UUCAGAAC 4824 GUUCUGAA CUGAUGAGGCCGUUAGGCCGAA ICAGGUGC 5328
    274 CACCUGCC U UCAGAACA 4825 UGUUCUGA CUGAUGAGGCCGUUAGGCCGAA IGCAGGUG 5329
    277 CUGCCUUC A GAACAGGG 4826 CCCUGUUC CUGAUGAGGCCGUUAGGCCGAA IAAGGCAG 5330
    282 UUCAGAAC A GGGCGCUC 4827 GAGCGCCC CUGAUGAGGCCGUUAGGCCGAA IUUCUGAA 5331
    289 CAGGGCGC U CCUGAGAC 4828 GUCUCAGG CUGAUGAGGCCGUUAGGCCGAA ICGCCCUG 5332
    291 GGGCGCUC C UGAGACCC 4829 GGGUCUCA CUGAUGAGGCCGUUAGGCCGAA IAGCGCCC 5333
    292 GGCGCUCC U GAGACCCU 4830 AGGGUCUC CUGAUGAGGCCGUUAGGCCGAA IGAGCGCC 5334
    298 CCUGAGAC C CUCCAGCG 4831 CGCUGGAG CUGAUGAGGCCGUUAGGCCGAA IUCUCAGG 5335
    299 CUGAGACC C UCCAGCGC 4832 GCGCUGGA CUGAUGAGGCCGUUAGGCCGAA IGUCUCAG 5336
    300 UGAGACCC U CCAGCGCU 4833 AGCGCUGG CUGAUGAGGCCGUUAGGCCGAA IGGUCUCA 5337
    302 AGACCCUC C AGCGCUGC 4834 GCAGCGCU CUGAUGAGGCCGUUAGGCCGAA IAGGGUCU 5338
    303 GACCCUCC A GCGCUGCC 4835 GGCAGCGC CUGAUGAGGCCGUUAGGCCGAA IGAGGGUC 5339
    308 UCCAGCGC U GCCUGGAG 4836 CUCCAGGC CUGAUGAGGCCGUUAGGCCGAA ICGCUGGA 5340
    311 AGCGCUGC C UGGAGGAG 4837 CUCCUCCA CUGAUGAGGCCGUUAGGCCGAA ICAGCGCU 5341
    312 GCGCUGCC U GGAGGAGA 4838 UCUCCUCC CUGAUGAGGCCGUUAGGCCGAA IGCAGCGC 5342
    324 GGAGAAUC A AGAGCUCC 4839 GGAGCUCU CUGAUGAGGCCGUUAGGCCGAA IAUUCUCC 5343
    330 UCAAGAGC U CCGAGAUG 4840 CAUCUCGG CUGAUGAGGCCGUUAGGCCGAA ICUCUUGA 5344
    332 AAGAGCUC C GAGAUGCC 4841 GGCAUCUC CUGAUGAGGCCGUUAGGCCGAA IAGCUCUU 5345
    340 CGAGAUGC C AUCCGGCA 4842 UGCCGGAU CUGAUGAGGCCGUUAGGCCGAA ICAUCUCG 5346
    341 GAGAUGCC A UCCGGCAG 4843 CUGCCGGA CUGAUGAGGCCGUUAGGCCGAA IGCAUCUC 5347
    344 AUGCCAUC C GGCAGAGC 4844 GCUCUGCC CUGAUGAGGCCGUUAGGCCGAA IAUGGCAU 5348
    348 CAUCCGGC A GAGCAACC 4845 GGUUGCUC CUGAUGAGGCCGUUAGGCCGAA ICCGGAUG 5349
    353 GGCAGAGC A ACCAGAUU 4846 AAUCUGGU CUGAUGAGGCCGUUAGGCCGAA ICUCUGCC 5350
    356 AGAGCAAC C AGAUUCUG 4847 CAGAAUCU CUGAUGAGGCCGUUAGGCCGAA IUUGCUCU 5351
    357 GAGCAACC A GAUUCUGC 4848 GCAGAAUC CUGAUGAGGCCGUUAGGCCGAA IGUUGCUC 5352
    363 CCAGAUUC U GCGGGAGC 4849 GCUCCCGC CUGAUGAGGCCGUUAGGCCGAA IAAUCUGG 5353
    374 GGGAGCGC U GCGAGGAG 4850 CUCCUCGC CUGAUGAGGCCGUUAGGCCGAA ICGCUCCC 5354
    384 CGAGGAGC U UCUGCAUU 4851 AAUGCAGA CUGAUGAGGCCGUUAGGCCGAA ICUCCUCG 5355
    387 GGAGCUUC U GCAUUUCC 4852 GGAAAUGC CUGAUGAGGCCGUUAGGCCGAA IAAGCUCC 5356
    390 GCUUCUGC A UUUCCAAG 4853 CUUGGAAA CUGAUGAGGCCGUUAGGCCGAA ICAGAAGC 5357
    395 UGCAUUUC C AAGCCAGC 4854 GCUGGCUU CUGAUGAGGCCGUUAGGCCGAA IAAAUGCA 5358
    396 GCAUUUCC A AGCCAGCC 4855 GGCUGGCU CUGAUGAGGCCGUUAGGCCGAA IGAAAUGC 5359
    400 UUCCAAGC C AGCCAGAG 4856 CUCUGGCU CUGAUGAGGCCGUUAGGCCGAA ICUUGGAA 5360
    401 UCCAAGCC A GCCAGAGG 4857 CCUCUGGC CUGAUGAGGCCGUUAGGCCGAA IGCUUGGA 5361
    404 AAGCCAGC C AGAGGGAG 4858 CUCCCUCU CUGAUGAGGCCGUUAGGCCGAA ICUGGCUU 5362
    405 AGCCAGCC A GAGGGAGG 4859 CCUCCCUC CUGAUGAGGCCGUUAGGCCGAA IGCUGGCU 5363
    425 AGGAGUUC C UCAUGUGC 4860 UCACAUGA CUGAUGAGGCCGUUAGGCCGAA IAACUCCU 5364
    426 GGAGUUCC U CAUGUGCA 4861 UGCACAUG CUGAUGAGGCCGUUAGGCCGAA IGAACUCC 5365
    428 AGUUCCUC A UGUGCAAG 4862 CUUGCACA CUGAUGAGGCCGUUAGGCCGAA IAGGAACU 5366
    434 UCAUGUGC A AGUUCCAG 4863 CUGGAACU CUGAUGAGGCCGUUAGGCCGAA ICACAUGA 5367
    440 GCAAGUUC C AGGAGGCC 4864 GGCCUCCU CUGAUGAGGCCGUUAGGCCGAA IAACUUGC 5368
    441 CAAGUUCC A GGAGGCCA 4865 UGGCCUCC CUGAUGAGGCCGUUAGGCCGAA IGAACUUG 5369
    448 CAGGAGGC C AGGAAACU 4866 AGUUUCCU CUGAUGAGGCCGUUAGGCCGAA ICCUCCUG 5370
    449 AGGAGGCC A GGAAACUG 4867 CAGUUUCC CUGAUGAGGCCGUUAGGCCGAA IGCCUCCU 5371
    456 CAGGAAAC U GGUGGAGA 4868 UCUCCACC CUGAUGAGGCCGUUAGGCCGAA IUUUCCUG 5372
    468 GGAGAGAC U CGGCCUGG 4869 CCAGGCCG CUGAUGAGGCCGUUAGGCCGAA IUCUCUCC 5373
    473 GACUCGGC C UGGAGAAG 4870 CUUCUCCA CUGAUGAGGCCGUUAGGCCGAA ICCGAGUC 5374
    474 ACUCGGCC U GGAGAAGC 4871 GCUUCUCC CUGAUGAGGCCGUUAGGCCGAA IGCCGAGU 5375
    483 GGAGAAGC U CGAUCUGA 4872 UCAGAUCG CUGAUGAGGCCGUUAGGCCGAA ICUUCUCC 5376
    489 GCUCGAUC U GAAGAGGC 4873 GCCUCUUC CUGAUGAGGCCGUUAGGCCGAA IAUCGAGC 5377
    498 GAAGAGGC A GAAGGAGC 4874 GCUCCUUC CUGAUGAGGCCGUUAGGCCGAA ICCUCUUC 5378
    507 GAAGGAGC A GGCUCUGC 4875 GCAGAGCC CUGAUGAGGCCGUUAGGCCGAA ICUCCUUC 5379
    511 GAGCAGGC U CUGCGGGA 4876 UCCCGCAG CUGAUGAGGCCGUUAGGCCGAA ICCUGCUC 5380
    513 GCAGGCUC U GCGGGAGG 4877 CCUCCCGC CUGAUGAGGCCGUUAGGCCGAA IAGCCUGC 5381
    528 GGUGGAGC A CCUGAAGA 4878 UCUUCAGG CUGAUGAGGCCGUUAGGCCGAA ICUCCACC 5382
    530 UGGAGCAC C UGAAGAGA 4879 UCUCUUCA CUGAUGAGGCCGUUAGGCCGAA IUGCUCCA 5383
    531 GGAGCACC U GAAGAGAU 4880 AUCUCUUC CUGAUGAGGCCGUUAGGCCGAA IGUGCUCC 5384
    542 AGAGAUGC C AGCAGCAG 4881 CUGCUGCU CUGAUGAGGCCGUUAGGCCGAA ICAUCUCU 5385
    543 GAGAUGCC A GCAGCAGA 4882 UCUGCUGC CUGAUGAGGCCGUUAGGCCGAA IGCAUCUC 5386
    546 AUGCCAGC A GCAGAUGG 4883 CCAUCUGC CUGAUGAGGCCGUUAGGCCGAA ICUGGCAU 5387
    549 CCAGCAGC A GAUGGCUG 4884 CAGCCAUC CUGAUGAGGCCGUUAGGCCGAA ICUGCUGG 5388
    556 CAGAUGGC U GAGGACAA 4885 UUGUCCUC CUGAUGAGGCCGUUAGGCCGAA ICCAUCUG 5389
    563 CUGAGGAC A AGGCCUCU 4886 AGAGGCCU CUGAUGAGGCCGUUAGGCCGAA IUCCUCAG 5390
    568 GACAAGGC C UCUGUGAA 4887 UUCACAGA CUGAUGAGGCCGUUAGGCCGAA ICCUUGUC 5391
    569 ACAAGGCC U CUGUGAAA 4888 UUUCACAG CUGAUGAGGCCGUUAGGCCGAA IGCCUUGU 5392
    571 AAGGCCUC U GUGAAAGC 4889 GCUUUCAC CUGAUGAGGCCGUUAGGCCGAA IAGGCCUU 5393
    580 GUGAAAGC C CAGGUGAC 4890 GUCACCUG CUGAUGAGGCCGUUAGGCCGAA ICUUUCAC 5394
    581 UGAAAGCC C AGGUGACG 4891 CGUCACCU CUGAUGAGGCCGUUAGGCCGAA IGCUUUCA 5395
    582 GAAAGCCC A GGUGACGU 4892 ACGUCACC CUGAUGAGGCCGUUAGGCCGAA IGGCUUUC 5396
    592 GUGACGUC C UUGCUCGG 4893 CCGAGCAA CUGAUGAGGCCGUUAGGCCGAA IACGUCAC 5397
    593 UGACGUCC U UGCUCGGG 4894 CCCGAGCA CUGAUGAGGCCGUUAGGCCGAA IGACGUCA 5398
    597 GUCCUUGC U CGGGGAGC 4895 GCUCCCCG CUGAUGAGGCCGUUAGGCCGAA ICAAGGAC 5399
    606 CGGGGAGC U GCAGGAGA 4896 UCUCCUGC CUGAUGAGGCCGUUAGGCCGAA ICUCCCCG 5400
    609 GGAGCUGC A GGAGAGCC 4897 GGCUCUCC CUGAUGAGGCCGUUAGGCCGAA ICAGCUCC 5401
    617 AGGAGAGC C AGAGUCGC 4898 GCGACUCU CUGAUGAGGCCGUUAGGCCGAA ICUCUCCU 5402
    618 GGAGAGCC A GAGUCGCU 4899 AGCGACUC CUGAUGAGGCCGUUAGGCCGAA IGCUCUCC 5403
    626 AGAGUCGC U UGGAGGCU 4900 AGCCUCCA CUGAUGAGGCCGUUAGGCCGAA ICGACUCU 5404
    634 UUGGAGGC U GCCACUAA 4901 UUAGUGGC CUGAUGAGGCCGUUAGGCCGAA ICCUCCAA 5405
    637 GAGGCUGC C ACUAAGGA 4902 UCCUUAGU CUGAUGAGGCCGUUAGGCCGAA ICAGCCUC 5406
    638 AGGCUGCC A CUAAGGAA 4903 UUCCUUAG CUGAUGAGGCCGUUAGGCCGAA IGCAGCCU 5407
    640 GCUGCCAC U AAGGAAUG 4904 CAUUCCUU CUGAUGAGGCCGUUAGGCCGAA IUGGCAGC 5408
    650 AGGAAUGC C AGGCUCUG 4905 CAGAGCCU CUGAUGAGGCCGUUAGGCCGAA ICAUUCCU 5409
    651 GGAAUGCC A GGCUCUGG 4906 CCAGAGCC CUGAUGAGGCCGUUAGGCCGAA IGCAUUCC 5410
    655 UGCCAGGC U CUGGAGGG 4907 CCCUCCAG CUGAUGAGGCCGUUAGGCCGAA ICCUGGCA 5411
    657 CCAGGCUC U GGAGGGUC 4908 GACCCUCC CUGAUGAGGCCGUUAGGCCGAA IAGCCUGG 5412
    670 GGUCGGGC C CGGGCGGC 4909 GCCGCCCG CUGAUGAGGCCGUUAGGCCGAA ICCCGACC 5413
    671 GUCGGGCC C GGGCGGCC 4910 GGCCGCCC CUGAUGAGGCCGUUAGGCCGAA IGCCCGAC 5414
    679 CGGGCGGC C AGCGAGCA 4911 UGCUCGCU CUGAUGAGGCCGUUAGGCCGAA ICCGCCCG 5415
    680 GGGCGGCC A GCGAGCAG 4912 CUGCUCGC CUGAUGAGGCCGUUAGGCCGAA IGCCGCCC 5416
    687 CAGCGAGC A GGCGCGGC 4913 GCCGCGCC CUGAUGAGGCCGUUAGGCCGAA ICUCGCUG 5417
    696 GGCGCGGC A GCUGGAGA 4914 UCUCCAGC CUGAUGAGGCCGUUAGGCCGAA ICCGCGCC 5418
    699 GCGGCAGC U GGAGAGUG 4915 CACUCUCC CUGAUGAGGCCGUUAGGCCGAA ICUGCCGC 5419
    720 CGAGGCGC U GCAGCAGC 4916 GCUGCUGC CUGAUGAGGCCGUUAGGCCGAA ICGCCUCG 5420
    723 GGCGCUGC A GCAGCAGC 4917 GCUGCUGC CUGAUGAGGCCGUUAGGCCGAA ICAGCGCC 5421
    726 GCUGCAGC A GCAGCACA 4918 UGUGCUGC CUGAUGAGGCCGUUAGGCCGAA ICUGCAGC 5422
    729 GCAGCAGC A GCACAGCG 4919 CGCUGUGC CUGAUGAGGCCGUUAGGCCGAA ICUGCUGC 5423
    732 GCAGCAGC A CAGCGUGC 4920 GCACGCUG CUGAUGAGGCCGUUAGGCCGAA ICUGCUGC 5424
    734 AGCAGCAC A GCGUGCAG 4921 CUGCACGC CUGAUGAGGCCGUUAGGCCGAA IUGCUGCU 5425
    741 CAGCGUGC A GGUGGACC 4922 GGUCCACC CUGAUGAGGCCGUUAGGCCGAA ICACGCUG 5426
    749 AGGUGGAC C AGCUGCGC 4923 GCGCAGCU CUGAUGAGGCCGUUAGGCCGAA IUCCACCU 5427
    750 GGUGGACC A GCUGCGCA 4924 UGCGCAGC CUGAUGAGGCCGUUAGGCCGAA IGUCCACC 5428
    753 GGACCAGC U GCGCAUGC 4925 GCAUGCGC CUGAUGAGGCCGUUAGGCCGAA ICUGGUCC 5429
    758 AGCUGCGC A UGCAGGGC 4926 GCCCUGCA CUGAUGAGGCCGUUAGGCCGAA ICGCAGCU 5430
    762 GCGCAUGC A GGGCCAGA 4927 UCUGGCCC CUGAUGAGGCCGUUAGGCCGAA ICAUGCGC 5431
    767 UGCAGGGC C AGAGCGUG 4928 CACGCUCU CUGAUGAGGCCGUUAGGCCGAA ICCCUGCA 5432
    768 GCAGGGCC A GAGCGUGG 4929 CCACGCUC CUGAUGAGGCCGUUAGGCCGAA IGCCCUGC 5433
    781 GUGGAGGC C GCGCUCCG 4930 CGGAGCGC CUGAUGAGGCCGUUAGGCCGAA ICCUCCAC 5434
    786 GGCCGCGC U CCGCAUGG 4931 CCAUGCGG CUGAUGAGGCCGUUAGGCCGAA ICGCGGCC 5435
    788 CCGCGCUC C GCAUGGAG 4932 CUCCAUGC CUGAUGAGGCCGUUAGGCCGAA IAGCGCGG 5436
    791 CGCUCCGC A UGGAGCGC 4933 GCGCUCCA CUGAUGAGGCCGUUAGGCCGAA ICGGAGCG 5437
    800 UGGAGCGC C AGGCCGCC 4934 GGCGGCCU CUGAUGAGGCCGUUAGGCCGAA ICGCUCCA 5438
    801 GGAGCGCC A GGCCGCCU 4935 AGGCGGCC CUGAUGAGGCCGUUAGGCCGAA IGCGCUCC 5439
    805 CGCCAGGC C GCCUCGGA 4936 UCCGAGGC CUGAUGAGGCCGUUAGGCCGAA ICCUGGCG 5440
    808 CAGGCCGC C UCGGAGGA 4937 UCCUCCGA CUGAUGAGGCCGUUAGGCCGAA ICGGCCUG 5441
    809 AGGCCGCC U CGGAGGAG 4938 CUCCUCCG CUGAUGAGGCCGUUAGGCCGAA IGCGGCCU 5442
    828 GAGGAAGC U GGCCCAGU 4939 ACUGGGCC CUGAUGAGGCCGUUAGGCCGAA ICUUCCUC 5443
    832 AAGCUGGC C CAGUUGCA 4940 UGCAACUG CUGAUGAGGCCGUUAGGCCGAA ICCAGCUU 5444
    833 AGCUGGCC C AGUUGCAG 4941 CUGCAACU CUGAUGAGGCCGUUAGGCCGAA IGCCAGCU 5445
    834 GCUGGCCC A GUUGCAGG 4942 CCUGCAAC CUGAUGAGGCCGUUAGGCCGAA IGGCCAGC 5446
    840 CCAGUUGC A GGUGGCCU 4943 AGGCCACC CUGAUGAGGCCGUUAGGCCGAA ICAACUGG 5447
    847 CAGGUGGC C UAUCACCA 4944 UGGUGAUA CUGAUGAGGCCGUUAGGCCGAA ICCACCUG 5448
    848 AGGUGGCC U AUCACCAG 4945 CUGGUGAU CUGAUGAGGCCGUUAGGCCGAA IGCCACCU 5449
    852 GGCCUAUC A CCAGCUCU 4946 AGAGCUGG CUGAUGAGGCCGUUAGGCCGAA IAUAGGCC 5450
    854 CCUAUCAC C AGCUCUUC 4947 GAAGAGCU CUGAUGAGGCCGUUAGGCCGAA IUGAUAGG 5451
    855 CUAUCACC A GCUCUUCC 4948 GGAAGAGC CUGAUGAGGCCGUUAGGCCGAA IGUGAUAG 5452
    858 UCACCAGC U CUUCCAAG 4949 CUUGGAAG CUGAUGAGGCCGUUAGGCCGAA ICUGGUGA 5453
    860 ACCAGCUC U UCCAAGAA 4950 UUCUUGGA CUGAUGAGGCCGUUAGGCCGAA IAGCUGGU 5454
    863 AGCUCUUC C AAGAAUAC 4951 GUAUUCUU CUGAUGAGGCCGUUAGGCCGAA IAAGAGCU 5455
    864 GCUCUUCC A AGAAUACG 4952 CGUAUUCU CUGAUGAGGCCGUUAGGCCGAA IGAAGAGC 5456
    875 AAUACGAC A ACCACAUC 4953 GAUGUGGU CUGAUGAGGCCGUUAGGCCGAA IUCGUAUU 5457
    878 ACGACAAC C ACAUCAAG 4954 CUUGAUGU CUGAUGAGGCCGUUAGGCCGAA IUUGUCGU 5458
    879 CGACAACC A CAUCAAGA 4955 UCUUGAUG CUGAUGAGGCCGUUAGGCCGAA IGUUGUCG 5459
    881 ACAACCAC A UCAAGAGC 4956 GCUCUUGA CUGAUGAGGCCGUUAGGCCGAA IUGGUUGU 5460
    884 ACCACAUC A AGAGCAGC 4957 GCUGCUCU CUGAUGAGGCCGUUAGGCCGAA IAUGUGGU 5461
    890 UCAAGAGC A GCGUGGUG 4958 CACCACGC CUGAUGAGGCCGUUAGGCCGAA ICUCUUGA 5462
    902 UGGUGGGC A GUGAGCGG 4959 CCGCUCAC CUGAUGAGGCCGUUAGGCCGAA ICCCACCA 5463
    924 AGGAAUGC A GCUGGAAG 4960 CUUCCAGC CUGAUGAGGCCGUUAGGCCGAA ICAUUCCU 5464
    927 AAUGCAGC U GGAAGAUC 4961 GAUCUUCC CUGAUGAGGCCGUUAGGCCGAA ICUGCAUU 5465
    936 GGAAGAUC U CAAACAGC 4962 GCUGUUUG CUGAUGAGGCCGUUAGGCCGAA IAUCUUCC 5466
    938 AAGAUCUC A AACAGCAG 4963 CUGCUGUU CUGAUGAGGCCGUUAGGCCGAA IAGAUCUU 5467
    942 UCUCAAAC A GCAGCUCC 4964 GGAGCUGC CUGAUGAGGCCGUUAGGCCGAA IUUUGAGA 5468
    945 CAAACAGC A GCUCCAGC 4965 GCUGGAGC CUGAUGAGGCCGUUAGGCCGAA ICUGUUUG 5469
    948 ACAGCAGC U CCAGCAGG 4966 CCUGCUGG CUGAUGAGGCCGUUAGGCCGAA ICUGCUGU 5470
    950 AGCAGCUC C AGCAGGCC 4967 GGCCUGCU CUGAUGAGGCCGUUAGGCCGAA IAGCUGCU 5471
    951 GCAGCUCC A GCAGGCCG 4968 CGGCCUGC CUGAUGAGGCCGUUAGGCCGAA IGAGCUGC 5472
    954 GCUCCAGC A GGCCGAGG 4969 CCUCGGCC CUGAUGAGGCCGUUAGGCCGAA ICUGGAGC 5473
    958 CAGCAGGC C GAGGAGGC 4970 GCCUCCUC CUGAUGAGGCCGUUAGGCCGAA ICCUGCUG 5474
    967 GAGGAGGC C CUGGUGGC 4971 GCCACCAG CUGAUGAGGCCGUUAGGCCGAA ICCUCCUC 5475
    968 AGGAGGCC C UGGUGGCC 4972 GGCCACCA CUGAUGAGGCCGUUAGGCCGAA IGCCUCCU 5476
    969 GGAGGCCC U GGUGGCCA 4973 UGGCCACC CUGAUGAGGCCGUUAGGCCGAA IGGCCUCC 5477
    976 CUGGUGGC C AAACAGGA 4974 UCCUGUUU CUGAUGAGGCCGUUAGGCCGAA ICCACCAG 5478
    977 UGGUGGCC A AACAGGAG 4975 CUCCUGUU CUGAUGAGGCCGUUAGGCCGAA IGCCACCA 5479
    981 GGCCAAAC A GGAGGUGA 4976 UCACCUCC CUGAUGAGGCCGUUAGGCCGAA IUUUGGCC 5480
    999 CGAUAAGC U GAAGGAGG 4977 CCUCCUUC CUGAUGAGGCCGUUAGGCCGAA ICUUAUCG 5481
    1012 GAGGAGGC C GAGCAGCA 4978 UGCUGCUC CUGAUGAGGCCGUUAGGCCGAA ICCUCCUC 5482
    1017 GGCCGAGC A GCACAAGA 4979 UCUUGUGC CUGAUGAGGCCGUUAGGCCGAA ICUCGGCC 5483
    1020 CGAGCAGC A CAAGAUUG 4980 CAAUCUUG CUGAUGAGGCCGUUAGGCCGAA ICUGCUCG 5484
    1022 AGCAGCAC A AGAUUGUG 4981 CACAAUCU CUGAUGAGGCCGUUAGGCCGAA IUGCUGCU 5485
    1039 AUGGAGAC C GUUCCGGU 4982 ACCGGAAC CUGAUGAGGCCGUUAGGCCGAA IUCUCCAU 5486
    1044 GACCGUUC C GGUGCUGA 4983 UCAGCACC CUGAUGAGGCCGUUAGGCCGAA IAACGGUC 5487
    1050 UCCGGUGC U GAAGGCCC 4984 GGGCCUUC CUGAUGAGGCCGUUAGGCCGAA ICACCGGA 5488
    1057 CUGAAGGC C CAGGCGGA 4985 UCCGCCUG CUGAUGAGGCCGUUAGGCCGAA ICCUUCAG 5489
    1058 UGAAGGCC C AGGCGGAU 4986 AUCCGCCU CUGAUGAGGCCGUUAGGCCGAA IGCCUUCA 5490
    1059 GAAGGCCC A GGCGGAUA 4987 UAUCCGCC CUGAUGAGGCCGUUAGGCCGAA IGGCCUUC 5491
    1070 CGGAUAUC U ACAAGGCG 4988 CGCCUUGU CUGAUGAGGCCGUUAGGCCGAA IAUAUCCG 5492
    1073 AUAUCUAC A AGGCGGAC 4989 GUCCGCCU CUGAUGAGGCCGUUAGGCCGAA IUAGAUAU 5493
    1082 AGGCGGAC U UCCAGGCU 4990 AGCCUGGA CUGAUGAGGCCGUUAGGCCGAA IUCCGCCU 5494
    1085 CGGACUUC C AGGCUGAG 4991 CUCAGCCU CUGAUGAGGCCGUUAGGCCGAA IAAGUCCG 5495
    1086 GGACUUCC A GGCUGAGA 4992 UCUCAGCC CUGAUGAGGCCGUUAGGCCGAA IGAAGUCC 5496
    1090 UUCCAGGC U GAGAGGCA 4993 UGCCUCUC CUGAUGAGGCCGUUAGGCCGAA ICCUGGAA 5497
    1098 UGAGAGGC A GGCCCGGG 4994 CCCGGGCC CUGAUGAGGCCGUUAGGCCGAA ICCUCUCA 5498
    1102 AGGCAGGC C CGGGAGAA 4995 UUCUCCCG CUGAUGAGGCCGUUAGGCCGAA ICCUGCCU 5499
    1103 GGCAGGCC C GGGAGAAG 4996 CUUCUCCC CUGAUGAGGCCGUUAGGCCGAA IGCCUGCC 5500
    1113 GGAGAAGC U GGCCGAGA 4997 UCUCGGCC CUGAUGAGGCCGUUAGGCCGAA ICUUCUCC 5501
    1117 AAGCUGGC C GAGAAGAA 4998 UUCUUCUC CUGAUGAGGCCGUUAGGCCGAA ICCAGCUU 5502
    1131 GAAGGAGC U CCUGCAGG 4999 CCUGCAGG CUGAUGAGGCCGUUAGGCCGAA ICUCCUUC 5503
    1133 AGGAGCUC C UGCAGGAG 5000 CUCCUGCA CUGAUGAGGCCGUUAGGCCGAA IAGCUCCU 5504
    1134 GGAGCUCC U GCAGGAGC 5001 GCUCCUGC CUGAUGAGGCCGUUAGGCCGAA IGAGCUCC 5505
    1137 GCUCCUGC A GGAGCAGC 5002 GCUGCUCC CUGAUGAGGCCGUUAGGCCGAA ICAGGAGC 5506
    1143 GCAGGAGC A GCUGGAGC 5003 GCUCCAGC CUGAUGAGGCCGUUAGGCCGAA ICUCCUGC 5507
    1146 GGAGCAGC U GGAGCAGC 5004 GCUGCUCC CUGAUGAGGCCGUUAGGCCGAA ICUGCUCC 5508
    1152 GCUGGAGC A GCUGCAGA 5005 UCUGCAGC CUGAUGAGGCCGUUAGGCCGAA ICUCCAGC 5509
    1155 GGAGCAGC U GCAGAGGG 5006 CCCUCUGC CUGAUGAGGCCGUUAGGCCGAA ICUGCUCC 5510
    1158 GCAGCUGC A GAGGGAGU 5007 ACUCCCUC CUGAUGAGGCCGUUAGGCCGAA ICAGCUGC 5511
    1169 GGGAGUAC A GCAAACUG 5008 CAGUUUGC CUGAUGAGGCCGUUAGGCCGAA IUACUCCC 5512
    1172 AGUACAGC A AACUGAAG 5009 CUUCAGUU CUGAUGAGGCCGUUAGGCCGAA ICUGUACU 5513
    1176 CAGCAAAC U GAAGGCCA 5010 UGGCCUUC CUGAUGAGGCCGUUAGGCCGAA IUUUGCUG 5514
    1183 CUGAAGGC C AGCUGUCA 5011 UGACAGCU CUGAUGAGGCCGUUAGGCCGAA ICCUUCAG 5515
    1184 UGAAGGCC A GCUGUCAG 5012 CUGACAGC CUGAUGAGGCCGUUAGGCCGAA IGCCUUCA 5516
    1187 AGGCCAGC U GUCAGGAG 5013 CUCCUGAC CUGAUGAGGCCGUUAGGCCGAA ICUGGCCU 5517
    1191 CAGCUGUC A GGAGUCGG 5014 CCGACUCC CUGAUGAGGCCGUUAGGCCGAA TACACCUG 5518
    1201 GAGUCGGC C AGGAUCGA 5015 UCGAUCCU CUGAUGAGGCCGUUAGGCCGAA ICCGACUC 5519
    1202 AGUCGGCC A GGAUCGAG 5016 CUCGAUCC CUGAUGAGGCCGUUAGGCCGAA IGCCGACU 5520
    1214 UCGAGGAC A UGAGGAAG 5017 CUUCCUCA CUGAUGAGGCCGUUAGGCCGAA IUCCUCGA 5521
    1227 GAAGCGGC A UGUCGAGG 5018 CCUCGACA CUGAUGAGGCCGUUAGGCCGAA ICCGCUUC 5522
    1238 UCGAGGUC U CCCAGGCC 5019 GGCCUGGG CUGAUGAGGCCGUUAGGCCGAA IACCUCGA 5523
    1240 GAGGUCUC C CAGGCCCC 5020 GGGGCCUG CUGAUGAGGCCGUUAGGCCGAA IAGACCUC 5524
    1241 AGGUCUCC C AGGCCCCC 5021 GGGGGCCU CUGAUGAGGCCGUUAGGCCGAA IGAGACCU 5525
    1242 GGUCUCCC A GGCCCCCU 5022 AGGGGGCC CUGAUGAGGCCGUUAGGCCGAA IGGAGACC 5526
    1246 UCCCAGGC C CCCUUGCC 5023 GGCAAGGG CUGAUGAGGCCGUUAGGCCGAA ICCUGGGA 5527
    1247 CCCAGGCC C CCUUGCCC 5024 GGGCAAGG CUGAUGAGGCCGUUAGGCCGAA IGCCUGGG 5528
    1248 CCAGGCCC C CUUGCCCC 5025 GGGGCAAG CUGAUGAGGCCGUUAGGCCGAA IGGCCUGG 5529
    1249 CAGGCCCC C UUGCCCCC 5026 GGGGGCAA CUGAUGAGGCCGUUAGGCCGAA IGGGCCUG 5530
    1250 AGGCCCCC U UGCCCCCC 5027 GGGGGGCA CUGAUGAGGCCGUUAGGCCGAA IGGGGCCU 5531
    1254 CCCCUUGC C CCCCGCCC 5028 GGGCGGGG CUGAUGAGGCCGUUAGGCCGAA ICAAGGGG 5532
    1255 CCCUUGCC C CCCGCCCC 5029 GGGGCGGG CUGAUGAGGCCGUUAGGCCGAA IGCAAGGG 5533
    1256 CCUUGCCC C CCGCCCCU 5030 AGGGGCGG CUGAUGAGGCCGUUAGGCCGAA IGGCAAGG 5534
    1257 CUUGCCCC C CGCCCCUG 5031 CAGGGGCG CUGAUGAGGCCGUUAGGCCGAA IGGGCAAG 5535
    1258 UUGCCCCC C GCCCCUGC 5032 GCAGGGGC CUGAUGAGGCCGUUAGGCCGAA IGGGGCAA 5536
    1261 CCCCCCGC C CCUGCCUA 5033 UAGGCAGG CUGAUGAGGCCGUUAGGCCGAA ICGGGGGG 5537
    1262 CCCCCGCC C CUGCCUAC 5034 GUAGGCAG CUGAUGAGGCCGUUAGGCCGAA IGCGGGGG 5538
    1263 CCCCGCCC C UGCCUACC 5035 GGUAGGCA CUGAUGAGGCCGUUAGGCCGAA IGGCGGGG 5539
    1264 CCCGCCCC U GCCUACCU 5036 AGGUAGGC CUGAUGAGGCCGUUAGGCCGAA IGGGCGGG 5540
    1267 GCCCCUGC C UACCUCUC 5037 GAGAGGUA CUGAUGAGGCCGUUAGGCCGAA ICAGGGGC 5541
    1268 CCCCUGCC U ACCUCUCC 5038 GGAGAGGU CUGAUGAGGCCGUUAGGCCGAA IGCAGGGG 5542
    1271 CUGCCUAC C UCUCCUCU 5039 AGAGGAGA CUGAUGAGGCCGUUAGGCCGAA IUAGGCAG 5543
    1272 UGCCUACC U CUCCUCUC 5040 GAGAGGAG CUGAUGAGGCCGUUAGGCCGAA IGUAGGCA 5544
    1274 CCUACCUC U CCUCUCCC 5041 GGGAGAGG CUGAUGAGGCCGUUAGGCCGAA IAGGUAGG 5545
    1276 UACCUCUC C UCUCCCCU 5042 AGGGGAGA CUGAUGAGGCCGUUAGGCCGAA IAGAGGUA 5546
    1277 ACCUCUCC U CUCCCCUG 5043 CAGGGGAG CUGAUGAGGCCGUUAGGCCGAA IGAGAGGU 5547
    1279 CUCUCCUC U CCCCUGGC 5044 GCCAGGGG CUGAUGAGGCCGUUAGGCCGAA IAGGAGAG 5548
    1281 CUCCUCUC C CCUGGCCC 5045 GGGCCAGG CUGAUGAGGCCGUUAGGCCGAA IAGAGGAG 5549
    1282 UCCUCUCC C CUGGCCCU 5046 AGGGCCAG CUGAUGAGGCCGUUAGGCCGAA IGAGAGGA 5550
    1283 CCUCUCCC C UGGCCCUG 5047 CAGGGCCA CUGAUGAGGCCGUUAGGCCGAA IGGAGAGG 5551
    1284 CUCUCCCC U GGCCCUGC 5048 GCAGGGCC CUGAUGAGGCCGUUAGGCCGAA IGGGAGAG 5552
    1288 CCCCUGGC C CUGCCCAG 5049 CUGGGCAG CUGAUGAGGCCGUUAGGCCGAA ICCAGGGG 5553
    1289 CCCUGGCC C UGCCCAGC 5050 GCUGGGCA CUGAUGAGGCCGUUAGGCCGAA IGCCAGGG 5554
    1290 CCUGGCCC U GCCCAGCC 5051 GGCUGGGC CUGAUGAGGCCGUUAGGCCGAA IGGCCAGG 5555
    1293 GGCCCUGC C CAGCCAGA 5052 UCUGGCUG CUGAUGAGGCCGUUAGGCCGAA ICAGGGCC 5556
    1294 GCCCUGCC C AGCCAGAG 5053 CUCUGGCU CUGAUGAGGCCGUUAGGCCGAA IGCAGGGC 5557
    1295 CCCUGCCC A GCCAGAGG 5054 CCUCUGGC CUGAUGAGGCCGUUAGGCCGAA IGGCAGGG 5558
    1298 UGCCCAGC C AGAGGAGG 5055 CCUCCUCU CUGAUGAGGCCGUUAGGCCGAA ICUGGGCA 5559
    1299 GCCCAGCC A GAGGAGGA 5056 UCCUCCUC CUGAUGAGGCCGUUAGGCCGAA IGCUGGGC 5560
    1310 GGAGGAGC C CCCCCGAG 5057 CUCGGGGG CUGAUGAGGCCGUUAGGCCGAA ICUCCUCC 5561
    1311 GAGGAGCC C CCCCGAGG 5058 CCUCGGGG CUGAUGAGGCCGUUAGGCCGAA IGGUCCUC 5562
    1312 AGGAGCCC C CCCGAGGA 5059 UCCUCGGG CUGAUGAGGCCGUUAGGCCGAA IGGCUCCU 5563
    1313 GGAGCCCC C CCGAGGAG 5060 CUCCUCGG CUGAUGAGGCCGUUAGGCCGAA IGGGCUCC 5564
    1314 GAGCCCCC C CGAGGAGC 5061 GCUCCUCG CUGAUGAGGCCGUUAGGCCGAA IGGGGCUC 5565
    1315 AGCCCCCC C GAGGAGCC 5062 GGCUCCUC CUGAUGAGGCCGUUAGGCCGAA IGGGGGCU 5566
    1323 CGAGGAGC C ACCUGACU 5063 AGUCAGGU CUGAUGAGGCCGUUAGGCCGAA ICUCCUCG 5567
    1324 GAGGAGCC A CCUGACUU 5064 AAGUCAGG CUGAUGAGGCCGUUAGGCCGAA IGCUCCUC 5568
    1326 GGAGCCAC C UGACUUCU 5065 AGAAGUCA CUGAUGAGGCCGUUAGGCCGAA IUGGCUCC 5569
    1327 GAGCCACC U GACUUCUG 5066 CAGAAGUC CUGAUGAGGCCGUUAGGCCGAA IGUGGCUC 5570
    1331 CACCUGAC U UCUGCUGU 5067 ACAGCAGA CUGAUGAGGCCGUUAGGCCGAA IUCAGGUG 5571
    1334 CUGACUUC U GCUGUCCC 5068 GGGACAGC CUGAUGAGGCCGUUAGGCCGAA IAAGUCAG 5572
    1337 ACUUCUGC U GUCCCAAG 5069 CUUGGGAC CUGAUGAGGCCGUUAGGCCGAA ICAGAAGU 5573
    1341 CUGCUGUC C CAAGUGCC 5070 GGCACUUG CUGAUGAGGCCGUUAGGCCGAA IACAGCAG 5574
    1342 UGCUGUCC C AAGUGCCA 5071 UGGCACUU CUGAUGAGGCCGUUAGGCCGAA IGACAGCA 5575
    1343 GCUGUCCC A AGUGCCAG 5072 CUGGCACU CUGAUGAGGCCGUUAGGCCGAA IGGACAGC 5576
    1349 CCAAGUGC C AGUAUCAG 5073 CUGAUACU CUGAUGAGGCCGUUAGGCCGAA ICACUUGG 5577
    1350 CAAGUGCC A GUAUCAGG 5074 CCUGAUAC CUGAUGAGGCCGUUAGGCCGAA IGCACUUG 5578
    1356 CCAGUAUC A GGCCCCUG 5075 CAGGGGCC CUGAUGAGGCCGUUAGGCCGAA IAUACUGG 5579
    1360 UAUCAGGC C CCUGAUAU 5076 AUAUCAGG CUGAUGAGGCCGUUAGGCCGAA ICCUGAUA 5580
    1361 AUCAGGCC C CUGAUAUG 5077 CAUAUCAG CUGAUGAGGCCGUUAGGCCGAA IGCCUGAU 5581
    1362 UCAGGCCC C UGAUAUGG 5078 CCAUAUCA CUGAUGAGGCCGUUAGGCCGAA IGGCCUGA 5582
    1363 CAGGCCCC U GAUAUGGA 5079 UCCAUAUC CUGAUGAGGCCGUUAGGCCGAA IGGGCCUG 5583
    1373 AUAUGGAC A CCCUGCAG 5080 CUGCAGGG CUGAUGAGGCCGUUAGGCCGAA IUCCAUAU 5584
    1375 AUGGACAC C CUGCAGAU 5081 AUCUGCAG CUGAUGAGGCCGUUAGGCCGAA IUGUCCAU 5585
    1376 UGGACACC C UGCAGAUA 5082 UAUCUGCA CUGAUGAGGCCGUUAGGCCGAA IGUGUCCA 5586
    1377 GGACACCC U GCAGAUAC 5083 GUAUCUGC CUGAUGAGGCCGUUAGGCCGAA IGGUGUCC 5587
    1380 CACCCUGC A GAUACAUG 5084 CAUGUAUC CUGAUGAGGCCGUUAGGCCGAA ICAGGGUG 5588
    1386 GCAGAUAC A UGUCAUGG 5085 CCAUGACA CUGAUGAGGCCGUUAGGCCGAA IUAUCUGC 5589
    1391 UACAUGUC A UGGAGUGC 5086 GCACUCCA CUGAUGAGGCCGUUAGGCCGAA IACAUGUA 5590
    1400 UGGAGUGC A UUGAGUAG 5087 CUACUCAA CUGAUGAGGCCGUUAGGCCGAA ICACUCCA 5591
    1412 AGUAGGGC C GGCCAGUG 5088 CACUGGCC CUGAUGAGGCCGUUAGGCCGAA ICCCUACU 5592
    1416 GGGCCGGC C AGUGCAAG 5089 CUUGCACU CUGAUGAGGCCGUUAGGCCGAA ICCGGCCC 5593
    1417 GGCCGGCC A GUGCAAGG 5090 CCUUGCAC CUGAUGAGGCCGUUAGGCCGAA IGCCGGCC 5594
    1422 GCCAGUGC A AGGCCACU 5091 AGUGGCCU CUGAUGAGGCCGUUAGGCCGAA ICACUGGC 5595
    1427 UGCAAGGC C ACUGCCUG 5092 CAGGCAGU CUGAUGAGGCCGUUAGGCCGAA ICCUUGCA 5596
    1428 GCAAGGCC A CUGCCUGC 5093 GCAGGCAG CUGAUGAGGCCGUUAGGCCGAA IGCCUUGC 5597
    1430 AAGGCCAC U GCCUGCCC 5094 GGGCAGGC CUGAUGAGGCCGUUAGGCCGAA IUGGCCUU 5598
    1433 GCCACUGC C UGCCCGAG 5095 CUCGGGCA CUGAUGAGGCCGUUAGGCCGAA ICAGUGGC 5599
    1434 CCACUGCC U GCCCGAGG 5096 CCUCGGGC CUGAUGAGGCCGUUAGGCCGAA IGCAGUGG 5600
    1437 CUGCCUGC C CGAGGACG 5097 CGUCCUCG CUGAUGAGGCCGUUAGGCCGAA ICAGGCAG 5601
    1438 UGCCUGCC C GAGGACGU 5098 ACGUCCUC CUGAUGAGGCCGUUAGGCCGAA IGCAGGCA 5602
    1449 GGACGUGC C CGGGACCG 5099 CGGUCCCG CUGAUGAGGCCGUUAGGCCGAA ICACGUCC 5603
    1450 GACGUGCC C GGGACCGU 5100 ACGGUCCC CUGAUGAGGCCGUUAGGCCGAA IGCACGUC 5604
    1456 CCCGGGAC C GUGCAGUC 5101 GACUGCAC CUGAUGAGGCCGUUAGGCCGAA IUCCCGGG 5605
    1461 GACCGUGC A GUCUGCGC 5102 GCGCAGAC CUGAUGAGGCCGUUAGGCCGAA ICACGGUC 5606
    1465 GUGCAGUC U GCGCUUUC 5103 GAAAGCGC CUGAUGAGGCCGUUAGGCCGAA IACUGCAC 5607
    1470 GUCUGCGC U UUCCUCUC 5104 GAGAGGAA CUGAUGAGGCCGUUAGGCCGAA ICGCAGAC 5608
    1474 GCGCUUUC C UCUCCCGC 5105 GCGGGAGA CUGAUGAGGCCGUUAGGCCGAA IAAAGCGC 5609
    1475 CGCUUUCC U CUCCCGCC 5106 GGCGGGAG CUGAUGAGGCCGUUAGGCCGAA IGAAAGCG 5610
    1477 CUUUCCUC U CCCGCCUG 5107 CAGGCGGG CUGAUGAGGCCGUUAGGCCGAA IAGGAAAG 5611
    1479 UUCCUCUC C CGCCUGCC 5108 GGCAGGCG CUGAUGAGGCCGUUAGGCCGAA IAGAGGAA 5612
    1480 UCCUCUCC C GCCUGCCU 5109 AGGCAGGC CUGAUGAGGCCGUUAGGCCGAA IGAGAGGA 5613
    1483 UCUCCCGC C UGCCUAGC 5110 GCUAGGCA CUGAUGAGGCCGUUAGGCCGAA ICGGGAGA 5614
    1484 CUCCCGCC U GCCUAGCC 5111 GGCUAGGC CUGAUGAGGCCGUUAGGCCGAA IGCGGGAG 5615
    1487 CCGCCUGC C UAGCCCAG 5112 CUGGGCUA CUGAUGAGGCCGUUAGGCCGAA ICAGGCGG 5616
    1488 CGCCUGCC U AGCCCAGG 5113 CCUGGGCU CUGAUGAGGCCGUUAGGCCGAA IGCAGGCG 5617
    1492 UGCCUAGC C CAGGAUGA 5114 UCAUCCUG CUGAUGAGGCCGUUAGGCCGAA ICUAGGCA 5618
    1493 GCCUAGCC C AGGAUGAA 5115 UUCAUCCU CUGAUGAGGCCGUUAGGCCGAA IGCUAGGC 5619
    1494 CCUAGCCC A GGAUGAAG 5116 CUUCAUCC CUGAUGAGGCCGUUAGGCCGAA IGGCUAGG 5620
    1506 UGAAGGGC U GGGUGGCC 5117 GGCCACCC CUGAUGAGGCCGUUAGGCCGAA ICCCUUCA 5621
    1514 UGGGUGGC C ACAACUGG 5118 CCAGUUGU CUGAUGAGGCCGUUAGGCCGAA ICCACCCA 5622
    1515 GGGUGGCC A CAACUGGG 5119 CCCAGUUG CUGAUGAGGCCGUUAGGCCGAA IGCCACCC 5623
    1517 GUGGCCAC A ACUGGGAU 5120 AUCCCAGU CUGAUGAGGCCGUUAGGCCGAA IUGGCCAC 5624
    1520 GCCACAAC U GGGAUGCC 5121 GGCAUCCC CUGAUGAGGCCGUUAGGCCGAA IUUGUGGC 5625
    1528 UGGGAUGC C ACCUGGAG 5122 CUCCAGGU CUGAUGAGGCCGUUAGGCCGAA ICAUCCCA 5626
    1529 GGGAUGCC A CCUGGAGC 5123 GCUCCAGG CUGAUGAGGCCGUUAGGCCGAA IGCAUCCC 5627
    1531 GAUGCCAC C UGGAGCCC 5124 GGGCUCCA CUGAUGAGGCCGUUAGGCCGAA IUGGCAUC 5628
    1532 AUGCCACC U GGAGCCCC 5125 GGGGCUCC CUGAUGAGGCCGUUAGGCCGAA IGUGGCAU 5629
    1538 CCUGGAGC C CCACCCAG 5126 CUGGGUGG CUGAUGAGGCCGUUAGGCCGAA ICUCCAGG 5630
    1539 CUGGAGCC C CACCCAGG 5127 CCUGGGUG CUGAUGAGGCCGUUAGGCCGAA IGCUCCAG 5631
    1540 UGGAGCCC C ACCCAGGA 5128 UCCUGGGU CUGAUGAGGCCGUUAGGCCGAA IGGCUCCA 5632
    1541 GGAGCCCC A CCCAGGAG 5129 CUCCUGGG CUGAUGAGGCCGUUAGGCCGAA IGGGCUCC 5633
    1543 AGCCCCAC C CAGGAGCU 5130 AGCUCCUG CUGAUGAGGCCGUUAGGCCGAA IUGGGGCU 5634
    1544 GCCCCACC C AGGAGCUG 5131 CAGCUCCU CUGAUGAGGCCGUUAGGCCGAA IGUGGGGC 5635
    1545 CCCCACCC A GGAGCUGG 5132 CCAGCUCC CUGAUGAGGCCGUUAGGCCGAA IGGUGGGG 5636
    1551 CCAGGAGC U GGCCGCGG 5133 CCGCGGCC CUGAUGAGGCCGUUAGGCCGAA ICUCCUGG 5637
    1555 GAGCUGGC C GCGGCACC 5134 GGUGCCGC CUGAUGAGGCCGUUAGGCCGAA ICCAGCUC 5638
    1561 GCCGCGGC A CCUUACGC 5135 GCGUAAGG CUGAUGAGGCCGUUAGGCCGAA ICCGCGGC 5639
    1563 CGCGGCAC C UUACGCUU 5136 AAGCGUAA CUGAUGAGGCCGUUAGGCCGAA IUGCCGCG 5640
    1564 GCGGCACC U UACGCUUC 5137 GAAGCGUA CUGAUGAGGCCGUUAGGCCGAA IGUGCCGC 5641
    1570 CCUUACGC U UCAGCUGU 5138 ACAGCUGA CUGAUGAGGCCGUUAGGCCGAA ICGUAAGG 5642
    1573 UACGCUUC A GCUGUUGA 5139 UCAACAGC CUGAUGAGGCCGUUAGGCCGAA IAAGCGUA 5643
    1576 GCUUCAGC U GUUGAUCC 5140 GGAUCAAC CUGAUGAGGCCGUUAGGCCGAA ICUGAAGC 5644
    1584 UGUUGAUC C GCUGGUCC 5141 GGACCAGC CUGAUGAGGCCGUUAGGCCGAA IAUCAACA 5645
    1587 UGAUCCGC U GGUCCCCU 5142 AGGGGACC CUGAUGAGGCCGUUAGGCCGAA ICGGAUCA 5646
    1592 CGCUGGUC C CCUCUUUU 5143 AAAAGAGG CUGAUGAGGCCGUUAGGCCGAA IACCAGCG 5647
    1593 GCUGGUCC C CUCUUUUG 5144 CAAAAGAG CUGAUGAGGCCGUUAGGCCGAA IGACCAGC 5648
    1594 CUGGUCCC C UCUUUUGG 5145 CCAAAAGA CUGAUGAGGCCGUUAGGCCGAA IGGACCAG 5649
    1595 UGGUCCCC U CUUUUGGG 5146 CCCAAAAG CUGAUGAGGCCGUUAGGCCGAA IGGGACCA 5650
    1597 GUCCCCUC U UUUGGGGU 5147 ACCCCAAA CUGAUGAGGCCGUUAGGCCGAA IAGGGGAC 5651
    1615 GAUGCGGC C CCGAUCAG 5148 CUGAUCGG CUGAUGAGGCCGUUAGGCCGAA ICCGCAUC 5652
    1616 AUGCGGCC C CGAUCAGG 5149 CCUGAUCG CUGAUGAGGCCGUUAGGCCGAA IGCCGCAU 5653
    1617 UGCGGCCC C GAUCAGGC 5150 GCCUGAUC CUGAUGAGGCCGUUAGGCCGAA IGGCCGCA 5654
    1622 CCCCGAUC A GGCCUGAC 5151 GUCAGGCC CUGAUGAGGCCGUUAGGCCGAA IAUCGGGG 5655
    1626 GAUCAGGC C UGACUCGC 5152 GCGAGUCA CUGAUGAGGCCGUUAGGCCGAA ICCUGAUC 5656
    1627 AUCAGGCC U GACUCGCU 5153 AGCGAGUC CUGAUGAGGCCGUUAGGCCGAA IGCCUGAU 5657
    1631 GGCCUGAC U CGCUGCUC 5154 GAGCAGCG CUGAUGAGGCCGUUAGGCCGAA IUCAGGCC 5658
    1635 UGACUCGC U GCUCUUUU 5155 AAAAGAGC CUGAUGAGGCCGUUAGGCCGAA ICGAGUCA 5659
    1638 CUCGCUGC U CUUUUUGU 5156 ACAAAAAG CUGAUGAGGCCGUUAGGCCGAA ICAGCGAG 5660
    1640 CGCUGCUC U UUUUGUUC 5157 GAACAAAA CUGAUGAGGCCGUUAGGCCGAA IAGCAGCG 5661
    1649 UUUUGUUC C CUUCUGUC 5158 GACAGAAG CUGAUGAGGCCGUUAGGCCGAA IAACAAAA 5662
    1650 UUUGUUCC C UUCUGUCU 5159 AGACAGAA CUGAUGAGGCCGUUAGGCCGAA IGAACAAA 5663
    1651 UUGUUCCC U UCUGUCUG 5160 CAGACAGA CUGAUGAGGCCGUUAGGCCGAA IGGAACAA 5664
    1654 UUCCCUUC U GUCUGCUC 5161 GAGCAGAC CUGAUGAGGCCGUUAGGCCGAA IAAGGGAA 5665
    1658 CUUCUGUC U GCUCGAAC 5162 GUUCGAGC CUGAUGAGGCCGUUAGGCCGAA IACAGAAG 5666
    1661 CUGUCUGC U CGAACCAC 5163 GUGGUUCG CUGAUGAGGCCGUUAGGCCGAA ICAGACAG 5667
    1667 GCUCGAAC C ACUUGCCU 5164 AGGCAAGU CUGAUGAGGCCGUUAGGCCGAA IUUCGAGC 5668
    1668 CUCGAACC A CUUGCCUC 5165 GAGGCAAG CUGAUGAGGCCGUUAGGCCGAA IGUUCGAG 5669
    1670 CGAACCAC U UGCCUCGG 5166 CCGAGGCA CUGAUGAGGCCGUUAGGCCGAA IUGGUUCG 5670
    1674 CCACUUGC C UCGGGCUA 5167 UAGCCCGA CUGAUGAGGCCGUUAGGCCGAA ICAAGUGG 5671
    1675 CACUUGCC U CGGGCUAA 5168 UUAGCCCG CUGAUGAGGCCGUUAGGCCGAA IGCAAGUG 5672
    1681 CCUCGGGC U AAUCCCUC 5169 GAGGGAUU CUGAUGAGGCCGUUAGGCCGAA ICCCGAGG 5673
    1686 GGCUAAUC C CUCCCUCU 5170 AGAGGGAG CUGAUGAGGCCGUUAGGCCGAA IAUUAGCC 5674
    1687 GCUAAUCC C UCCCUCUU 5171 AAGAGGGA CUGAUGAGGCCGUUAGGCCGAA IGAUUAGC 5675
    1688 CUAAUCCC U CCCUCUUC 5172 GAAGAGGG CUGAUGAGGCCGUUAGGCCGAA IGGAUUAG 5676
    1690 AAUCCCUC C CUCUUCCU 5173 AGGAAGAG CUGAUGAGGCCGUUAGGCCGAA IAGGGAUU 5677
    1691 AUCCCUCC C UCUUCCUC 5174 GAGGAAGA CUGAUGAGGCCGUUAGGCCGAA IGAGGGAU 5678
    1692 UCCCUCCC U CUUCCUCC 5175 GGAGGAAG CUGAUGAGGCCGUUAGGCCGAA IGGAGGGA 5679
    1694 CCUCCCUC U UCCUCCAC 5176 GUGGAGGA CUGAUGAGGCCGUUAGGCCGAA IAGGGAGG 5680
    1697 CCCUCUUC C UCCACCCG 5177 CGGGUGGA CUGAUGAGGCCGUUAGGCCGAA IAAGAGGG 5681
    1698 CCUCUUCC U CCACCCGG 5178 CCGGGUGG CUGAUGAGGCCGUUAGGCCGAA IGAAGAGG 5682
    1700 UCUUCCUC C ACCCGGCA 5179 UGCCGGGU CUGAUGAGGCCGUUAGGCCGAA IAGGAAGA 5683
    1701 CUUCCUCC A CCCGGCAC 5180 GUGCCGGG CUGAUGAGGCCGUUAGGCCGAA IGAGGAAG 5684
    1703 UCCUCCAC C CGGCACUG 5181 CAGUGCCG CUGAUGAGGCCGUUAGGCCGAA IUGGAGGA 5685
    1704 CCUCCACC C GGCACUGG 5182 CCAGUGCC CUGAUGAGGCCGUUAGGCCGAA IGUGGAGG 5686
    1708 CACCCGGC A CUGGGGAA 5183 UUCCCCAG CUGAUGAGGCCGUUAGGCCGAA ICCGGGUG 5687
    1710 CCCGGCAC U GGGGAAGU 5184 ACUUCCCC CUGAUGAGGCCGUUAGGCCGAA IUGCCGGG 5688
    1720 GGGAAGUC A AGAAUGGG 5185 CCCAUUCU CUGAUGAGGCCGUUAGGCCGAA IACUUCCC 5689
    1731 AAUGGGGC C UGGGGCUC 5186 GAGCCCCA CUGAUGAGGCCGUUAGGCCGAA ICCCCAUU 5690
    1732 AUGGGGCC U GGGGCUCU 5187 AGAGCCCC CUGAUGAGGCCGUUAGGCCGAA IGCCCCAU 5691
    1738 CCUGGGGC U CUCAGGGA 5188 UCCCUGAG CUGAUGAGGCCGUUAGGCCGAA ICCCCAGG 5692
    1740 UGGGGCUC U CAGGGAGA 5189 UCUCCCUG CUGAUGAGGCCGUUAGGCCGAA IAGCCCCA 5693
    1742 GGGCUCUC A GGGAGAAC 5190 GUUCUCCC CUGAUGAGGCCGUUAGGCCGAA IAGAGCCC 5694
    1751 GGGAGAAC U GCUUCCCC 5191 GGGGAAGC CUGAUGAGGCCGUUAGGCCGAA IUUCUCCC 5695
    1754 AGAACUGC U UCCCCUGG 5192 CCAGGGGA CUGAUGAGGCCGUUAGGCCGAA ICAGUUCU 5696
    1757 ACUGCUUC C CCUGGCAG 5193 CUGCCAGG CUGAUGAGGCCGUUAGGCCGAA IAAGCAGU 5697
    1758 CUGCUUCC C CUGGCAGA 5194 UCUGCCAG CUGAUGAGGCCGUUAGGCCGAA IGAAGCAG 5698
    1759 UGCUUCCC C UGGCAGAG 5195 CUCUGCCA CUGAUGAGGCCGUUAGGCCGAA IGGAAGCA 5699
    1760 GCUUCCCC U GGCAGAGC 5196 GCUCUGCC CUGAUGAGGCCGUUAGGCCGAA IGGGAAGC 5700
    1764 CCCCUGGC A GAGCUGGG 5197 CCCAGCUC CUGAUGAGGCCGUUAGGCCGAA ICCAGGGG 5701
    1769 GGCAGAGC U GGGUGGCA 5198 UGCCACCC CUGAUGAGGCCGUUAGGCCGAA ICUCUGCC 5702
    1777 UGGGUGGC A GCUCUUCC 5199 GGAAGAGC CUGAUGAGGCCGUUAGGCCGAA ICCACCCA 5703
    1780 GUGGCAGC U CUUCCUCC 5200 GGAGGAAG CUGAUGAGGCCGUUAGGCCGAA ICUGCCAC 5704
    1782 GGCAGCUC U UCCUCCCA 5201 UGGGAGGA CUGAUGAGGCCGUUAGGCCGAA IAGCUGCC 5705
    1785 AGCUCUUC C UCCCACCG 5202 CGGUGGGA CUGAUGAGGCCGUUAGGCCGAA IAAGAGCU 5706
    1786 GCUCUUCC U CCCACCGG 5203 CCGGUGGG CUGAUGAGGCCGUUAGGCCGAA IGAAGAGC 5707
    1788 UCUUCCUC C CACCGGAC 5204 GUCCGGUG CUGAUGAGGCCGUUAGGCCGAA IAGGAAGA 5708
    1789 CUUCCUCC C ACCGGACA 5205 UGUCCGGU CUGAUGAGGCCGUUAGGCCGAA IGAGGAAG 5709
    1790 UUCCUCCC A CCGGACAC 5206 GUGUCCGG CUGAUGAGGCCGUUAGGCCGAA IGGAGGAA 5710
    1792 CCUCCCAC C GGACACCG 5207 CGGUGUCC CUGAUGAGGCCGUUAGGCCGAA IUGGGAGG 5711
    1797 CACCGGAC A CCGACCCG 5208 CGGGUCGG CUGAUGAGGCCGUUAGGCCGAA IUCCGGUG 5712
    1799 CCGGACAC C GACCCGCC 5209 GGCGGGUC CUGAUGAGGCCGUUAGGCCGAA IUGUCCGG 5713
    1803 ACACCGAC C CGCCCGCC 5210 GGCGGGCG CUGAUGAGGCCGUUAGGCCGAA IUCGGUGU 5714
    1804 CACCGACC C GCCCGCCG 5211 CGGCGGGC CUGAUGAGGCCGUUAGGCCGAA IGUCGGUG 5715
    1807 CGACCCGC C CGCCGCUG 5212 CAGCGGCG CUGAUGAGGCCGUUAGGCCGAA ICGGGUCG 5716
    1808 GACCCGCC C GCCGCUGU 5213 ACAGCGGC CUGAUGAGGCCGUUAGGCCGAA IGCGGGUC 5717
    1811 CCGCCCGC C GCUGUGCC 5214 GGCACAGC CUGAUGAGGCCGUUAGGCCGAA ICGGGCGG 5718
    1814 CCCGCCGC U GUGCCCUG 5215 CAGGGCAC CUGAUGAGGCCGUUAGGCCGAA ICGGCGGG 5719
    1819 CGCUGUGC C CUGGGAGU 5216 ACUCCCAG CUGAUGAGGCCGUUAGGCCGAA ICACAGCG 5720
    1820 GCUGUGCC C UGGGAGUG 5217 CACUCCCA CUGAUGAGGCCGUUAGGCCGAA IGCACAGC 5721
    1821 CUGUGCCC U GGGAGUGC 5218 GCACUCCC CUGAUGAGGCCGUUAGGCCGAA IGGCACAG 5722
    1830 GGGAGUGC U GCCCUCUU 5219 AAGAGGGC CUGAUGAGGCCGUUAGGCCGAA ICACUCCC 5723
    1833 AGUGCUGC C CUCUUACC 5220 GGUAAGAG CUGAUGAGGCCGUUAGGCCGAA ICAGCACU 5724
    1834 GUGCUGCC C UCUUACCA 5221 UGGUAAGA CUGAUGAGGCCGUUAGGCCGAA IGCAGCAC 5725
    1835 UGCUGCCC U CUUACCAU 5222 AUGGUAAG CUGAUGAGGCCGUUAGGCCGAA IGGCAGCA 5726
    1837 CUGCCCUC U UACCAUGC 5223 GCAUGGUA CUGAUGAGGCCGUUAGGCCGAA IAGGGCAG 5727
    1841 CCUCUUAC C AUGCACAC 5224 GUGUGCAU CUGAUGAGGCCGUUAGGCCGAA IUAAGAGG 5728
    1842 CUCUUACC A UGCACACG 5225 CGUGUGCA CUGAUGAGGCCGUUAGGCCGAA IGUAAGAG 5729
    1846 UACCAUGC A CACGGGUG 5226 CACCCGUG CUGAUGAGGCCGUUAGGCCGAA ICAUGGUA 5730
    1848 CCAUGCAC A CGGGUGCU 5227 AGCACCCG CUGAUGAGGCCGUUAGGCCGAA IUGCAUGG 5731
    1856 ACGGGUGC U CUCCUUUU 5228 AAAAGGAG CUGAUGAGGCCGUUAGGCCGAA ICACCCGU 5732
    1858 GGGUGCUC U CCUUUUGG 5229 CCAAAAGG CUGAUGAGGCCGUUAGGCCGAA IAGCACCC 5733
    1860 GUGCUCUC C UUUUGGGC 5230 GCCCAAAA CUGAUGAGGCCGUUAGGCCGAA IAGAGCAC 5734
    1861 UGCUCUCC U UUUGGGCU 5231 AGCCCAAA CUGAUGAGGCCGUUAGGCCGAA IGAGAGCA 5735
    1869 UUUUGGGC U GCAUGCUA 5232 UAGCAUGC CUGAUGAGGCCGUUAGGCCGAA ICCCAAAA 5736
    1872 UGGGCUGC A UGCUAUUC 5233 GAAUAGCA CUGAUGAGGCCGUUAGGCCGAA ICAGCCCA 5737
    1876 CUGCAUGC U AUUCCAUU 5234 AAUGGAAU CUGAUGAGGCCGUUAGGCCGAA ICAUGCAG 5738
    1881 UGCUAUUC C AUUUUGCA 5235 UGCAAAAU CUGAUGAGGCCGUUAGGCCGAA IAAUAGCA 5739
    1882 GCUAUUCC A UUUUGCAG 5236 CUGCAAAA CUGAUGAGGCCGUUAGGCCGAA IGAAUAGC 5740
    1889 CAUUUUGC A GCCAGACC 5237 GGUCUGGC CUGAUGAGGCCGUUAGGCCGAA ICAAAAUG 5741
    1892 UUUGCAGC C AGACCGAU 5238 AUCGGUCU CUGAUGAGGCCGUUAGGCCGAA ICUGCAAA 5742
    1893 UUGCAGCC A GACCGAUG 5239 CAUCGGUC CUGAUGAGGCCGUUAGGCCGAA IGCUGCAA 5743
    1897 AGCCAGAC C GAUGUGUA 5240 UACACAUC CUGAUGAGGCCGUUAGGCCGAA IUCUGGCU 5744
    1912 UAUUUAAC C AGUCACUA 5241 UAGUGACU CUGAUGAGGCCGUUAGGCCGAA IUUAAAUA 5745
    1913 AUUUAACC A GUCACUAU 5242 AUAGUGAC CUGAUGAGGCCGUUAGGCCGAA IGUUAAAU 5746
    1917 AACCAGUC A CUAUUGAU 5243 AUCAAUAG CUGAUGAGGCCGUUAGGCCGAA IACUGGUU 5747
    1919 CCAGUCAC U AUUGAUGG 5244 CCAUCAAU CUGAUGAGGCCGUUAGGCCGAA IUGACUGG 5748
    1930 UGAUGGAC A UUUGGGUU 5245 AACCCAAA CUGAUGAGGCCGUUAGGCCGAA IUCCAUCA 5749
    1944 GUUGUUUC C CAUCUUUU 5246 AAAAGAUG CUGAUGAGGCCGUUAGGCCGAA IAAACAAC 5750
    1945 UUGUUUCC C AUCUUUUU 5247 AAAAAGAU CUGAUGAGGCCGUUAGGCCGAA IGAAACAA 5751
    1946 UGUUUCCC A UCUUUUUG 5248 CAAAAAGA CUGAUGAGGCCGUUAGGCCGAA IGGAAACA 5752
    1949 UUCCCAUC U UUUUGUUA 5249 UAACAAAA CUGAUGAGGCCGUUAGGCCGAA IAUGGGAA 5753
    1959 UUUGUUAC C AUAAAUAA 5250 UUAUUUAU CUGAUGAGGCCGUUAGGCCGAA IUAACAAA 5754
    1960 UUGUUACC A UAAAUAAU 5251 AUUAUUUA CUGAUGAGGCCGUUAGGCCGAA IGUAACAA 5755
    1972 AUAAUGGC A UAGUAAAA 5252 UUUUACUA CUGAUGAGGCCGUUAGGCCGAA ICCAUUAU 5756

    Input Sequence = NM_003639. Cut Site = CH/.

    Arm Length = 8. Core Sequence = CUGAUGAG GCCGUUAGGC CGAA

    NM_003639 (Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), mRNA.; 1994 bp)

    Underlined region can be any X sequence or linker, as described herein.

    “I” stands for Inosine.
  • TABLE V
    Human IKK-gamma Zinzyme and Substrate Sequence
    Seq Seq
    Pos Substrate ID Zinzyme ID
    13 CGAGCAUG G CCCUUGUG 5757 CACAAGGG GCCGAAAGGCGAGUGAGGUCU CAUGCUCG 6034
    19 UGGCCCUU G UGAUCCAG 5758 CUGGAUCA GCCGAAAGGCGAGUGAGGUCU AAGGGCCA 6035
    28 UGAUCCAG G UGGGGAAA 5759 UUUCCCCA GCCGAAAGGCGAGUGAGGUCU CUGGAUCA 6036
    42 AAACUAAG G CCCAGAGA 5760 UCUCUGGG GCCGAAAGGCGAGUGAGGUCU CUUAGUUU 6037
    52 CCAGAGAA G UGAGGACC 5761 GGUCCUCA GCCGAAAGGCGAGUGAGGUCU UUCUCUGG 6038
    63 AGGACCCC G CAGACUAU 5762 AUAGUCUG GCCGAAAGGCGAGUGAGGUCU GGGGUCCU 6039
    80 CAAUCCCA G UCUCUUCC 5763 GGAAGAGA GCCGAAAGGCGAGUGAGGUCU UGGGAUUG 6040
    100 CACUCCCU G UGAAGCUC 5764 GAGCUUCA GCCGAAAGGCGAGUGAGGUCU AGGGAGUG 6041
    105 CCUGUGAA G CUCUCCAG 5765 CUGGAGAG GCCGAAAGGCGAGUGAGGUCU UUCACAGG 6042
    113 GCUCUCCA G CAUCAUCG 5766 CGAUGAUG GCCGAAAGGCGAGUGAGGUCU UGGAGAGC 6043
    124 UCAUCGAG G UCCCAUCA 5767 UGAUGGGA GCCGAAAGGCGAGUGAGGUCU CUCGAUGA 6044
    133 UCCCAUCA G CCCUUGCC 5768 GGCAAGGG GCCGAAAGGCGAGUGAGGUCU UGAUGGGA 6045
    139 CAGCCCUU G CCCUGUUG 5769 CAACAGGG GCCGAAAGGCGAGUGAGGUCU AAGGGCUG 6046
    144 CUUGCCCU G UUGGAUGA 5770 UCAUCCAA GCCGAAAGGCGAGUGAGGUCU AGGGCAAG 6047
    157 AUGAAUAG G CACCUCUG 5771 CAGAGGUG GCCGAAAGGCGAGUGAGGUCU CUAUUCAU 6046
    171 CUGGAAGA G CCAACUGU 5772 ACAGUUGG GCCGAAAGGCGAGUGAGGUCU UCUUCCAG 6049
    178 AGCCAACU G UGUGAGAU 5773 AUCUCACA GCCGAAAGGCGAGUGAGGUCU AGUUGGCU 6050
    180 CCAACUGU G UGAGAUGG 5774 CCAUCUCA GCCGAAAGGCGAGUGAGGUCU ACAGUUGG 6051
    188 GUGAGAUG G UGCAGCCC 5775 GGGCUGCA GCCGAAAGGCGAGUGAGGUCU CAUCUCAC 6052
    190 GAGAUGGU G CAGCCCAG 5776 CUGGGCUG GCCGAAAGGCGAGUGAGGUCU ACCAUCUC 6053
    193 AUGGUGCA G CCCAGUGG 5777 CCACUGGG GCCGAAAGGCGAGUGAGGUCU UGCACCAU 6054
    198 GCAGCCCA G UGGUGGCC 5778 GGCCACCA GCCGAAAGGCGAGUGAGGUCU UGGGCUGC 6055
    201 GCCCAGUG G UGGCCCGG 5779 CCGGGCCA GCCGAAAGGCGAGUGAGGUCU CACUGGGC 6056
    204 CAGUGGUG G CCCGGCAG 5780 CUGCCGGG GCCGAAAGGCGAGUGAGGUCU CACCACUG 6057
    209 GUGGCCCG G CAGCAGAU 5781 AUCUGCUG GCCGAAAGGCGAGUGAGGUCU CGGGCCAC 6058
    212 GCCCGGCA G CAGAUCAG 5782 CUGAUCUG GCCGAAAGGCGAGUGAGGUCU UGCCGGGC 6059
    224 AUCAGGAC G UACUGGGC 5783 GCCCAGUA GCCGAAAGGCGAGUGAGGUCU GUCCUGAU 6060
    231 CGUACUGG G CGAAGAGU 5784 ACUCUUCG GCCGAAAGGCGAGUGAGGUCU CCAGUACG 6061
    238 GGCGAAGA G UCUCCUCU 5785 AGAGGAGA GCCGAAAGGCGAGUGAGGUCU UCUUCGCC 6062
    253 CUGGGGAA G CCAGCCAU 5786 AUGGCUGG GCCGAAAGGCGAGUGAGGUCU UUCCCCAG 6063
    257 GGAAGCCA G CCAUGCUG 5787 CAGCAUGG GCCGAAAGGCGAGUGAGGUCU UGGCUUCC 6064
    262 CCAGCCAU G CUGCACCU 5788 AGGUGCAG GCCGAAAGGCGAGUGAGGUCU AUGGCUGG 6065
    265 GCCAUGCU G CACCUGCC 5789 GGCAGGUG GCCGAAAGGCGAGUGAGGUCU AGCAUGGC 6066
    271 CUGCACCU G CCUUCAGA 5790 UCUGAAGG GCCGAAAGGCGAGUGAGGUCU AGGUGCAG 6067
    285 AGAACAGG G CGCUCCUG 5791 CAGGAGCG GCCGAAAGGCGAGUGAGGUCU CCUGUUCU 6068
    287 AACAGGGC G CUCCUGAG 5792 CUCAGGAG GCCGAAAGGCGAGUGAGGUCU GCCCUGUU 6069
    304 ACCCUCCA G CGCUGCCU 5793 AGGCAGCG GCCGAAAGGCGAGUGAGGUCU UGGAGGGU 6070
    306 CCUCCAGC G CUGCCUGG 5794 CCAGGCAG GCCGAAAGGCGAGUGAGGUCU GCUGGAGG 6071
    309 CCAGCGCU G CCUGGAGG 5795 CCUCCAGG GCCGAAAGGCGAGUGAGGUCU AGCGCUGG 6072
    328 AAUCAAGA G CUCCGAGA 5796 UCUCGGAG GCCGAAAGGCGAGUGAGGUCU UCUUGAUU 6073
    338 UCCGAGAU G CCAUCCGG 5797 CCGGAUGG GCCGAAAGGCGAGUGAGGUCU AUCUCGGA 6074
    346 GCCAUCCG G CAGAGCAA 5798 UUGCUCUG GCCGAAAGGCGAGUGAGGUCU CGGAUGGC 6075
    351 CCGGCAGA G CAACCAGA 5799 UCUGGUUG GCCGAAAGGCGAGUGAGGUCU UCUGCCGG 6076
    364 CAGAUUCU G CGGGAGCG 5800 CGCUCCCG GCCGAAAGGCGAGUGAGGUCU AGAAUCUG 6077
    370 CUGCGGGA G CGCUGCGA 5801 UCGCAGCG GCCGAAAGGCGAGUGAGGUCU UCCCGCAG 6078
    372 GCGGGAGC G CUGCGAGG 5802 CCUCGCAG GCCGAAAGGCGAGUGAGGUCU GCUCCCGC 6079
    375 GGAGCGCU G CGAGGAGC 5803 GCUCCUCG GCCGAAAGGCGAGUGAGGUCU AGCGCUCC 6080
    382 UGCGAGGA G CUUCUGCA 5804 UGCAGAAG GCCGAAAGGCGAGUGAGGUCU UCCUCGCA 6081
    388 GAGCUUCU G CAUUUCCA 5805 UGGAAAUG GCCGAAAGGCGAGUGAGGUCU AGAAGCUC 6082
    398 AUUUCCAA G CCAGCCAG 5806 CUGGCUGG GCCGAAAGGCGAGUGAGGUCU UUGGAAAU 6083
    402 CCAAGCCA G CCAGAGGG 5807 CCCUCUGG GCCGAAAGGCGAGUGAGGUCU UGGCUUGG 6084
    421 GAGAAGGA G UUCCUCAU 5808 AUGAGGAA GCCGAAAGGCGAGUGAGGUCU UCCUUCUC 6085
    430 UUCCUCAU G UGCAAGUU 5809 AACUUGCA GCCGAAAGGCGAGUGAGGUCU AUGAGGAA 6086
    432 CCUCAUGU G CAAGUUCC 5810 GGAACUUG GCCGAAAGGCGAGUGAGGUCU ACAUGAGG 6087
    436 AUGUGCAA G UUCCAGGA 5811 UCCUGGAA GCCGAAAGGCGAGUGAGGUCU UUGCACAU 6088
    446 UCCAGGAG G CCAGGAAA 5812 UUUCCUGG GCCGAAAGGCGAGUGAGGUCU CUCCUGGA 6089
    458 GGAAACUG G UGGAGAGA 5813 UCUCUCCA GCCGAAAGGCGAGUGAGGUCU CAGUUUCC 6090
    471 GAGACUCG G CCUGGAGA 5814 UCUCCAGG GCCGAAAGGCGAGUGAGGUCU CGAGUCUC 6091
    481 CUGGAGAA G CUCGAUCU 5815 AGAUCGAG GCCGAAAGGCGAGUGAGGUCU UUCUCCAG 6092
    496 CUGAAGAG G CAGAAGGA 5816 UCCUUCUG GCCGAAAGGCGAGUGAGGUCU CUCUUCAG 6093
    505 CAGAAGGA G CAGGCUCU 5817 AGAGCCUG GCCGAAAGGCGAGUGAGGUCU UCCUUCUG 6094
    509 AGGAGCAG G CUCUGCGG 5818 CCGCAGAG GCCGAAAGGCGAGUGAGGUCU CUGCUCCU 6095
    514 CAGGCUCU G CGGGAGGU 5819 ACCUCCCG GCCGAAAGGCGAGUGAGGUCU AGAGCCUG 6096
    521 UGCGGGAG G UGGAGCAC 5820 GUGCUCCA GCCGAAAGGCGAGUGAGGUCU CUCCCGCA 6097
    526 GAGGUGGA G CACCUGAA 5821 UUCAGGUG GCCGAAAGGCGAGUGAGGUCU UCCACCUC 6098
    540 GAAGAGAU G CCAGCAGC 5822 GCUGCUGG GCCGAAAGGCGAGUGAGGUCU AUCUCUUC 6099
    544 AGAUGCCA G CAGCAGAU 5823 AUCUGCUG GCCGAAAGGCGAGUGAGGUCU UGGCAUCU 6100
    547 UGCCAGCA G CAGAUGGC 5824 GCCAUCUG GCCGAAAGGCGAGUGAGGUCU UGCUGGCA 6101
    554 AGCAGAUG G CUGAGGAC 5825 GUCCUCAG GCCGAAAGGCGAGUGAGGUCU CAUCUGCU 6102
    566 AGGACAAG G CCUCUGUG 5826 CACAGAGG GCCGAAAGGCGAGUGAGGUCU CUUGUCCU 6103
    572 AGGCCUCU G UGAAAGCC 5827 GGCUUUCA GCCGAAAGGCGAGUGAGGUCU AGAGGCCU 6104
    578 CUGUGAAA G CCCAGGUG 5828 CACCUGGG GCCGAAAGGCGAGUGAGGUCU UUUCACAG 6105
    584 AAGCCCAG G UGACGUCC 5829 GGACGUCA GCCGAAAGGCGAGUGAGGUCU CUGGGCUU 6106
    589 CAGGUGAC G UCCUUGCU 5830 AGCAAGGA GCCGAAAGGCGAGUGAGGUCU GUCACCUG 6107
    595 ACGUCCUU G CUCGGGGA 5831 UCCCCGAG GCCGAAAGGCGAGUGAGGUCU AAGGACGU 6108
    604 CUCGGGGA G CUGCAGGA 5832 UCCUGCAG GCCGAAAGGCGAGUGAGGUCU UCCCCGAG 6109
    607 GGGGAGCU G CAGGAGAG 5833 CUCUCCUG GCCGAAAGGCGAGUGAGGUCU AGCUCCCC 6110
    615 GCAGGAGA G CCAGAGUC 5834 GACUCUGG GCCGAAAGGCGAGUGAGGUCU UCUCCUGC 6111
    621 GAGCCAGA G UCGCUUGG 5835 CCAAGCGA GCCGAAAGGCGAGUGAGGUCU UCUGGCUC 6112
    624 CCAGAGUC G CUUGGAGG 5836 CCUCCAAG GCCGAAAGGCGAGUGAGGUCU GACUCUGG 6113
    632 GCUUGGAG G CUGCCACU 5837 AGUGGCAG GCCGAAAGGCGAGUGAGGUCU CUCCAAGC 6114
    635 UGGAGGCU G CCACUAAG 5838 CUUAGUGG GCCGAAAGGCGAGUGAGGUCU AGCCUCCA 6115
    648 UAAGGAAU G CCAGGCUC 5839 GAGCCUGG GCCGAAAGGCGAGUGAGGUCU AUUCCUUA 6116
    653 AAUGCCAG G CUCUGGAG 5840 CUCCAGAG GCCGAAAGGCGAGUGAGGUCU CUGGCAUU 6117
    663 UCUGGAGG G UCGGGCCC 5841 GGGCCCGA GCCGAAAGGCGAGUGAGGUCU CCUCCAGA 6118
    668 AGGGUCGG G CCCGGGCG 5842 CGCCCGGG GCCGAAAGGCGAGUGAGGUCU CCGACCCU 6119
    674 GGGCCCGG G CGGCCAGC 5843 GCUGGCCG GCCGAAAGGCGAGUGAGGUCU CCGGGCCC 6120
    677 CCCGGGCG G CCAGCGAG 5844 CUCGCUGG GCCGAAAGGCGAGUGAGGUCU CGCCCGGG 6121
    681 GGCGGCCA G CGAGCAGG 5845 CCUGCUCG GCCGAAAGGCGAGUGAGGUCU UGGCCGCC 6122
    685 GCCAGCGA G CAGGCGCG 5846 CGCGCCUG GCCGAAAGGCGAGUGAGGUCU UCGCUGGC 6123
    689 GCGAGCAG G CGCGGCAG 5847 CUGCCGCG GCCGAAAGGCGAGUGAGGUCU CUGCUCGC 6124
    691 GAGCAGGC G CGGCAGCU 5848 AGCUGCCG GCCGAAAGGCGAGUGAGGUCU GCCUGCUC 6125
    694 CAGGCGCG G CAGCUGGA 5849 UCCAGCUG GCCGAAAGGCGAGUGAGGUCU CGCGCCUG 6126
    697 GCGCGGCA G CUGGAGAG 5850 CUCUCCAG GCCGAAAGGCGAGUGAGGUCU UGCCGCGC 6127
    705 GCUGGAGA G UGAGCGCG 5851 CGCGCUCA GCCGAAAGGCGAGUGAGGUCU UCUCCAGC 6128
    709 GAGAGUGA G CGCGAGGC 5852 GCCUCGCG GCCGAAAGGCGAGUGAGGUCU UCACUCUC 6129
    711 GAGUGAGC G CGAGGCGC 5853 GCGCCUCG GCCGAAAGGCGAGUGAGGUCU GCUCACUC 6130
    716 AGCGCGAG G CGCUGCAG 5854 CUGCAGCG GCCGAAAGGCGAGUGAGGUCU CUCGCGCU 6131
    718 CGCGAGGC G CUGCAGCA 5855 UGCUGCAG GCCGAAAGGCGAGUGAGGUCU GCCUCGCG 6132
    721 GAGGCGCU G CAGCAGCA 5856 UGCUGCUG GCCGAAAGGCGAGUGAGGUCU AGCGCCUC 6133
    724 GCGCUGCA G CAGCAGCA 5857 UGCUGCUG GCCGAAAGGCGAGUGAGGUCU UGCAGCGC 6134
    727 CUGCAGCA G CAGCACAG 5858 CUGUGCUG GCCGAAAGGCGAGUGAGGUCU UGCUGCAG 6135
    730 CAGCAGCA G CACAGCGU 5859 ACGCUGUG GCCGAAAGGCGAGUGAGGUCU UGCUGCUG 6136
    735 GCAGCACA G CGUGCAGG 5860 CCUGCACG GCCGAAAGGCGAGUGAGGUCU UGUGCUGC 6137
    737 AGCACAGC G UGCAGGUG 5861 CACCUGCA GCCGAAAGGCGAGUGAGGUCU GCUGUGCU 6138
    739 CACAGCGU G CAGGUGGA 5862 UCCACCUG GCCGAAAGGCGAGUGAGGUCU ACGCUGUG 6139
    743 GCGUGCAG G UGGACCAG 5863 CUGGUCCA GCCGAAAGGCGAGUGAGGUCU CUGCACGC 6140
    751 GUGGACCA G CUGCGCAU 5864 AUGCGCAG GCCGAAAGGCGAGUGAGGUCU UGGUCCAC 6141
    754 GACCAGCU G CGCAUGCA 5865 UGCAUGCG GCCGAAAGGCGAGUGAGGUCU AGCUGGUC 6142
    756 CCAGCUGC G CAUGCAGG 5866 CCUGCAUG GCCGAAAGGCGAGUGAGGUCU GCAGCUGG 6143
    760 CUGCGCAU G CAGGGCCA 5867 UGGCCCUG GCCGAAAGGCGAGUGAGGUCU AUGCGCAG 6144
    765 CAUGCAGG G CCAGAGCG 5868 CGCUCUGG GCCGAAAGGCGAGUGAGGUCU CCUGCAUG 6145
    771 GGGCCAGA G CGUGGAGG 5869 CCUCCACG GCCGAAAGGCGAGUGAGGUCU UCUGGCCC 6146
    773 GCCAGAGC G UGGAGGCC 5870 GGCCUCCA GCCGAAAGGCGAGUGAGGUCU GCUCUGGC 6147
    779 GCGUGGAG G CCGCGCUC 5871 GAGCGCGG GCCGAAAGGCGAGUGAGGUCU CUCCACGC 6148
    782 UGGAGGCC G CGCUCCGC 5872 GCGGAGCG GCCGAAAGGCGAGUGAGGUCU GGCCUCCA 6149
    784 GAGGCCGC G CUCCGCAU 5873 AUGCGGAG GCCGAAAGGCGAGUGAGGUCU GCGGCCUC 6150
    789 CGCGCUCC G CAUGGAGC 5874 GCUCCAUG GCCGAAAGGCGAGUGAGGUCU GGAGCGCG 6151
    796 CGCAUGGA G CGCCAGGC 5875 GCCUGGCG GCCGAAAGGCGAGUGAGGUCU UCCAUGCG 6152
    798 CAUGGAGC G CCAGGCCG 5876 CGGCCUGG GCCGAAAGGCGAGUGAGGUCU GCUCCAUG 6153
    803 AGCGCCAG G CCGCCUCG 5877 CGAGGCGG GCCGAAAGGCGAGUGAGGUCU CUGGCGCU 6154
    806 GCCAGGCC G CCUCGGAG 5878 CUCCGAGG GCCGAAAGGCGAGUGAGGUCU GGCCUGGC 6155
    826 AAGAGGAA G CUGGCCCA 5879 UGGGCCAG GCCGAAAGGCGAGUGAGGUCU UUCCUCUU 6156
    830 GGAAGCUG G CCCAGUUG 5880 CAACUGGG GCCGAAAGGCGAGUGAGGUCU CAGCUUCC 6157
    835 CUGGCCCA G UUGCAGGU 5881 ACCUGCAA GCCGAAAGGCGAGUGAGGUCU UGGGCCAG 6158
    838 GCCCAGUU G CAGGUGGC 5882 GCCACCUG GCCGAAAGGCGAGUGAGGUCU AACUGGGC 6159
    842 AGUUGCAG G UGGCCUAU 5883 AUAGGCCA GCCGAAAGGCGAGUGAGGUCU CUGCAACU 6160
    845 UGCAGGUG G CCUAUCAC 5884 GUGAUAGG GCCGAAAGGCGAGUGAGGUCU CACCUGCA 6161
    856 UAUCACCA G CUCUUCCA 5885 UGGAAGAG GCCGAAAGGCGAGUGAGGUCU UGGUGAUA 6162
    888 CAUCAAGA G CAGCGUGG 5886 CCACGCUG GCCGAAAGGCGAGUGAGGUCU UCUUGAUG 6163
    891 CAAGAGCA G CGUGGUGG 5887 CCACCACG GCCGAAAGGCGAGUGAGGUCU UGCUCUUG 6164
    893 AGAGCAGC G UGGUGGGC 5888 GCCCACCA GCCGAAAGGCGAGUGAGGUCU GCUGCUCU 6165
    896 GCAGCGUG G UGGGCAGU 5889 ACUGCCCA GCCGAAAGGCGAGUGAGGUCU CACGCUGC 6166
    900 CGUGGUGG G CAGUGAGC 5890 GCUCACUG GCCGAAAGGCGAGUGAGGUCU CCACCACG 6167
    903 GGUGGGCA G UGAGCGGA 5891 UCCGCUCA GCCGAAAGGCGAGUGAGGUCU UGCCCACC 6168
    907 GGCAGUGA G CGGAAGCG 5892 CGCUUCCG GCCGAAAGGCGAGUGAGGUCU UCACUGCC 6169
    913 GAGCGGAA G CGAGGAAU 5893 AUUCCUCG GCCGAAAGGCGAGUGAGGUCU UUCCGCUC 6170
    922 CGAGGAAU G CAGCUGGA 5894 UCCAGCUG GCCGAAAGGCGAGUGAGGUCU AUUCCUCG 6171
    925 GGAAUGCA G CUGGAAGA 5895 UCUUCCAG GCCGAAAGGCGAGUGAGGUCU UGCAUUCC 6172
    943 CUCAAACA G CAGCUCCA 5896 UGGAGCUG GCCGAAAGGCGAGUGAGGUCU UGUUUGAG 6173
    946 AAACAGCA G CUCCAGCA 5897 UGCUGGAG GCCGAAAGGCGAGUGAGGUCU UGCUGUUU 6174
    952 CAGCUCCA G CAGGCCGA 5898 UCGGCCUG GCCGAAAGGCGAGUGAGGUCU UGGAGCUG 6175
    956 UCCAGCAG G CCGAGGAG 5899 CUCCUCGG GCCGAAAGGCGAGUGAGGUCU CUGCUGGA 6176
    965 CCGAGGAG G CCCUGGUG 5900 CACCAGGG GCCGAAAGGCGAGUGAGGUCU CUCCUCGG 6177
    971 AGGCCCUG G UGGCCAAA 5901 UUUGGCCA GCCGAAAGGCGAGUGAGGUCU CAGGGCCU 6178
    974 CCCUGGUG G CCAAACAG 5902 CUGUUUGG GCCGAAAGGCGAGUGAGGUCU CACCAGGG 6179
    986 AACAGGAG G UGAUCGAU 5903 AUCGAUCA GCCGAAAGGCGAGUGAGGUCU CUCCUGUU 6180
    997 AUCGAUAA G CUGAAGGA 5904 UCCUUCAG GCCGAAAGGCGAGUGAGGUCU UUAUCGAU 6181
    1010 AGGAGGAG G CCGAGCAG 5905 CUGCUCGG GCCGAAAGGCGAGUGAGGUCU CUCCUCCU 6182
    1015 GAGGCCGA G CAGCACAA 5906 UUGUGCUG GCCGAAAGGCGAGUGAGGUCU UCGGCCUC 6183
    1018 GCCGAGCA G CACAAGAU 5907 AUCUUGUG GCCGAAAGGCGAGUGAGGUCU UGCUCGGC 6184
    1028 ACAAGAUU G UGAUGGAG 5908 CUCCAUCA GCCGAAAGGCGAGUGAGGUCU AAUCUUGU 6185
    1040 UGGAGACC G UUCCGGUG 5909 CACCGGAA GCCGAAAGGCGAGUGAGGUCU GGUCUCCA 6186
    1046 CCGUUCCG G UGCUGAAG 5910 CUUCAGCA GCCGAAAGGCGAGUGAGGUCU CGGAACGG 6187
    1048 GUUCCGGU G CUGAAGGC 5911 GCCUUCAG GCCGAAAGGCGAGUGAGGUCU ACCGGAAC 6188
    1055 UGCUGAAG G CCCAGGCG 5912 CGCCUGGG GCCGAAAGGCGAGUGAGGUCU CUUCAGCA 6189
    1061 AGGCCCAG G CGGAUAUC 5913 GAUAUCCG GCCGAAAGGCGAGUGAGGUCU CUGGGCCU 6190
    1076 UCUACAAG G CGGACUUC 5914 GAAGUCCG GCCGAAAGGCGAGUGAGGUCU CUUGUAGA 6191
    1088 ACUUCCAG G CUGAGAGG 5915 CCUCUCAG GCCGAAAGGCGAGUGAGGUCU CUGGAAGU 6192
    1096 GCUGAGAG G CAGGCCCG 5916 CGGGCCUG GCCGAAAGGCGAGUGAGGUCU CUCUCAGC 6193
    1100 AGAGGCAG G CCCGGGAG 5917 CUCCCGGG GCCGAAAGGCGAGUGAGGUCU CUGCCUCU 6194
    1111 CGGGAGAA G CUGGCCGA 5918 UCGGCCAG GCCGAAAGGCGAGUGAGGUCU UUCUCCCG 6195
    1115 AGAAGCUG G CCGAGAAG 5919 CUUCUCGG GCCGAAAGGCGAGUGAGGUCU CAGCUUCU 6196
    1129 AAGAAGGA G CUCCUGCA 5920 UGCAGGAG GCCGAAAGGCGAGUGAGGUCU UCCUUCUU 6197
    1135 GAGCUCCU G CAGGAGCA 5921 UGCUCCUG GCCGAAAGGCGAGUGAGGUCU AGGAGCUC 6198
    1141 CUGCAGGA G CAGCUGGA 5922 UCCAGCUG GCCGAAAGGCGAGUGAGGUCU UCCUGCAG 6199
    1144 CAGGAGCA G CUGGAGCA 5923 UGCUCCAG GCCGAAAGGCGAGUGAGGUCU UGCUCCUG 6200
    1150 CAGCUGGA G CAGCUGCA 5924 UGCAGCUG GCCGAAAGGCGAGUGAGGUCU UCCAGCUG 6201
    1153 CUGGAGCA G CUGCAGAG 5925 CUCUGCAG GCCGAAAGGCGAGUGAGGUCU UGCUCCAG 6202
    1156 GAGCAGCU G CAGAGGGA 5926 UCCCUCUG GCCGAAAGGCGAGUGAGGUCU AGCUGCUC 6203
    1165 CAGAGGGA G UACAGCAA 5927 UUGCUGUA GCCGAAAGGCGAGUGAGGUCU UCCCUCUG 6204
    1170 GGAGUACA G CAAACUGA 5928 UCAGUUUG GCCGAAAGGCGAGUGAGGUCU UGUACUCC 6205
    1181 AACUGAAG G CCAGCUGU 5929 ACAGCUGG GCCGAAAGGCGAGUGAGGUCU CUUCAGUU 6206
    1185 GAAGGCCA G CUGUCAGG 5930 CCUGACAG GCCGAAAGGCGAGUGAGGUCU UGGCCUUC 6207
    1188 GGCCAGCU G UCAGGAGU 5931 ACUCCUGA GCCGAAAGGCGAGUGAGGUCU AGCUGGCC 6208
    1195 UGUCAGGA G UCGGCCAG 5932 CUGGCCGA GCCGAAAGGCGAGUGAGGUCU UCCUGACA 6209
    1199 AGGAGUCG G CCAGGAUC 5933 GAUCCUGG GCCGAAAGGCGAGUGAGGUCU CGACUCCU 6210
    1222 AUGAGGAA G CGGCAUGU 5934 ACAUGCCG GCCGAAAGGCGAGUGAGGUCU UUCCUCAU 6211
    1225 AGGAAGCG G CAUGUCGA 5935 UCGACAUG GCCGAAAGGCGAGUGAGGUCU CGCUUCCU 6212
    1229 AGCGGCAU G UCGAGGUC 5936 GACCUCGA GCCGAAAGGCGAGUGAGGUCU AUGCCGCU 6213
    1235 AUGUCGAG G UCUCCCAG 5937 CUGGGAGA GCCGAAAGGCGAGUGAGGUCU CUCGACAU 6214
    1244 UCUCCCAG G CCCCCUUG 5938 CAAGGGGG GCCGAAAGGCGAGUGAGGUCU CUGGGAGA 6215
    1252 GCCCCCUU G CCCCCCGC 5939 GCGGGGGG GCCGAAAGGCGAGUGAGGUCU AAGGGGGC 6216
    1259 UGCCCCCC G CCCCUGCC 5940 GGCAGGGG GCCGAAAGGCGAGUGAGGUCU GGGGGGCA 6217
    1265 CCGCCCCU G CCUACCUC 5941 GAGGUAGG GCCGAAAGGCGAGUGAGGUCU AGGGGCGG 6218
    1286 CUCCCCUG G CCCUGCCC 5942 GGGCAGGG GCCGAAAGGCGAGUGAGGUCU CAGGGGAG 6219
    1291 CUGGCCCU G CCCAGCCA 5943 UGGCUGGG GCCGAAAGGCGAGUGAGGUCU AGGGCCAG 6220
    1296 CCUGCCCA G CCAGAGGA 5944 UCCUCUGG GCCGAAAGGCGAGUGAGGUCU UGGGCAGG 6221
    1308 GAGGAGGA G CCCCCCCG 5945 CGGGGGGG GCCGAAAGGCGAGUGAGGUCU UCCUCCUC 6222
    1321 CCCGAGGA G CCACCUGA 5946 UCAGGUGG GCCGAAAGGCGAGUGAGGUCU UCCUCGGG 6223
    1335 UGACUUCU G CUGUCCCA 5947 UGGGACAG GCCGAAAGGCGAGUGAGGUCU AGAAGUCA 6224
    1338 CUUCUGCU G UCCCAAGU 5948 ACUUGGGA GCCGAAAGGCGAGUGAGGUCU AGCAGAAG 6225
    1345 UGUCCCAA G UGCCAGUA 5949 UACUGGCA GCCGAAAGGCGAGUGAGGUCU UUGGGACA 6226
    1347 UCCCAAGU G CCAGUAUC 5950 GAUACUGG GCCGAAAGGCGAGUGAGGUCU ACUUGGGA 6227
    1351 AAGUGCCA G UAUCAGGC 5951 GCCUGAUA GCCGAAAGGCGAGUGAGGUCU UGGCACUU 6228
    1358 AGUAUCAG G CCCCUGAU 5952 AUCAGGGG GCCGAAAGGCGAGUGAGGUCU CUGAUACU 6229
    1378 GACACCCU G CAGAUACA 5953 UGUAUCUG GCCGAAAGGCGAGUGAGGUCU AGGGUGUC 6230
    1388 AGAUACAU G UCAUGGAG 5954 CUCCAUGA GCCGAAAGGCGAGUGAGGUCU AUGUAUCU 6231
    1396 GUCAUGGA G UGCAUUGA 5955 UCAAUGCA GCCGAAAGGCGAGUGAGGUCU UCCAUGAC 6232
    1398 CAUGGAGU G CAUUGAGU 5956 ACUCAAUG GCCGAAAGGCGAGUGAGGUCU ACUCCAUG 6233
    1405 UGCAUUGA G UAGGGCCG 5957 CGGCCCUA GCCGAAAGGCGAGUGAGGUCU UCAAUGCA 6234
    1410 UGAGUAGG G CCGGCCAG 5958 CUGGCCGG GCCGAAAGGCGAGUGAGGUCU CCUACUCA 6235
    1414 UAGGGCCG G CCAGUGCA 5959 UGCACUGG GCCGAAAGGCGAGUGAGGUCU CGGCCCUA 6236
    1418 GCCGGCCA G UGCAAGGC 5960 GCCUUGCA GCCGAAAGGCGAGUGAGGUCU UGGCCGGC 6237
    1420 CGGCCAGU G CAAGGCCA 5961 UGGCCUUG GCCGAAAGGCGAGUGAGGUCU ACUGGCCG 6238
    1425 AGUGCAAG G CCACUGCC 5962 GGCAGUGG GCCGAAAGGCGAGUGAGGUCU CUUGCACU 6239
    1431 AGGCCACU G CCUGCCCG 5963 CGGGCAGG GCCGAAAGGCGAGUGAGGUCU AGUGGCCU 6240
    1435 CACUGCCU G CCCGAGGA 5964 UCCUCGGG GCCGAAAGGCGAGUGAGGUCU AGGCAGUG 6241
    1445 CCGAGGAC G UGCCCGGG 5965 CCCGGGCA GCCGAAAGGCGAGUGAGGUCU GUCCUCGG 6242
    1447 GAGGACGU G CCCGGGAC 5966 GUCCCGGG GCCGAAAGGCGAGUGAGGUCU ACGUCCUC 6243
    1457 CCGGGACC G UGCAGUCU 5967 AGACUGCA GCCGAAAGGCGAGUGAGGUCU GGUCCCGG 6244
    1459 GGGACCGU G CAGUCUGC 5968 GCAGACUG GCCGAAAGGCGAGUGAGGUCU ACGGUCCC 6245
    1462 ACCGUGCA G UCUGCGCU 5969 AGCGCAGA GCCGAAAGGCGAGUGAGGUCU UGCACGGU 6246
    1466 UGCAGUCU G CGCUUUCC 5970 GGAAAGCG GCCGAAAGGCGAGUGAGGUCU AGACUGCA 6247
    1468 CAGUCUGC G CUUUCCUC 5971 GAGGAAAG GCCGAAAGGCGAGUGAGGUCU GCAGACUG 6248
    1481 CCUCUCCC G CCUGCCUA 5972 UAGGCAGG GCCGAAAGGCGAGUGAGGUCU GGGAGAGG 6249
    1485 UCCCGCCU G CCUAGCCC 5973 GGGCUAGG GCCGAAAGGCGAGUGAGGUCU AGGCGGGA 6250
    1490 CCUGCCUA G CCCAGGAU 5974 AUCCUGGG GCCGAAAGGCGAGUGAGGUCU UAGGCAGG 6251
    1504 GAUGAAGG G CUGGGUGG 5975 CCACCCAG GCCGAAAGGCGAGUGAGGUCU CCUUCAUC 6252
    1509 AGGGCUGG G UGGCCACA 5976 UGUGGCCA GCCGAAAGGCGAGUGAGGUCU CCAGCCCU 6253
    1512 GCUGGGUG G CCACAACU 5977 AGUUGUGG GCCGAAAGGCGAGUGAGGUCU CACCCAGC 6254
    1526 ACUGGGAU G CCACCUGG 5978 CCAGGUGG GCCGAAAGGCGAGUGAGGUCU AUCCCAGU 6255
    1536 CACCUGGA G CCCCACCC 5979 GGGUGGGG GCCGAAAGGCGAGUGAGGUCU UCCAGGUG 6256
    1549 ACCCAGGA G CUGGCCGC 5980 GCGGCCAG GCCGAAAGGCGAGUGAGGUCU UCCUGGGU 6257
    1553 AGGAGCUG G CCGCGGCA 5981 UGCCGCGG GCCGAAAGGCGAGUGAGGUCU CAGCUCCU 6258
    1556 AGCUGGCC G CGGCACCU 5982 AGGUGCCG GCCGAAAGGCGAGUGAGGUCU GGCCAGCU 6259
    1559 UGGCCGCG G CACCUUAC 5983 GUAAGGUG GCCGAAAGGCGAGUGAGGUCU CGCGGCCA 6260
    1568 CACCUUAC G CUUCAGCU 5984 AGCUGAAG GCCGAAAGGCGAGUGAGGUCU GUAAGGUG 6261
    1574 ACGCUUCA G CUGUUGAU 5985 AUCAACAG GCCGAAAGGCGAGUGAGGUCU UGAAGCGU 6262
    1577 CUUCAGCU G UUGAUCCG 5986 CGGAUCAA GCCGAAAGGCGAGUGAGGUCU AGCUGAAG 6263
    1585 GUUGAUCC G CUGGUCCC 5987 GGGACCAG GCCGAAAGGCGAGUGAGGUCU GGAUCAAC 6264
    1589 AUCCGCUG G UCCCCUCU 5988 AGAGGGGA GCCGAAAGGCGAGUGAGGUCU CAGCGGAU 6265
    1604 CUUUUGGG G UAGAUGCG 5989 CGCAUCUA GCCGAAAGGCGAGUGAGGUCU CCCAAAAG 6266
    1610 GGGUAGAU G CGGCCCCG 5990 CGGGGCCG GCCGAAAGGCGAGUGAGGUCU AUCUACCC 6267
    1613 UAGAUGCG G CCCCGAUC 5991 GAUCGGGG GCCGAAAGGCGAGUGAGGUCU CGCAUCUA 6268
    1624 CCGAUCAG G CCUGACUC 5992 GAGUCAGG GCCGAAAGGCGAGUGAGGUCU CUGAUCGG 6269
    1633 CCUGACUC G CUGCUCUU 5993 AAGAGCAG GCCGAAAGGCGAGUGAGGUCU GAGUCAGG 6270
    1636 GACUCGCU G CUCUUUUU 5994 AAAAAGAG GCCGAAAGGCGAGUGAGGUCU AGCGAGUC 6271
    1645 CUCUUUUU G UUCCCUUC 5995 GAAGGGAA GCCGAAAGGCGAGUGAGGUCU AAAAAGAG 6272
    1655 UCCCUUCU G UCUGCUCG 5996 CGAGCAGA GCCGAAAGGCGAGUGAGGUCU AGAAGGGA 6273
    1659 UUCUGUCU G CUCGAACC 5997 GGUUCGAG GCCGAAAGGCGAGUGAGGUCU AGACAGAA 6274
    1672 AACCACUU G CCUCGGGC 5998 GCCCGAGG GCCGAAAGGCGAGUGAGGUCU AAGUGGUU 6275
    1679 UGCCUCGG G CUAAUCCC 5999 GGGAUUAG GCCGAAAGGCGAGUGAGGUCU CCGAGGCA 6276
    1706 UCCACCCG G CACUGGGG 6000 CCCCAGUG GCCGAAAGGCGAGUGAGGUCU CGGGUGGA 6277
    1717 CUGGGGAA G UCAAGAAU 6001 AUUCUUGA GCCGAAAGGCGAGUGAGGUCU UUCCCCAG 6278
    1729 AGAAUGGG G CCUGGGGC 6002 GCCCCAGG GCCGAAAGGCGAGUGAGGUCU CCCAUUCU 6279
    1736 GGCCUGGG G CUCUCAGG 6003 CCUGAGAG GCCGAAAGGCGAGUGAGGUCU CCCAGGCC 6280
    1752 GGAGAACU G CUUCCCCU 6004 AGGGGAAG GCCGAAAGGCGAGUGAGGUCU AGUUCUCC 6281
    1762 UUCCCCUG G CAGAGCUG 6005 CAGCUCUG GCCGAAAGGCGAGUGAGGUCU CAGGGGAA 6282
    1767 CUGGCAGA G CUGGGUGG 6006 CCACCCAG GCCGAAAGGCGAGUGAGGUCU UCUGCCAG 6283
    1772 AGAGCUGG G UGGCAGCU 6007 AGCUGCCA GCCGAAAGGCGAGUGAGGUCU CCAGCUCU 6284
    1775 GCUGGGUG G CAGCUCUU 6008 AAGAGCUG GCCGAAAGGCGAGUGAGGUCU CACCCAGC 6285
    1778 GGGUGGCA G CUCUUCCU 6009 AGGAAGAG GCCGAAAGGCGAGUGAGGUCU UGCCACCC 6286
    1805 ACCGACCC G CCCGCCGC 6010 GCGGCGGG GCCGAAAGGCGAGUGAGGUCU GGGUCGGU 6287
    1809 ACCCGCCC G CCGCUGUG 6011 CACAGCGG GCCGAAAGGCGAGUGAGGUCU GGGCGGGU 6288
    1812 CGCCCGCC G CUGUGCCC 6012 GGGCACAG GCCGAAAGGCGAGUGAGGUCU GGCGGGCG 6289
    1815 CCGCCGCU G UGCCCUGG 6013 CCAGGGCA GCCGAAAGGCGAGUGAGGUCU AGCGGCGG 6290
    1817 GCCGCUGU G CCCUGGGA 6014 UCCCAGGG GCCGAAAGGCGAGUGAGGUCU ACAGCGGC 6291
    1826 CCCUGGGA G UGCUGCCC 6015 GGGCAGCA GCCGAAAGGCGAGUGAGGUCU UCCCAGGG 6292
    1828 CUGGGAGU G CUGCCCUC 6016 GAGGGCAG GCCGAAAGGCGAGUGAGGUCU ACUCCCAG 6293
    1831 GGAGUGCU G CCCUCUUA 6017 UAAGAGGG GCCGAAAGGCGAGUGAGGUCU AGCACUCC 6294
    1844 CUUACCAU G CACACGGG 6018 CCCGUGUG GCCGAAAGGCGAGUGAGGUCU AUGGUAAG 6295
    1852 GCACACGG G UGCUCUCC 6019 GGAGAGCA GCCGAAAGGCGAGUGAGGUCU CCGUGUGC 6296
    1854 ACACGGGU G CUCUCCUU 6020 AAGGAGAG GCCGAAAGGCGAGUGAGGUCU ACCCGUGU 6297
    1867 CCUUUUGG G CUGCAUGC 6021 GCAUGCAG GCCGAAAGGCGAGUGAGGUCU CCAAAAGG 6298
    1870 UUUGGGCU G CAUGCUAU 6022 AUAGCAUG GCCGAAAGGCGAGUGAGGUCU AGCCCAAA 6299
    1874 GGCUGCAU G CUAUUCCA 6023 UGGAAUAG GCCGAAAGGCGAGUGAGGUCU AUGCAGCC 6300
    1887 UCCAUUUU G CAGCCAGA 6024 UCUGGCUG GCCGAAAGGCGAGUGAGGUCU AAAAUGGA 6301
    1890 AUUUUGCA G CCAGACCG 6025 CGGUCUGG GCCGAAAGGCGAGUGAGGUCU UGCAAAAU 6302
    1901 AGACCGAU G UGUAUUUA 6026 UAAAUACA GCCGAAAGGCGAGUGAGGUCU AUCGGUCU 6303
    1903 ACCGAUGU G UAUUUAAC 6027 GUUAAAUA GCCGAAAGGCGAGUGAGGUCU ACAUCGGU 6304
    1914 UUUAACCA G UCACUAUU 6028 AAUAGUGA GCCGAAAGGCGAGUGAGGUCU UGGUUAAA 6305
    1936 ACAUUUGG G UUGUUUCC 6029 GGAAACAA GCCGAAAGGCGAGUGAGGUCU CCAAAUGU 6306
    1939 UUUGGGUU G UUUCCCAU 6030 AUGGGAAA GCCGAAAGGCGAGUGAGGUCU AACCCAAA 6307
    1954 AUCUUUUU G UUACCAUA 6031 UAUGGUAA GCCGAAAGGCGAGUGAGGUCU AAAAAGAU 6308
    1970 AAAUAAUG G CAUAGUAA 6032 UUACUAUG GCCGAAAGGCGAGUGAGGUCU CAUUAUUU 6309
    1975 AUGGCAUA G UAAAAAAA 6033 UUUUUUUA GCCGAAAGGCGAGUGAGGUCU UAUGCCAU 6310

    Input Sequence = NM_003639. Cut Site = G/Y

    Arm Length = 8. Core Sequence = GCcgaaagGCGaGuCaaGGuCu

    NM_003639 (Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), mRNA.; 1994 bp)
  • TABLE VI
    Human IKK-gamma DNAzyme and Substrate Sequence
    Seq Seq
    Pos Substrate ID DNAzyme ID
    10 GCACGAGC A UGGCCCUU 4749 AAGGGCCA GGCTAGCTACAACGA GCTCGTGC 6380
    13 CGAGCAUG G CCCUUGUG 5757 CACAAGGG GGCTAGCTACAACGA CATGCTCG 6381
    19 UGGCCCUU G UGAUCCAG 5758 CTGGATCA GGCTAGCTACAACGA AAGGGCCA 6382
    22 CCCUUGUG A UCCAGGUG 6311 CACCTGGA GGCTAGCTACAACGA CACAAGGG 6383
    28 UGAUCCAG G UGGGGAAA 5759 TTTCCCCA GGCTAGCTACAACGA CTGGATCA 6384
    36 GUGGGGAA A CUAAGGCC 6312 GGCCTTAG GGCTAGCTACAACGA TTCCCCAC 6385
    42 AAACUAAG G CCCAGAGA 5760 TCTCTGGG GGCTAGCTACAACGA CTTAGTTT 6386
    52 CCAGAGAA G UGAGGACC 5761 GGTCCTCA GGCTAGCTACAACGA TTCTCTGG 6387
    58 AAGUGAGG A CCCCGCAG 6313 CTGCGGGG GGCTAGCTACAACGA CCTCACTT 6388
    63 AGGACCCC G CAGACUAU 5762 ATAGTCTG GGCTAGCTACAACGA GGGGTCCT 6389
    67 CCCCGCAG A CUAUCAAU 6314 ATTGATAG GGCTAGCTACAACGA CTGCGGGG 6390
    70 CGCAGACU A UCAAUCCC 4364 GGGATTGA GGCTAGCTACAACGA AGTCTGCG 6391
    74 GACUAUCA A UCCCAGUC 6315 GACTGGGA GGCTAGCTACAACGA TGATAGTC 6392
    80 CAAUCCCA G UCUCUUCC 5763 GGAAGAGA GGCTAGCTACAACGA TGGGATTG 6393
    93 UUCCCCUC A CUCCCUGU 4774 ACAGGGAG GGCTAGCTACAACGA GAGGGGAA 6394
    100 CACUCCCU G UGAAGCUC 5764 GAGCTTCA GGCTAGCTACAACGA AGGGAGTG 6395
    105 CCUGUGAA G CUCUCCAG 5765 CTGGAGAG GGCTAGCTACAACGA TTCACAGG 6396
    113 GCUCUCCA G CAUCAUCG 5766 CGATGATG GGCTAGCTACAACGA TGGAGAGC 6397
    115 UCUCCAGC A UCAUCGAG 4783 CTCGATGA GGCTAGCTACAACGA GCTGGAGA 6398
    118 CCAGCAUC A UCGAGGUC 4784 GACCTCGA GGCTAGCTACAACGA GATGCTGG 6399
    124 UCAUCGAG G UCCCAUCA 5767 TGATGGGA GGCTAGCTACAACGA CTCGATGA 6400
    129 GAGGUCCC A UCAGCCCU 4787 AGGGCTGA GGCTAGCTACAACGA GGGACCTC 6401
    133 UCCCAUCA G CCCUUGCC 5768 GGCAAGGG GGCTAGCTACAACGA TGATGGGA 6402
    139 CAGCCCUU G CCCUGUUG 5769 CAACAGGG GGCTAGCTACAACGA AAGGGCTG 6403
    144 CUUGCCCU G DUGGAUGA 5770 TCATCCAA GGCTAGCTACAACGA AGGGCAAG 6404
    149 CCUGUUGG A UGAAUAGG 6316 CCTATTCA GGCTAGCTACAACGA CCAACAGG 6405
    153 UUGGAUGA A UAGGCACC 6317 GGTGCCTA GGCTAGCTACAACGA TCATCCAA 6406
    157 AUGAAUAG G CACCUCUG 5771 CAGAGGTG GGCTAGCTACAACGA CTATTCAT 6407
    159 GAAUAGGC A CCUCUGGA 4795 TCCAGAGG GGCTAGCTACAACGA GCCTATTC 6408
    171 CUGGAAGA G CCAACUGU 5772 ACAGTTGG GGCTAGCTACAACGA TCTTCCAG 6409
    175 AAGAGCCA A CUGUGUGA 6318 TCACACAG GGCTAGCTACAACGA TGGCTCTT 6410
    178 AGCCAACU G UGUGAGAU 5773 ATCTCACA GGCTAGCTACAACGA AGTTGGCT 6411
    180 CCAACUGU G UGAGAUGG 5774 CCATCTCA GGCTAGCTACAACGA ACAGTTGG 6412
    185 UGUGUGAG A UGGUGCAG 6319 CTGCACCA GGCTAGCTACAACGA CTCACACA 6413
    188 GUGAGAUG G UGCAGCCC 5775 GGGCTGCA GGCTAGCTACAACGA CATCTCAC 6414
    190 GAGAUGGU G CAGCCCAG 5776 CTGGGCTG GGCTAGCTACAACGA ACCATCTC 6415
    193 AUGGUGCA G CCCAGUGG 5777 CCACTGGG GGCTAGCTACAACGA TGCACCAT 6416
    198 GCAGCCCA G UGGUGGCC 5778 GGCCACCA GGCTAGCTACAACGA TGGGCTGC 6417
    201 GCCCAGUG G UGGCCCGG 5779 CCGGGCCA GGCTAGCTACAACGA CACTGGGC 6418
    204 CAGUGGUG G CCCGGCAG 5780 CTGCCGGG GGCTAGCTACAACGA CACCACTG 6419
    209 GUGGCCCG G CAGCAGAU 5781 ATCTGCTG GGCTAGCTACAACGA CGGGCCAC 6420
    212 GCCCGGCA G CAGAUCAG 5782 CTGATCTG GGCTAGCTACAACGA TGCCGGGC 6421
    216 GGCAGCAG A UCAGGACG 6320 CGTCCTGA GGCTAGCTACAACGA CTGCTGCC 6422
    222 AGAUCAGG A CGUACUGG 6321 CCAGTACG GGCTAGCTACAACGA CCTGATCT 6423
    224 AUCAGGAC G UACUGGGC 5783 GCCCAGTA GGCTAGCTACAACGA GTCCTGAT 6424
    226 CAGGACGU A CUGGGCGA 4384 TCGCCCAG GGCTAGCTACAACGA ACGTCCTG 6425
    231 CGUACUGG G CGAAGAGU 5784 ACTCTTCG GGCTAGCTACAACGA CCAGTACG 6426
    238 GGCGAAGA G UCUCCUCU 5785 AGAGGAGA GGCTAGCTACAACGA TCTTCGCC 6427
    253 CUGGGGAA G CCAGCCAU 5786 ATGGCTGG GGCTAGCTACAACGA TTCCCCAG 6428
    257 GGAAGCCA G CCAUGCUG 5787 CAGCATGG GGCTAGCTACAACGA TGGCTTCC 6429
    260 AGCCAGCC A UGCUGCAC 4819 GTGCAGCA GGCTAGCTACAACGA GGCTGGCT 6430
    262 CCAGCCAU G CUGCACCU 5788 AGGTGCAG GGCTAGCTACAACGA ATGGCTGG 6431
    265 GCCAUGCU G CACCUGCC 5789 GGCAGGTG GGCTAGCTACAACGA AGCATGGC 6432
    267 CAUGCUGC A CCUGCCUU 4821 AAGGCAGG GGCTAGCTACAACGA GCAGCATG 6433
    271 CUGCACCU G CCUUCAGA 5790 TCTGAAGG GGCTAGCTACAACGA AGGTGCAG 6434
    280 CCUUCAGA A CAGGGCGC 6322 GCGCCCTG GGCTAGCTACAACGA TCTGAAGG 6435
    285 AGAACAGG G CGCUCCUG 5791 CAGGAGCG GGCTAGCTACAACGA CCTGTTCT 6436
    287 AACAGGGC G CUCCUGAG 5792 CTCAGGAG GGCTAGCTACAACGA GCCCTGTT 6437
    296 CUCCUGAG A CCCUCCAG 6323 CTGGAGGG GGCTAGCTACAACGA CTCAGGAG 6438
    304 ACCCUCCA G CGCUGCCU 5793 AGGCAGCG GGCTAGCTACAACGA TGGAGGGT 6439
    306 CCUCCAGC G CUGCCUGG 5794 CCAGGCAG GGCTAGCTACAACGA GCTGGAGG 6440
    309 CCAGCGCU G CCUGGAGG 5795 CCTCCAGG GGCTAGCTACAACGA AGCGCTGG 6441
    321 GGAGGAGA A UCAAGAGC 6324 GCTCTTGA GGCTAGCTACAACGA TCTCCTCC 6442
    328 AAUCAAGA G CUCCGAGA 5796 TCTCGGAG GGCTAGCTACAACGA TCTTGATT 6443
    336 GCUCCGAG A UGCCAUCC 6325 GGATGGCA GGCTAGCTACAACGA CTCGGAGC 6444
    338 UCCGAGAU G CCAUCCGG 5797 CCGGATGG GGCTAGCTACAACGA ATCTCGGA 6445
    341 GAGAUGCC A UCCGGCAG 4843 CTGCCGGA GGCTAGCTACAACGA GGCATCTC 6446
    346 GCCAUCCG G CAGAGCAA 5798 TTGCTCTG GGCTAGCTACAACGA CGGATGGC 6447
    351 CCGGCAGA G CAACCAGA 5799 TCTGGTTG GGCTAGCTACAACGA TCTGCCGG 6448
    354 GCAGAGCA A CCAGAUUC 6326 GAATCTGG GGCTAGCTACAACGA TGCTCTGC 6449
    359 GCAACCAG A UUCUGCGG 6327 CCGCAGAA GGCTAGCTACAACGA CTGGTTGC 6450
    364 CAGAUUCU G CGGGAGCG 5800 CGCTCCCG GGCTAGCTACAACGA AGAATCTG 6451
    370 CUGCGGGA G CGCUGCGA 5801 TCGCAGCG GGCTAGCTACAACGA TCCCGCAG 6452
    372 GCGGGAGC G CUGCGAGG 5802 CCTCGCAG GGCTAGCTACAACGA GCTCCCGC 6453
    375 GGAGCGCU G CGAGGAGC 5803 GCTCCTCG GGCTAGCTACAACGA AGCGCTCC 6454
    382 UGCGAGGA G CUUCUGCA 5804 TGCAGAAG GGCTAGCTACAACGA TCCTCGCA 6455
    388 GAGCUUCU G CAUUUCCA 5805 TGGAAATG GGCTAGCTACAACGA AGAAGCTC 6456
    390 GCUUCUGC A UUUCCAAG 4853 CTTGGAAA GGCTAGCTACAACGA GCAGAAGC 6457
    398 AUUUCCAA G CCAGCCAG 5806 CTGGCTGG GGCTAGCTACAACGA TTGGAAAT 6458
    402 CCAAGCCA G CCAGAGGG 5807 CCCTCTGG GGCTAGCTACAACGA TGGCTTGG 6459
    421 GAGAAGGA G UUCCUCAU 5808 ATGAGGAA GGCTAGCTACAACGA TCCTTCTC 6460
    428 AGUUCCUC A UGUGCAAG 4862 CTTGCACA GGCTAGCTACAACGA GAGGAACT 6461
    430 UUCCUCAU G UGCAAGUU 5809 AACTTGCA GGCTAGCTACAACGA ATGAGGAA 6462
    432 CCUCAUGU G CAAGUUCC 5810 GGAACTTG GGCTAGCTACAACGA ACATGAGG 6463
    436 AUGUGCAA G UUCCAGGA 5811 TCCTGGAA GGCTAGCTACAACGA TTGCACAT 6464
    446 UCCAGGAG G CCAGGAAA 5812 TTTCCTGG GGCTAGCTACAACGA CTCCTGGA 6465
    454 GCCAGGAA A CUGGUGGA 6328 TCCACCAG GGCTAGCTACAACGA TTCCTGGC 6466
    458 GGAAACUG G UGGAGAGA 5813 TCTCTCCA GGCTAGCTACAACGA CAGTTTCC 6467
    466 GUGGAGAG A CUCGGCCU 6329 AGGCCGAG GGCTAGCTACAACGA CTCTCCAC 6468
    471 GAGACUCG G CCUGGAGA 5814 TCTCCAGG GGCTAGCTACAACGA CGAGTCTC 6469
    481 CUGGAGAA G CUCGAUCU 5815 AGATCGAG GGCTAGCTACAACGA TTCTCCAG 6470
    486 GAAGCUCG A UCUGAAGA 6330 TCTTCAGA GGCTAGCTACAACGA CGAGCTTC 6471
    496 CUGAAGAG G CAGAAGGA 5816 TCCTTCTG GGCTAGCTACAACGA CTCTTCAG 6472
    505 CAGAAGGA G CAGGCUCU 5817 AGAGCCTG GGCTAGCTACAACGA TCCTTCTG 6473
    509 AGGAGCAG G CUCUGCGG 5818 CCGCAGAG GGCTAGCTACAACGA CTGCTCCT 6474
    514 CAGGCUCU G CGGGAGGU 5819 ACCTCCCG GGCTAGCTACAACGA AGAGCCTG 6475
    521 UGCGGGAG G UGGAGCAC 5820 GTGCTCCA GGCTAGCTACAACGA CTCCCGCA 6476
    526 GAGGUGGA G CACCUGAA 5821 TTCAGGTG GGCTAGCTACAACGA TCCACCTC 6477
    528 GGUGGAGC A CCUGAAGA 4878 TCTTCAGG GGCTAGCTACAACGA GCTCCACC 6478
    538 CUGAAGAG A UGCCAGCA 6331 TGCTGGCA GGCTAGCTACAACGA CTCTTCAG 6479
    540 GAAGAGAU G CCAGCAGC 5822 GCTGCTGG GGCTAGCTACAACGA ATCTCTTC 6480
    544 AGAUGCCA G CAGCAGAU 5823 ATCTGCTG GGCTAGCTACAACGA TGGCATCT 6481
    547 UGCCAGCA G CAGAUGGC 5824 GCCATCTG GGCTAGCTACAACGA TGCTGGCA 6482
    551 AGCAGCAG A UGGCUGAG 6332 CTCAGCCA GGCTAGCTACAACGA CTGCTGCT 6483
    554 AGCAGAUG G CUGAGGAC 5825 GTCCTCAG GGCTAGCTACAACGA CATCTGCT 6484
    561 GGCUGAGG A CAAGGCCU 6333 AGGCCTTG GGCTAGCTACAACGA CCTCAGCC 6485
    566 AGGACAAG G CCUCUGUG 5826 CACAGAGG GGCTAGCTACAACGA CTTGTCCT 6486
    572 AGGCCUCU G UGAAAGCC 5827 GGCTTTCA GGCTAGCTACAACGA AGAGGCCT 6487
    578 CUGUGAAA G CCCAGGUG 5828 CACCTGGG GGCTAGCTACAACGA TTTCACAG 6488
    584 AAGCCCAG G UGACGUCC 5829 GGACGTCA GGCTAGCTACAACGA CTGGGCTT 6489
    587 GCCAGGUG A CGUCCUUG 6334 CAAGGACG GGCTAGCTACAACGA CACCTGGG 6490
    589 CAGGUGAC G UCCUUGCU 5830 AGCAAGGA GGCTAGCTACAACGA GTCACCTG 6491
    595 ACGUCCUU G CUCGGGGA 5831 TCCCCGAG GGCTAGCTACAACGA AAGGACGT 6492
    604 CUCGGGGA G CUGCAGGA 5832 TCCTGCAG GGCTAGCTACAACGA TCCCCGAG 6493
    607 GGGGAGCU G CAGGAGAG 5833 CTCTCCTG GGCTAGCTACAACGA AGCTCCCC 6494
    615 GCAGGAGA G CCAGAGUC 5834 GACTCTGG GGCTAGCTACAACGA TCTCCTGC 6495
    621 GAGCCAGA G UCGCUUGG 5835 CCAAGCGA GGCTAGCTACAACGA TCTGGCTC 6496
    624 CCAGAGUC G CUUGGAGG 5836 CCTCCAAG GGCTAGCTACAACGA GACTCTGG 6497
    632 GCUUGGAG G CUGCCACU 5837 AGTGGCAG GGCTAGCTACAACGA CTCCAAGC 6498
    635 UGGAGGCU G CCACUAAG 5838 CTTAGTGG GGCTAGCTACAACGA AGCCTCCA 6499
    638 AGGCUGCC A CUAAGGAA 4903 TTCCTTAG GGCTAGCTACAACGA GGCAGCCT 6500
    646 ACUAAGGA A UGCCAGGC 6335 GCCTGGCA GGCTAGCTACAACGA TCCTTAGT 6501
    648 UAAGGAAU G CCAGGCUC 5839 GAGCCTGG GGCTAGCTACAACGA ATTCCTTA 6502
    653 AAUGCCAG G CUCUGGAG 5840 CTCCAGAG GGCTAGCTACAACGA CTGGCATT 6503
    663 UCUGGAGG G UCGGGCCC 5841 GGGCCCGA GGCTAGCTACAACGA CCTCCAGA 6504
    668 AGGGUCGG G CCCGGGCG 5842 CGCCCGGG GGCTAGCTACAACGA CCGACCCT 6505
    674 GGGCCCGG G CGGCCAGC 5843 GCTGGCCG GGCTAGCTACAACGA CCGGGCCC 6506
    677 CCCGGGCG G CCAGCGAG 5844 CTCGCTGG GGCTAGCTACAACGA CGCCCGGG 6507
    681 GGCGGCCA G CGAGCAGG 5845 CCTGCTCG GGCTAGCTACAACGA TGGCCGCC 6508
    685 GCCAGCGA G CAGGCGCG 5846 CGCGCCTG GGCTAGCTACAACGA TCGCTGGC 6509
    689 GCGAGCAG G CGCGGCAG 5847 CTGCCGCG GGCTAGCTACAACGA CTGCTCGC 6510
    691 GAGCAGGC G CGGCAGCU 5848 AGCTGCCG GGCTAGCTACAACGA GCCTGCTC 6511
    694 CAGGCGCG G CAGCUGGA 5849 TCCAGCTG GGCTAGCTACAACGA CGCGCCTG 6512
    697 GCGCGGCA G CUGGAGAG 5850 CTCTCCAG GGCTAGCTACAACGA TGCCGCGC 6513
    705 GCUGGAGA G UGAGCGCG 5851 CGCGCTCA GGCTAGCTACAACGA TCTCCAGC 6514
    709 GAGAGUGA G CGCGAGGC 5852 GCCTCGCG GGCTAGCTACAACGA TCACTCTC 6515
    711 GAGUGAGC G CGAGGCGC 5853 GCGCCTCG GGCTAGCTACAACGA GCTCACTC 6516
    716 AGCGCGAG G CGCUGCAG 5854 CTGCAGCG GGCTAGCTACAACGA CTCGCGCT 6517
    718 CGCGAGGC G CUGCAGCA 5855 TGCTGCAG GGCTAGCTACAACGA GCCTCGCG 6518
    721 GAGGCGCU G CAGCAGCA 5856 TGCTGCTG GGCTAGCTACAACGA AGCGCCTC 6519
    724 GCGCUGCA G CAGCAGCA 5857 TGCTGCTG GGCTAGCTACAACGA TGCAGCGC 6520
    727 CUGCAGCA G CAGCACAG 5858 CTGTGCTG GGCTAGCTACAACGA TGCTGCAG 6521
    730 CAGCAGCA G CACAGCGU 5859 ACGCTGTG GGCTAGCTACAACGA TGCTGCTG 6522
    732 GCAGCAGC A CAGCGUGC 4920 GCACGCTG GGCTAGCTACAACGA GCTGCTGC 6523
    735 GCAGCACA G CGUGCAGG 5860 CCTGCACG GGCTAGCTACAACGA TGTGCTGC 6524
    737 AGCACAGC G UGCAGGUG 5861 CACCTGCA GGCTAGCTACAACGA GCTGTGCT 6525
    739 CACAGCGU G CAGGUGGA 5862 TCCACCTG GGCTAGCTACAACGA ACGCTGTG 6526
    743 GCGUGCAG G UGGACCAG 5863 CTGGTCCA GGCTAGCTACAACGA CTGCACGC 6527
    747 GCAGGUGG A CCAGCUGC 6336 GCAGCTGG GGCTAGCTACAACGA CCACCTGC 6528
    751 GUGGACCA G CUGCGCAU 5864 ATGCGCAG GGCTAGCTACAACGA TGGTCCAC 6529
    754 GACCAGCU G CGCAUGCA 5865 TGCATGCG GGCTAGCTACAACGA AGCTGGTC 6530
    756 CCAGCUGC G CAUGCAGG 5866 CCTGCATG GGCTAGCTACAACGA GCAGCTGG 6531
    758 AGCUGCGC A UGCAGGGC 4926 GCCCTGCA GGCTAGCTACAACGA GCGCAGCT 6532
    760 CUGCGCAU G CAGGGCCA 5867 TGGCCCTG GGCTAGCTACAACGA ATGCGCAG 6533
    765 CAUGCAGG G CCAGAGCG 5868 CGCTCTGG GGCTAGCTACAACGA CCTGCATG 6534
    771 GGGCCAGA G CGUGGAGG 5869 CCTCCACG GGCTAGCTACAACGA TCTGGCCC 6535
    773 GCCAGAGC G UGGAGGCC 5870 GGCCTCCA GGCTAGCTACAACGA GCTCTGGC 6536
    779 GCGUGGAG G CCGCGCUC 5871 GAGCGCGG GGCTAGCTACAACGA CTCCACGC 6537
    782 UGGAGGCC G CGCUCCGC 5872 GCGGAGCG GGCTAGCTACAACGA GGCCTCCA 6538
    784 GAGGCCGC G CUCCGCAU 5873 ATGCGGAG GGCTAGCTACAACGA GCGGCCTC 6539
    789 CGCGCUCC G CAUGGAGC 5874 GCTCCATG GGCTAGCTACAACGA GGAGCGCG 6540
    791 CGCUCCGC A UGGAGCGC 4933 GCGCTCCA GGCTAGCTACAACGA GCGGAGCG 6541
    796 CGCAUGGA G CGCCAGGC 5875 GCCTGGCG GGCTAGCTACAACGA TCCATGCG 6542
    798 CAUGGAGC G CCAGGCCG 5876 CGGCCTGG GGCTAGCTACAACGA GCTCCATG 6543
    803 AGCGCCAG G CCGCCUCG 5877 CGAGGCGG GGCTAGCTACAACGA CTGGCGCT 6544
    806 GCCAGGCC G CCUCGGAG 5878 CTCCGAGG GGCTAGCTACAACGA GGCCTGGC 6545
    826 AAGAGGAA G CUGGCCCA 5879 TGGGCCAG GGCTAGCTACAACGA TTCCTCTT 6546
    830 GGAAGCUG G CCCAGUUG 5880 CAACTGGG GGCTAGCTACAACGA CAGCTTCC 6547
    835 CUGGCCCA G UUGCAGGU 5881 ACCTGCAA GGCTAGCTACAACGA TGGGCCAG 6548
    838 GCCCAGUU G CAGGUGGC 5882 GCCACCTG GGCTAGCTACAACGA AACTGGGC 6549
    842 AGUUGCAG G UGGCCUAU 5883 ATAGGCCA GGCTAGCTACAACGA CTGCAACT 6550
    845 UGCAGGUG G CCUAUCAC 5884 GTGATAGG GGCTAGCTACAACGA CACCTGCA 6551
    849 GGUGGCCU A UCACCAGC 4423 GCTGGTGA GGCTAGCTACAACGA AGGCCACC 6552
    852 GGCCUAUC A CCAGCUCU 4946 AGAGCTGG GGCTAGCTACAACGA GATAGGCC 6553
    856 UAUCACCA G CUCUUCCA 5885 TGGAAGAG GGCTAGCTACAACGA TGGTGATA 6554
    868 UUCCAAGA A UACGACAA 6337 TTGTCGTA GGCTAGCTACAACGA TCTTGGAA 6555
    870 CCAAGAAU A CGACAACC 4428 GGTTGTCG GGCTAGCTACAACGA ATTCTTGG 6556
    873 AGAAUACG A CAACCACA 6338 TGTGGTTG GGCTAGCTACAACGA CGTATTCT 6557
    876 AUACGACA A CCACAUCA 6339 TGATGTGG GGCTAGCTACAACGA TGTCGTAT 6558
    879 CGACAACC A CAUCAAGA 4955 TCTTGATG GGCTAGCTACAACGA GGTTGTCG 6559
    881 ACAACCAC A UCAAGAGC 4956 GCTCTTGA GGCTAGCTACAACGA GTGGTTGT 6560
    888 CAUCAAGA G CAGCGUGG 5886 CCACGCTG GGCTAGCTACAACGA TCTTGATG 6561
    891 CAAGAGCA G CGUGGUGG 5887 CCACCACG GGCTAGCTACAACGA TGCTCTTG 6562
    893 AGAGCAGC G UGGUGGGC 5888 GCCCACCA GGCTAGCTACAACGA GCTGCTCT 6563
    896 GCAGCGUG 0 UGGGCAGU 5889 ACTGCCCA GGCTAGCTACAACGA CACGCTGC 6564
    900 CGUGGUGG G CAGUGAGC 5890 GCTCACTG GGCTAGCTACAACGA CCACCACG 6565
    903 GGUGGGCA G UGAGCGGA 5891 TCCGCTCA GGCTAGCTACAACGA TGCCCACC 6566
    907 GGCAGUGA G CGGAAGCG 5892 CGCTTCCG GGCTAGCTACAACGA TCACTGCC 6567
    913 GAGCGGAA G CGAGGAAU 5893 ATTCCTCG GGCTAGCTACAACGA TTCCGCTC 6568
    920 AGCGAGGA A UGCAGCUG 6340 CAGCTGCA GGCTAGCTACAACGA TCCTCGCT 6569
    922 CGAGGAAU G CAGCUGGA 5894 TCCAGCTG GGCTAGCTACAACGA ATTCCTCG 6570
    925 GGAAUGCA G CUGGAAGA 5895 TCTTCCAG GGCTAGCTACAACGA TGCATTCC 6571
    933 GCUGGAAG A UCUCAAAC 6341 GTTTGAGA GGCTAGCTACAACGA CTTCCAGC 6572
    940 GAUCUCAA A CAGCAGCU 6342 AGCTGCTG GGCTAGCTACAACGA TTGAGATC 6573
    943 CUCAAACA G CAGCUCCA 5896 TGGAGCTG GGCTAGCTACAACGA TGTTTGAG 6574
    946 AAACAGCA G CUCCAGCA 5897 TGCTGGAG GGCTAGCTACAACGA TGCTGTTT 6575
    952 CAGCUCCA G CAGGCCGA 5898 TCGGCCTG GGCTAGCTACAACGA TGGAGCTG 6576
    956 UCCAGCAG G CCGAGGAG 5899 CTCCTCGG GGCTAGCTACAACGA CTGCTGGA 6577
    965 CCGAGGAG G CCCUGGUG 5900 CACCAGGG GGCTAGCTACAACGA CTCCTCGG 6578
    971 AGGCCCUG G UGGCCAAA 5901 TTTGGCCA GGCTAGCTACAACGA CAGGGCCT 6579
    974 CCCUGGUG G CCAAACAG 5902 CTGTTTGG GGCTAGCTACAACGA CACCAGGG 6580
    979 GUGGCCAA A CAGGAGGU 6343 ACCTCCTG GGCTAGCTACAACGA TTGGCCAC 6581
    986 AACAGGAG G UGAUCGAU 5903 ATCGATCA GGCTAGCTACAACGA CTCCTGTT 6582
    989 AGGAGGUG A UCGAUAAG 6344 CTTATCGA GGCTAGCTACAACGA CACCTCCT 6583
    993 GGUGAUCG A UAAGCUGA 6345 TCAGCTTA GGCTAGCTACAACGA CGATCACC 6584
    997 AUCGAUAA G CUGAAGGA 5904 TCCTTCAG GGCTAGCTACAACGA TTATCGAT 6585
    1010 AGGAGGAG G CCGAGCAG 5905 CTGCTCGG GGCTAGCTACAACGA CTCCTCCT 6586
    1015 GAGGCCGA G CAGCACAA 5906 TTGTGCTG GGCTAGCTACAACGA TCGGCCTC 6587
    1018 GCCGAGCA G CACAAGAU 5907 ATCTTGTG GGCTAGCTACAACGA TGCTCGGC 6588
    1020 CGAGCAGC A CAAGAUUG 4980 CAATCTTG GGCTAGCTACAACGA GCTGCTCG 6589
    1025 AGCACAAG A UUGUGAUG 6346 CATCACAA GGCTAGCTACAACGA CTTGTGCT 6590
    1028 ACAAGAUU G UGAUGGAG 5908 CTCCATCA GGCTAGCTACAACGA AATCTTGT 6591
    1031 AGAUUGUG A UGGAGACC 6347 GGTCTCCA GGCTAGCTACAACGA CACAATCT 6592
    1037 UGAUGGAG A CCGUUCCG 6348 CGGAACGG GGCTAGCTACAACGA CTCCATCA 6593
    1040 UGGAGACC G UUCCGGUG 5909 CACCGGAA GGCTAGCTACAACGA GGTCTCCA 6594
    1046 CCGUUCCG G UGCUGAAG 5910 CTTCAGCA GGCTAGCTACAACGA CGGAACGG 6595
    1048 GUUCCGGU G CUGAAGGC 5911 GCCTTCAG GGCTAGCTACAACGA ACCGGAAC 6596
    1055 UGCUGAAG G CCCAGGCG 5912 CGCCTGGG GGCTAGCTACAACGA CTTCAGCA 6597
    1061 AGGCCCAG G CGGAUAUC 5913 GATATCCG GGCTAGCTACAACGA CTGGGCCT 6598
    1065 CCAGGCGG A UAUCUACA 6349 TGTAGATA GGCTAGCTACAACGA CCGCCTGG 6599
    1067 AGGCGGAU A UCUACAAG 4438 CTTGTAGA GGCTAGCTACAACGA ATCCGCCT 6600
    1071 GGAUAUCU A CAAGGCGG 4440 CCGCCTTG GGCTAGCTACAACGA AGATATCC 6601
    1076 UCUACAAG G CGGACUUC 5914 GAAGTCCG GGCTAGCTACAACGA CTTGTAGA 6602
    1080 CAAGGCGG A CUUCCAGG 6350 CCTGGAAG GGCTAGCTACAACGA CCGCCTTG 6603
    1088 ACUUCCAG G CUGAGAGG 5915 CCTCTCAG GGCTAGCTACAACGA CTGGAAGT 6604
    1096 GCUGAGAG G CAGGCCCG 5916 CGGGCCTG GGCTAGCTACAACGA CTCTCAGC 6605
    1100 AGAGGCAG G CCCGGGAG 5917 CTCCCGGG GGCTAGCTACAACGA CTGCCTCT 6606
    1111 CGGGAGAA G CUGGCCGA 5918 TCGGCCAG GGCTAGCTACAACGA TTCTCCCG 6607
    1115 AGAAGCUG G CCGAGAAG 5919 CTTCTCGG GGCTAGCTACAACGA CAGCTTCT 6608
    1129 AAGAAGGA G CUCCUGCA 5920 TGCAGGAG GGCTAGCTACAACGA TCCTTCTT 6609
    1135 GAGCUCCU G CAGGAGCA 5921 TGCTCCTG GGCTAGCTACAACGA AGGAGCTC 6610
    1141 CUGCAGGA G CAGCUGGA 5922 TCCAGCTG GGCTAGCTACAACGA TCCTGCAG 6611
    1144 CAGGAGCA G CUGGAGCA 5923 TGCTCCAG GGCTAGCTACAACGA TGCTCCTG 6612
    1150 CAGCUGGA G CAGCUGCA 5924 TGCAGCTG GGCTAGCTACAACGA TCCAGCTG 6613
    1153 CUGGAGCA G CUGCAGAG 5925 CTCTGCAG GGCTAGCTACAACGA TGCTCCAG 6614
    1156 GAGCAGCU G CAGAGGGA 5926 TCCCTCTG GGCTAGCTACAACGA AGCTGCTC 6615
    1165 CAGAGGGA G UACAGCAA 5927 TTGCTGTA GGCTAGCTACAACGA TCCCTCTG 6616
    1167 GAGGGAGU A CAGCAAAC 4444 GTTTGCTG GGCTAGCTACAACGA ACTCCCTC 6617
    1170 GGAGUACA G CAAACUGA 5928 TCAGTTTG GGCTAGCTACAACGA TGTACTCC 6618
    1174 UACAGCAA A CUGAAGGC 6351 GCCTTCAG GGCTAGCTACAACGA TTGCTGTA 6619
    1181 AACUGAAG G CCAGCUGU 5929 ACAGCTGG GGCTAGCTACAACGA CTTCAGTT 6620
    1185 GAAGGCCA G CUGUCAGG 5930 CCTGACAG GGCTAGCTACAACGA TGGCCTTC 6621
    1188 GGCCAGCU G UCAGGAGU 5931 ACTCCTGA GGCTAGCTACAACGA AGCTGGCC 6622
    1195 UGUCAGGA G UCGGCCAG 5932 CTGGCCGA GGCTAGCTACAACGA TCCTGACA 6623
    1199 AGGAGUCG G CCAGGAUC 5933 GATCCTGG GGCTAGCTACAACGA CGACTCCT 6624
    1205 CGGCCAGG A UCGAGGAC 6352 GTCCTCGA GGCTAGCTACAACGA CCTGGCCG 6625
    1212 GAUCGAGG A CAUGAGGA 6353 TCCTCATG GGCTAGCTACAACGA CCTCGATC 6626
    1214 UCGAGGAC A UGAGGAAG 5017 CTTCCTCA GGCTAGCTACAACGA GTCCTCGA 6627
    1222 AUGAGGAA G CGGCAUGU 5934 ACATGCCG GGCTAGCTACAACGA TTCCTCAT 6628
    1225 AGGAAGCG G CAUGUCGA 5935 TCGACATG GGCTAGCTACAACGA CGCTTCCT 6629
    1227 GAAGCGGC A UGUCGAGG 5018 CCTCGACA GGCTAGCTACAACGA GCCGCTTC 6630
    1229 AGCGGCAU G UCGAGGUC 5936 GACCTCGA GGCTAGCTACAACGA ATGCCGCT 6631
    1235 AUGUCGAG G UCUCCCAG 5937 CTGGGAGA GGCTAGCTACAACGA CTCGACAT 6632
    1244 UCUCCCAG G CCCCCUUG 5938 CAAGGGGG GGCTAGCTACAACGA CTGGGAGA 6633
    1252 GCCCCCUU G CCCCCCGC 5939 GCGGGGGG GGCTAGCTACAACGA AAGGGGGC 6634
    1259 UGCCCCCC G CCCCUGCC 5940 GGCAGGGG GGCTAGCTACAACGA GGGGGGCA 6635
    1265 CCGCCCCU G CCUACCUC 5941 GAGGTAGG GGCTAGCTACAACGA AGGGGCGG 6636
    1269 CCCUGCCU A CCUCUCCU 4452 AGGAGAGG GGCTAGCTACAACGA AGGCAGGG 6637
    1286 CUCCCCUG G CCCUGCCC 5942 GGGCAGGG GGCTAGCTACAACGA CAGGGGAG 6638
    1291 CUGGCCCU G CCCAGCCA 5943 TGGCTGGG GGCTAGCTACAACGA AGGGCCAG 6639
    1296 CCUGCCCA G CCAGAGGA 5944 TCCTCTGG GGCTAGCTACAACGA TGGGCAGG 6640
    1308 GAGGAGGA G CCCCCCCG 5945 CGGGGGGG GGCTAGCTACAACGA TCCTCCTC 6641
    1321 CCCGAGGA G CCACCUGA 5946 TCAGGTGG GGCTAGCTACAACGA TCCTCGGG 6642
    1324 GAGGAGCC A CCUGACUU 5064 AAGTCAGG GGCTAGCTACAACGA GGCTCCTC 6643
    1329 GCCACCUG A CUUCUGCU 6354 AGCAGAAG GGCTAGCTACAACGA CAGGTGGC 6644
    1335 UGACUUCU G CUGUCCCA 5947 TGGGACAG GGCTAGCTACAACGA AGAAGTCA 6645
    1338 CUUCUGCU G UCCCAAGU 5948 ACTTGGGA GGCTAGCTACAACGA AGCAGAAG 6646
    1345 UGUCCCAA G UGCCAGUA 5949 TACTGGCA GGCTAGCTACAACGA TTGGGACA 6647
    1347 UCCCAAGU G CCAGUAUC 5950 GATACTGG GGCTAGCTACAACGA ACTTGGGA 6648
    1351 AAGUGCCA G UAUCAGGC 5951 GCCTGATA GGCTAGCTACAACGA TGGCACTT 6649
    1353 GUGCCAGU A UCAGGCCC 4460 GGGCCTGA GGCTAGCTACAACGA ACTGGCAC 6650
    1358 AGUAUCAG G CCCCUGAU 5952 ATCAGGGG GGCTAGCTACAACGA CTGATACT 6651
    1365 GGCCCCUG A UAUGGACA 6355 TGTCCATA GGCTAGCTACAACGA CAGGGGCC 6652
    1367 CCCCUGAU A UGGACACC 4462 GGTGTCCA GGCTAGCTACAACGA ATCAGGGG 6653
    1371 UGAUAUGG A CACCCUGC 6356 GCAGGGTG GGCTAGCTACAACGA CCATATCA 6654
    1373 AUAUGGAC A CCCUGCAG 5080 CTGCAGGG GGCTAGCTACAACGA GTCCATAT 6655
    1378 GACACCCU G CAGAUACA 5953 TGTATCTG GGCTAGCTACAACGA AGGGTGTC 6656
    1382 CCCUGCAG A UACAUGUC 6357 GACATGTA GGCTAGCTACAACGA CTGCAGGG 6657
    1384 CUGCAGAU A CAUGUCAU 4463 ATGACATG GGCTAGCTACAACGA ATCTGCAG 6658
    1386 GCAGAUAC A UGUCAUGG 5085 CCATGACA GGCTAGCTACAACGA GTATCTGC 6659
    1388 AGAUACAU G UCAUGGAG 5954 CTCCATGA GGCTAGCTACAACGA ATGTATCT 6660
    1391 UACAUGUC A UGGAGUGC 5086 GCACTCCA GGCTAGCTACAACGA GACATGTA 6661
    1396 GUCAUGGA G UGCAUUGA 5955 TCAATGCA GGCTAGCTACAACGA TCCATGAC 6662
    1398 CAUGGAGU G CAUUGAGU 5956 ACTCAATG GGCTAGCTACAACGA ACTCCATG 6663
    1400 UGGAGUGC A UUGAGUAG 5087 CTACTCAA GGCTAGCTACAACGA GCACTCCA 6664
    1405 UGCAUUGA G UAGGGCCG 5957 CGGCCCTA GGCTAGCTACAACGA TCAATGCA 6665
    1410 UGAGUAGG G CCGGCCAG 5958 CTGGCCGG GGCTAGCTACAACGA CCTACTCA 6666
    1414 UAGGGCCG G CCAGUGCA 5959 TGCACTGG GGCTAGCTACAACGA CGGCCCTA 6667
    1418 GCCGGCCA G UGCAAGGC 5960 GCCTTGCA GGCTAGCTACAACGA TGGCCGGC 6668
    1420 CGGCCAGU G CAAGGCCA 5961 TGGCCTTG GGCTAGCTACAACGA ACTGGCCG 6669
    1425 AGUGCAAG G CCACUGCC 5962 GGCAGTGG GGCTAGCTACAACGA CTTGCACT 6670
    1428 GCAAGGCC A CUGCCUGC 5093 GCAGGCAG GGCTAGCTACAACGA GGCCTTGC 6671
    1431 AGGCCACU G CCUGCCCG 5963 CGGGCAGG GGCTAGCTACAACGA AGTGGCCT 6672
    1435 CACUGCCU G CCCGAGGA 5964 TCCTCGGG GGCTAGCTACAACGA AGGCAGTG 6673
    1443 GCCCGAGG A CGUGCCCG 6358 CGGGCACG GGCTAGCTACAACGA CCTCGGGC 6674
    1445 CCGAGGAC G UGCCCGGG 5965 CCCGGGCA GGCTAGCTACAACGA GTCCTCGG 6675
    1447 GAGGACGU G CCCGGGAC 5966 GTCCCGGG GGCTAGCTACAACGA ACGTCCTC 6676
    1454 UGCCCGGG A CCGUGCAG 6359 CTGCACGG GGCTAGCTACAACGA CCCGGGCA 6677
    1457 CCGGGACC G UGCAGUCU 5967 AGACTGCA GGCTAGCTACAACGA GGTCCCGG 6678
    1459 GGGACCGU G CAGUCUGC 5968 GCAGACTG GGCTAGCTACAACGA ACGGTCCC 6679
    1462 ACCGUGCA G UCUGCGCU 5969 AGCGCAGA GGCTAGCTACAACGA TGCACGGT 6680
    1466 UGCAGUCU G CGCUUUCC 5970 GGAAAGCG GGCTAGCTACAACGA AGACTGCA 6681
    1468 CAGUCUGC G CUUUCCUC 5971 GAGGAAAG GGCTAGCTACAACGA GCAGACTG 6682
    1481 CCUCUCCC G CCUGCCUA 5972 TAGGCAGG GGCTAGCTACAACGA GGGAGAGG 6683
    1485 UCCCGCCU G CCUAGCCC 5973 GGGCTAGG GGCTAGCTACAACGA AGGCGGGA 6684
    1490 CCUGCCUA G CCCAGGAU 5974 ATCCTGGG GGCTAGCTACAACGA TAGGCAGG 6685
    1497 AGCCCAGG A UGAAGGGC 6360 GCCCTTCA GGCTAGCTACAACGA CCTGGGCT 6686
    1504 GAUGAAGG G CUGGGUGG 5975 CCACCCAG GGCTAGCTACAACGA CCTTCATC 6687
    1509 AGGGCUGG G UGGCCACA 5976 TGTGGCCA GGCTAGCTACAACGA CCAGCCCT 6688
    1512 GCUGGGUG G CCACAACU 5977 AGTTGTGG GGCTAGCTACAACGA CACCCAGC 6689
    1515 GGGUGGCC A CAACUGGG 5119 CCCAGTTG GGCTAGCTACAACGA GGCCACCC 6690
    1518 UGGCCACA A CUGGGAUG 6361 CATCCCAG GGCTAGCTACAACGA TGTGGCCA 6691
    1524 CAACUGGG A UGCCACCU 6362 AGGTGGCA GGCTAGCTACAACGA CCCAGTTG 6692
    1526 ACUGGGAU G CCACCUGG 5978 CCAGGTGG GGCTAGCTACAACGA ATCCCAGT 6693
    1529 GGGAUGCC A CCUGGAGC 5123 GCTCCAGG GGCTAGCTACAACGA GGCATCCC 6694
    1536 CACCUGGA G CCCCACCC 5979 GGGTGGGG GGCTAGCTACAACGA TCCAGGTG 6695
    1541 GGAGCCCC A CCCAGGAG 5129 CTCCTGGG GGCTAGCTACAACGA GGGGCTCC 6696
    1549 ACCCAGGA G CUGGCCGC 5980 GCGGCCAG GGCTAGCTACAACGA TCCTGGGT 6697
    1553 AGGAGCUG G CCGCGGCA 5981 TGCCGCGG GGCTAGCTACAACGA CAGCTCCT 6698
    1556 AGCUGGCC G CGGCACCU 5982 AGGTGCCG GGCTAGCTACAACGA GGCCAGCT 6699
    1559 UGGCCGCG G CACCUUAC 5983 GTAAGGTG GGCTAGCTACAACGA CGCGGCCA 6700
    1561 GCCGCGGC A CCUUACGC 5135 GCGTAAGG GGCTAGCTACAACGA GCCGCGGC 6701
    1566 GGCACCUU A CGCUUCAG 4475 CTGAAGCG GGCTAGCTACAACGA AAGGTGCC 6702
    1568 CACCUUAC G CUUCAGCU 5984 AGCTGAAG GGCTAGCTACAACGA GTAAGGTG 6703
    1574 ACGCUUCA G CUGUUGAU 5985 ATCAACAG GGCTAGCTACAACGA TGAAGCGT 6704
    1577 CUUCAGCU G UUGAUCCG 5986 CGGATCAA GGCTAGCTACAACGA AGCTGAAG 6705
    1581 AGCUGUUG A UCCGCUGG 6363 CCAGCGGA GGCTAGCTACAACGA CAACAGCT 6706
    1585 GUUGAUCC G CUGGUCCC 5987 GGGACCAG GGCTAGCTACAACGA GGATCAAC 6707
    1589 AUCCGCUG G UCCCCUCU 5988 AGAGGGGA GGCTAGCTACAACGA CAGCGGAT 6708
    1604 CUUUUGGG G UAGAUGCG 5989 CGCATCTA GGCTAGCTACAACGA CCCAAAAG 6709
    1608 UGGGGUAG A UGCGGCCC 6364 GGGCCGCA GGCTAGCTACAACGA CTACCCCA 6710
    1610 GGGUAGAU G CGGCCCCG 5990 CGGGGCCG GGCTAGCTACAACGA ATCTACCC 6711
    1613 UAGAUGCG G CCCCGAUC 5991 GATCGGGG GGCTAGCTACAACGA CGCATCTA 6712
    1619 CGGCCCCG A UCAGGCCU 6365 AGGCCTGA GGCTAGCTACAACGA CGGGGCCG 6713
    1624 CCGAUCAG G CCUGACUC 5992 GAGTCAGG GGCTAGCTACAACGA CTGATCGG 6714
    1629 CAGGCCUG A CUCGCUGC 6366 GCAGCGAG GGCTAGCTACAACGA CAGGCCTG 6715
    1633 CCUGACUC G CUGCUCUU 5993 AAGAGCAG GGCTAGCTACAACGA GAGTCAGG 6716
    1636 GACUCGCU G CUCUUUUU 5994 AAAAAGAG GGCTAGCTACAACGA AGCGAGTC 6717
    1645 CUCUUUUU G UUCCCUUC 5995 GAAGGGAA GGCTAGCTACAACGA AAAAAGAG 6718
    1655 UCCCUUCU G UCUGCUCG 5996 CGAGCAGA GGCTAGCTACAACGA AGAAGGGA 6719
    1659 UUCUGUCU G CUCGAACC 5997 GGTTCGAG GGCTAGCTACAACGA AGACAGAA 6720
    1665 CUGCUCGA A CCACUUGC 6367 GCAAGTGG GGCTAGCTACAACGA TCGAGCAG 6721
    1668 CUCGAACC A CUUGCCUC 5165 GAGGCAAG GGCTAGCTACAACGA GGTTCGAG 6722
    1672 AACCACUU G CCUCGGGC 5998 GCCCGAGG GGCTAGCTACAACGA AAGTGGTT 6723
    1679 UGCCUCGG G CUAAUCCC 5999 GGGATTAG GGCTAGCTACAACGA CCGAGGCA 6724
    1683 UCGGGCUA A UCCCUCCC 6368 GGGAGGGA GGCTAGCTACAACGA TAGCCCGA 6725
    1701 CUUCCUCC A CCCGGCAC 5180 GTGCCGGG GGCTAGCTACAACGA GGAGGAAG 6726
    1706 UCCACCCG G CACUGGGG 6000 CCCCAGTG GGCTAGCTACAACGA CGGGTGGA 6727
    1708 CACCCGGC A CUGGGGAA 5183 TTCCCCAG GGCTAGCTACAACGA GCCGGGTG 6728
    1717 CUGGGGAA G UCAAGAAU 6001 ATTCTTGA GGCTAGCTACAACGA TTCCCCAG 6729
    1724 AGUCAAGA A UGGGGCCU 6369 AGGCCCCA GGCTAGCTACAACGA TCTTGACT 6730
    1729 AGAAUGGG G CCUGGGGC 6002 GCCCCAGG GGCTAGCTACAACGA CCCATTCT 6731
    1736 GGCCUGGG G CUCUCAGG 6003 CCTGAGAG GGCTAGCTACAACGA CCCAGGCC 6732
    1749 CAGGGAGA A CUGCUUCC 6370 GGAAGCAG GGCTAGCTACAACGA TCTCCCTG 6733
    1752 GGAGAACU G CUUCCCCU 6004 AGGGGAAG GGCTAGCTACAACGA AGTTCTCC 6734
    1762 UUCCCCUG G CAGAGCUG 6005 CAGCTCTG GGCTAGCTACAACGA CAGGGGAA 6735
    1767 CUGGCAGA G CUGGGUGG 6006 CCACCCAG GGCTAGCTACAACGA TCTGCCAG 6736
    1772 AGAGCUGG G UGGCAGCU 6007 AGCTGCCA GGCTAGCTACAACGA CCAGCTCT 6737
    1775 GCUGGGUG G CAGCUCUU 6008 AAGAGCTG GGCTAGCTACAACGA CACCCAGC 6738
    1778 GGGUGGCA G CUCUUCCU 6009 AGGAAGAG GGCTAGCTACAACGA TGCCACCC 6739
    1790 UUCCUCCC A CCGGACAC 5206 GTGTCCGG GGCTAGCTACAACGA GGGAGGAA 6740
    1795 CCCACCGG A CACCGACC 6371 GGTCGGTG GGCTAGCTACAACGA CCGGTGGG 6741
    1797 CACCGGAC A CCGACCCG 5208 CGGGTCGG GGCTAGCTACAACGA GTCCGGTG 6742
    1801 GGACACCG A CCCGCCCG 6372 CGGGCGGG GGCTAGCTACAACGA CGGTGTCC 6743
    1805 ACCGACCC G CCCGCCGC 6010 GCGGCGGG GGCTAGCTACAACGA GGGTCGGT 6744
    1809 ACCCGCCC G CCGCUGUG 6011 CACAGCGG GGCTAGCTACAACGA GGGCGGGT 6745
    1812 CGCCCGCC G CUGUGCCC 6012 GGGCACAG GGCTAGCTACAACGA GGCGGGCG 6746
    1815 CCGCCGCU G UGCCCUGG 6013 CCAGGGCA GGCTAGCTACAACGA AGCGGCGG 6747
    1817 GCCGCUGU G CCCUGGGA 6014 TCCCAGGG GGCTAGCTACAACGA ACAGCGGC 6748
    1826 CCCUGGGA G UGCUGCCC 6015 GGGCAGCA GGCTAGCTACAACGA TCCCAGGG 6749
    1828 CUGGGAGU G CUGCCCUC 6016 GAGGGCAG GGCTAGCTACAACGA ACTCCCAG 6750
    1831 GGAGUGCU G CCCUCUUA 6017 TAAGAGGG GGCTAGCTACAACGA AGCACTCC 6751
    1839 GCCCUCUU A CCAUGCAC 4519 GTGCATGG GGCTAGCTACAACGA AAGAGGGC 6752
    1842 CUCUUACC A UGCACACG 5225 CGTGTGCA GGCTAGCTACAACGA GGTAAGAG 6753
    1844 CUUACCAU G CACACGGG 6018 CCCGTGTG GGCTAGCTACAACGA ATGGTAAG 6754
    1846 UACCAUGC A CACGGGUG 5226 CACCCGTG GGCTAGCTACAACGA GCATGGTA 6755
    1848 CCAUGCAC A CGGGUGCU 5227 AGCACCCG GGCTAGCTACAACGA GTGCATGG 6756
    1852 GCACACGG G UGCUCUCC 6019 GGAGAGCA GGCTAGCTACAACGA CCGTGTGC 6757
    1854 ACACGGGU G CUCUCCUU 6020 AAGGAGAG GGCTAGCTACAACGA ACCCGTGT 6758
    1867 CCUUUUGG G CUGCAUGC 6021 GCATGCAG GGCTAGCTACAACGA CCAAAAGG 6759
    1870 UUUGGGCU G CAUGCUAU 6022 ATAGCATG GGCTAGCTACAACGA AGCCCAAA 6760
    1872 UGGGCUGC A UGCUAUUC 5233 GAATAGCA GGCTAGCTACAACGA GCAGCCCA 6761
    1874 GGCUGCAU G CUAUUCCA 6023 TGGAATAG GGCTAGCTACAACGA ATGCAGCC 6762
    1877 UGCAUGCU A UUCCAUUU 4525 AAATGGAA GGCTAGCTACAACGA AGCATGCA 6763
    1882 GCUAUUCC A UUUUGCAG 5236 CTGCAAAA GGCTAGCTACAACGA GGAATAGC 6764
    1887 UCCAUUUU G CAGCCAGA 6024 TCTGGCTG GGCTAGCTACAACGA AAAATGGA 6765
    1890 AUUUUGCA G CCAGACCG 6025 CGGTCTGG GGCTAGCTACAACGA TGCAAAAT 6766
    1895 GCAGCCAG A CCGAUGUG 6373 CACATCGG GGCTAGCTACAACGA CTGGCTGC 6767
    1899 CCAGACCG A UGUGUAUU 6374 AATACACA GGCTAGCTACAACGA CGGTCTGG 6768
    1901 AGACCGAU G UGUAUUUA 6026 TAAATACA GGCTAGCTACAACGA ATCGGTCT 6769
    1903 ACCGAUGU G UAUUUAAC 6027 GTTAAATA GGCTAGCTACAACGA ACATCGGT 6770
    1905 CGAUGUGU A UUUAACCA 4531 TGGTTAAA GGCTAGCTACAACGA ACACATCG 6771
    1910 UGUAUUUA A CCAGUCAC 6375 GTGACTGG GGCTAGCTACAACGA TAAATACA 6772
    1914 UUUAACCA G UCACUAUU 6028 AATAGTGA GGCTAGCTACAACGA TGGTTAAA 6773
    1917 AACCAGUC A CUAUUGAU 5243 ATCAATAG GGCTAGCTACAACGA GACTGGTT 6774
    1920 CAGUCACU A UUGAUGGA 4536 TCCATCAA GGCTAGCTACAACGA AGTGACTG 6775
    1924 CACUAUUG A UGGACAUU 6376 AATGTCCA GGCTAGCTACAACGA CAATAGTG 6776
    1928 AUUGAUGG A CAUUUGGG 6377 CCCAAATG GGCTAGCTACAACGA CCATCAAT 6777
    1930 UGAUGGAC A UUUGGGUU 5245 AACCCAAA GGCTAGCTACAACGA GTCCATCA 6778
    1936 ACAUUUGG G UUGUUUCC 6029 GGAAACAA GGCTAGCTACAACGA CCAAATGT 6779
    1939 UUUGGGUU G UUUCCCAU 6030 ATGGGAAA GGCTAGCTACAACGA AACCCAAA 6780
    1946 UGUUUCCC A UCUUUUUG 5248 CAAAAAGA GGCTAGCTACAACGA GGGAAACA 6781
    1954 AUCUUUUU G UUACCAUA 6031 TATGGTAA GGCTAGCTACAACGA AAAAAGAT 6782
    1957 UUUUUGUU A CCAUAAAU 4550 ATTTATGG GGCTAGCTACAACGA AACAAAAA 6783
    1960 UUGUUACC A UAAAUAAU 5251 ATTATTTA GGCTAGCTACAACGA GGTAACAA 6784
    1964 UACCAUAA A UAAUGGCA 6378 TGCCATTA GGCTAGCTACAACGA TTATGGTA 6785
    1967 CAUAAAUA A UGGCAUAG 6379 CTATGCCA GGCTAGCTACAACGA TATTTATG 6786
    1970 AAAUAAUG G CAUAGUAA 6032 TTACTATG GGCTAGCTACAACGA CATTATTT 6787
    1972 AUAAUGGC A UAGUAAAA 5252 TTTTACTA GGCTAGCTACAACGA GCCATTAT 6788
    1975 AUGGCAUA G UAAAAAAA 6033 TTTTTTTA GGCTAGCTACAACGA TATGCCAT 6789

    Input Sequence = NM_003639. Cut Site = R/Y

    Arm Length = 8. Core Sequence = GGCTAGCTACAACGA

    NM_003639 (Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), mRNA.; 1994 bp)
  • TABLE VII
    Human IKK-gamma Amberzyme and Substrate Sequence
    Seq Seq
    Pos Substrate ID Amberzyme ID
    12 ACGAGCAU G GCCCUUGU 6790 ACAAGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCUCGU 7142
    13 CGAGCAUG G CCCUUGUG 5757 CACAAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGCUCG 7143
    19 UGGCCCUU G UGAUCCAG 5758 CUGGAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGGCCA 7144
    21 GCCCUUGU G AUCCAGGU 6791 ACCUGGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAGGGC 7145
    27 GUGAUCCA G GUGGGGAA 6792 UUCCCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAUCAC 7146
    28 UGAUCCAG G UGGGGAAA 5759 UUUCCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGAUCA 7147
    30 AUCCAGGU G GGGAAACU 6793 AGUUUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUGGAU 7148
    31 UCCAGGUG G GGAAACUA 6794 UAGUUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCUGGA 7149
    32 CCAGGUGG G GAAACUAA 6795 UUAGUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACCUGG 7150
    33 CAGGUGGG G AAACUAAG 6796 CUUAGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCACCUG 7151
    41 GAAACUAA G GCCCAGAG 6797 CUCUGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAGUUUC 7152
    42 AAACUAAG G CCCAGAGA 5760 UCUCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUAGUUU 7153
    47 AAGGCCCA G AGAAGUGA 6798 UCACUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCCUU 7154
    49 GGCCCAGA G AAGUGAGG 6799 CCUCACUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGGCC 7155
    52 CCAGAGAA G UGAGGACC 5761 GGUCCUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUCUGG 7156
    54 AGAGAAGU G AGGACCCC 6800 GGGGUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUCUCU 7157
    56 AGAAGUGA G GACCCCGC 6801 GCGGGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCACUUCU 7158
    57 GAAGUGAG G ACCCCGCA 6802 UGCGGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCACUUC 7159
    63 AGGACCCC G CAGACUAU 5762 AUAGUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGGUCCU 7160
    66 ACCCCGCA G ACUAUCAA 6803 UUGAUAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGGGGU 7161
    80 CAAUCCCA G UCUCUUCC 5763 GGAAGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGAUUG 7162
    100 CACUCCCU G UGAAGCUC 5764 GAGCUUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGAGUG 7163
    102 CUCCCUGU G AAGCUCUC 6804 GAGAGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGGGAG 7164
    105 CCUGUGAA G CUCUCCAG 5765 CUGGAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCACAGG 7165
    113 GCUCUCCA G CAUCAUCG 5766 CGAUGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAGAGC 7166
    121 GCAUCAUC G AGGUCCCA 6805 UGGGACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUGAUGC 7167
    123 AUCAUCGA G GUCCCAUC 6806 GAUGGGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGAUGAU 7168
    124 UCAUCGAG G UCCCAUCA 5767 UGAUGGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGAUGA 7169
    133 UCCCAUCA G CCCUUGCC 5768 GGCAAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUGGGA 7170
    139 CAGCCCUU G CCCUGUUG 5769 CAACAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGGCUG 7171
    144 CUUGCCCU G UUGGAUGA 5770 UCAUCCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGCAAG 7172
    147 GCCCUGUU G GAUGAAUA 6807 UAUUCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACAGGGC 7173
    148 CCCUGUUG G AUGAAUAG 6808 CUAUUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAACAGGG 7174
    151 UGUUGGAU G AAUAGGCA 6809 UGCCUAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCAACA 7175
    156 GAUGAAUA G GCACCUCU 6810 AGAGGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUCAUC 7176
    157 AUGAAUAG G CACCUCUG 5771 CAGAGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAUUCAU 7177
    165 GCACCUCU G GAAGAGCC 6811 GGCUCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGGUGC 7178
    166 CACCUCUG G AAGAGCCA 6812 UGGCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGGUG 7179
    169 CUCUGGAA G AGCCAACU 6813 AGUUGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCAGAG 7180
    171 CUGGAAGA G CCAACUGU 5772 ACAGUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCCAG 7181
    178 AGCCAACU G UGUGAGAU 5773 AUCUCACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUGGCU 7182
    180 CCAACUGU G UGAGAUGG 5774 CCAUCUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGUUGG 7183
    182 AACUGUGU G AGAUGGUG 6814 CACCAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACAGUU 7184
    184 CUGUGUGA G AUGGUGCA 6815 UGCACCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCACACAG 7185
    187 UGUGAGAU G GUGCAGCC 6816 GGCUGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUCACA 7186
    188 GUGAGAUG G UGCAGCCC 5775 GGGCUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCUCAC 7187
    190 GAGAUGGU G CAGCCCAG 5776 CUGGGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCAUCUC 7188
    193 AUGGUGCA G CCCAGUGG 5777 CCACUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCACCAU 7189
    198 GCAGCCCA G UGGUGGCC 5778 GGCCACCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCUGC 7190
    200 AGCCCAGU G GUGGCCCG 6817 CGGGCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGGGCU 7191
    201 GCCCAGUG G UGGCCCGG 5779 CCGGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACUGGGC 7192
    203 CCAGUGGU G GCCCGGCA 6818 UGCCGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCACUGG 7193
    204 CAGUGGUG G CCCGGCAG 5780 CUGCCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCACUG 7194
    208 GGUGGCCC G GCAGCAGA 6819 UCUGCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCCACC 7195
    209 GUGGCCCG G CAGCAGAU 5781 AUCUGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGCCAC 7196
    212 GCCCGGCA G CAGAUCAG 5782 CUGAUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCGGGC 7197
    215 CGGCAGCA G AUCAGGAC 6820 GUCCUGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGCCG 7198
    220 GCAGAUCA G GACGUACU 6821 AGUACGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUCUGC 7199
    221 CAGAUCAG G ACGUACUG 6822 CAGUACGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAUCUG 7200
    224 AUCAGGAC G UACUGGGC 5783 GCCCAGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCCUGAU 7201
    229 GACGUACU G GGCGAAGA 6823 UCUUCGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUACGUC 7202
    230 ACGUACUG G GCGAAGAG 6824 CUCUUCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUACGU 7203
    231 CGUACUGG G CGAAGAGU 5784 ACUCUUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGUACG 7204
    233 UACUGGGC G AAGAGUCU 6825 AGACUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCCAGUA 7205
    236 UGGGCGAA G AGUCUCCU 6826 AGGAGACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCGCCCA 7206
    238 GGCGAAGA G UCUCCUCU 5785 AGAGGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCGCC 7207
    247 UCUCCUCU G GGGAAGCC 6827 GGCUUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGGAGA 7208
    248 CUCCUCUG G GGAAGCCA 6828 UGGCUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGGAG 7209
    249 UCCUCUGG G GAAGCCAG 6829 CUGGCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGAGGA 7210
    250 CCUCUGGG G AAGCCAGC 6830 GCUGGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGAGG 7211
    253 CUGGGGAA G CCAGCCAU 5786 AUGGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCCAG 7212
    257 GGAAGCCA G CCAUGCUG 5787 CAGCAUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUUCC 7213
    262 CCAGCCAU G CUGCACCU 5788 AGGUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGCUGG 7214
    265 GCCAUGCU G CACCUGCC 5789 GGCAGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAUGGC 7215
    271 CUGCACCU G CCUUCAGA 5790 UCUGAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUGCAG 7216
    278 UGCCUUCA G AACAGGGC 6831 GCCCUGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAGGCA 7217
    283 UCAGAACA G GGCGCUCC 6832 GGAGCGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUCUGA 7218
    284 CAGAACAG G GCGCUCCU 6833 AGGAGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUUCUG 7219
    285 AGAACAGG G CGCUCCUG 5791 CAGGAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGUUCU 7220
    287 AACAGGGC G CUCCUGAG 5792 CUCAGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCCUGUU 7221
    293 GCGCUCCU G AGACCCUC 6834 GAGGGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGCGC 7222
    295 GCUCCUGA G ACCCUCCA 6835 UGGAGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGGAGC 7223
    304 ACCCUCCA G CGCUGCCU 5793 AGGCAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAGGGU 7224
    306 CCUCCAGC G CUGCCUGG 5794 CCAGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGGAGG 7225
    309 CCAGCGCU G CCUGGAGG 5795 CCUCCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGCUGG 7226
    313 CGCUGCCU G GAGGAGAA 6836 UUCUCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCAGCG 7227
    314 GCUGCCUG G AGGAGAAU 6837 AUUCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGCAGC 7228
    316 UGCCUGGA G GAGAAUCA 6838 UGAUUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGGCA 7229
    317 GCCUGGAG G AGAAUCAA 6839 UUGAUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCAGGC 7230
    319 CUGGAGGA G AAUCAAGA 6840 UCUUGAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCCAG 7231
    326 AGAAUCAA G AGCUCCGA 6841 UCGGAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAUUCU 7232
    328 AAUCAAGA G CUCCGAGA 5796 UCUCGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUGAUU 7233
    333 AGAGCUCC G AGAUGCCA 6842 UGGCAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAGCUCU 7234
    335 AGCUCCGA G AUGCCAUC 6843 GAUGGCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGAGCU 7235
    338 UCCGAGAU G CCAUCCGG 5797 CCGGAUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUCGGA 7236
    345 UGCCAUCC G GCAGAGCA 6844 UGCUCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAUGGCA 7237
    346 GCCAUCCG G CAGAGCAA 5798 UUGCUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGAUGGC 7238
    349 AUCCGGCA G AGCAACCA 6845 UGGUUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCGGAU 7239
    351 CCGGCAGA G CAACCAGA 5799 UCUGGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGCCGG 7240
    358 AGCAACCA G AUUCUGCG 6846 CGCAGAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUUGCU 7241
    364 CAGAUUCU G CGGGAGCG 5800 CGCUCCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAUCUG 7242
    366 GAUUCUGC G GGAGCGCU 6847 AGCGCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGAAUC 7243
    367 AUUCUGCG G GAGCGCUG 6848 CAGCGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCAGAAU 7244
    368 UUCUGCGG G AGCGCUGC 6849 GCAGCGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCAGAA 7245
    370 CUGCGGGA G CGCUGCGA 5801 UCGCAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCGCAG 7246
    372 GCGGGAGC G CUGCGAGG 5802 CCUCGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUCCCGC 7247
    375 GGAGCGCU G CGAGGAGC 5803 GCUCCUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGCUCC 7248
    377 AGCGCUGC G AGGAGCUU 6850 AAGCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGCGCU 7249
    379 CGCUGCGA G GAGCUUCU 6851 AGAAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGCACCG 7250
    380 GCUGCGAG G AGCUUCUG 6852 CAGAAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGCAGC 7251
    382 UGCGAGGA G CUUCUGCA 5804 UGCAGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCGCA 7252
    388 GAGCUUCU G CAUUUCCA 5805 UGGAAAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGCUC 7253
    398 AUUUCCAA G CCAGCCAG 5806 CUGGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGCAAAU 7254
    402 CCAAGCCA G CCACAGGG 5807 CCCUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUUCG 7255
    406 GCCAGCCA G AGGGACCA 6853 UCCUCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCUGCC 7256
    408 CAGCCAGA G CCACGAGA 6854 UCUCCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCCCUC 7257
    409 ACCCAGAC G GAGCAGAA 6855 UUCUCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUCGCU 7258
    410 CCCACACC G AGCAGAAC 6856 CUUCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCUGCC 7259
    412 CAGAGGCA G GAGAACGA 6657 UCCUUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCUCUC 7260
    413 AGAGGGAG G ACAACCAC 6858 CUCCUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCCUCU 7261
    415 AGGGAGGA G AAGGACUU 6859 AACUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCCCU 7262
    418 CACGAGAA G GACUUCCU 6860 AGGAACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUCCUC 7263
    419 AGCAGAAG G ACUUCCUC 6861 GAGCAACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUCCU 7264
    421 GACAACGA G UUCCUCAU 5808 AUCAGCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUUCUC 7265
    430 UUCCUCAU G UCCAACUU 5809 AACUUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAGCAA 7266
    432 CCUCAUCU G CAAGUUCC 5810 CGAACUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAUGAGC 7267
    436 AUCUCCAA G UUCCACCA 5811 UCCUCCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCACAU 7268
    442 AACUUCCA G CACCCCAC 6862 CUCCCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAACUU 7269
    443 ACUUCCAC G ACCCCACC 6863 CCUCCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCAACU 7270
    445 UUCCACCA G CCCACCAA 6864 UUCCUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCCAA 7271
    446 UCCACCAC G CCACCAAA 5812 UUUCCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUCCA 7272
    450 CCACCCCA G CAAACUCC 6865 CCACUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCCUCC 7273
    451 CACCCCAC G AAACUCCU 6866 ACCACUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCCCUC 7274
    457 ACCAAACU G CUCCACAC 6867 CUCUCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUUCCU 7275
    458 CCAAACUC G UCCACACA 5813 UCUCUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACUUUCC 7276
    460 AAACUCCU G CACACACU 6868 ACUCUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCACUUU 7277
    461 AACUCCUC G ACACACUC 6869 CACUCUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCACUU 7278
    463 CUGGUCCA G ACACUCCC 6870 CCCACUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCACCAC 7279
    465 CCUCCACA G ACUCCCCC 6871 CCCCCACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCCACC 7280
    470 ACACACUC G CCCUCCAC 6872 CUCCACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACUCUCU 7281
    471 CACACUCC G CCUCCACA 5814 UCUCCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACUCUC 7282
    475 CUCCCCCU G CACAACCU 6873 ACCUUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCCCAC 7283
    476 UCGGCCUG G AGAACCUC 6874 CACCUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCCCCA 7284
    478 GGCCUGGA G AACCUCCA 6875 UCCACCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCACCCC 7285
    481 CUGGACAA G CUCCAUCU 5815 AGAUCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUCCAC 7286
    485 AGAAGCUC G AUCUGAAG 6876 CUUCAGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGCUUCU 7287
    490 CUCGAUCU G AAGAGGCA 6877 UGCCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUCGAG 7288
    493 GAUCUGAA G AGGCAGAA 6878 UUCUGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGAUC 7289
    495 UCUGAAGA G GCAGAAGG 6879 CCUUCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCAGA 7290
    496 CUGAAGAG G CAGAAGGA 5816 UCCUUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUUCAG 7291
    499 AAGAGGCA G AAGGAGCA 6880 UGCUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUCUU 7292
    502 AGGCAGAA G GAGCAGGC 6881 GCCUGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGCCU 7293
    503 GGCAGAAG G AGCAGGCU 6882 AGCCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUGCC 7294
    505 CAGAAGGA G CAGGCUCU 5817 AGAGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUUCUG 7295
    508 AAGGAGCA G GCUCUGCG 6883 CGCAGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCCUU 7296
    509 AGGAGCAG G CUCUGCGG 5818 CCGCAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCUCCU 7297
    514 CAGGCUCU G CGGGAGGU 5819 ACCUCCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGCCUG 7298
    516 GGCUCUGC G GGAGGUGG 6884 CCACCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGAGCC 7299
    517 GCUCUGCG G GAGGUGGA 6885 UCCACCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCAGAGC 7300
    518 CUCUGCGG G AGGUGGAG 6886 CUCCACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCAGAG 7301
    520 CUGCGGGA G GUGGAGCA 6887 UGCUCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCGCAG 7302
    521 UGCGGGAG G UGGAGCAC 5820 GUGCUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCCGCA 7303
    523 CGGGAGGU G GAGCACCU 6888 AGGUGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUCCCG 7304
    524 GGGAGGUG G AGCACCUG 6889 CAGGUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCUCCC 7305
    526 GAGGUGGA G CACCUGAA 5821 UUCAGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCACCUC 7306
    532 GAGCACCU G AAGAGAUG 6890 CAUCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUGCUC 7307
    535 CACCUGAA G AGAUGCCA 6891 UGGCAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGGUG 7308
    537 CCUGAAGA G AUGCCAGC 6892 GCUGGCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCAGG 7309
    540 GAAGAGAU G CCAGCAGC 5822 GCUGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUCUUC 7310
    544 AGAUGCCA G CAGCAGAU 5823 AUCUGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCAUCU 7311
    547 UGCCAGCA G CAGAUGGC 5824 GCCAUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGGCA 7312
    550 CAGCAGCA G AUGGCUGA 6893 UCAGCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGCUG 7313
    553 CAGCAGAU G GCUGAGGA 6894 UCCUCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUGCUG 7314
    554 AGCAGAUG G CUGAGGAC 5825 GUCCUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCUGCU 7315
    557 AGAUGGCU G AGGACAAG 6895 CUUGUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCAUCU 7316
    559 AUGGCUGA G GACAAGGC 6896 GCCUUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGCCAU 7317
    560 UGGCUGAG G ACAAGGCC 6897 GGCCUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCAGCCA 7318
    565 GAGGACAA G GCCUCUGU 6898 ACAGAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUCCUC 7319
    566 AGGACAAG G CCUCUGUG 5826 CACAGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGUCCU 7320
    572 AGGCCUCU G UGAAAGCC 5827 GGCUUUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGGCCU 7321
    574 GCCUCUGU G AAAGCCCA 6899 UGGGCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGAGGC 7322
    578 CUGUGAAA G CCCAGGUG 5828 CACCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCACAG 7323
    583 AAAGCCCA G GUGACGUC 6900 GACGUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCUUU 7324
    584 AAGCCCAG G UGACGUCC 5829 GGACGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGCUU 7325
    586 GCCCAGGU G ACGUCCUU 6901 AAGGACGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUGGGC 7326
    589 CAGGUGAC G UCCUUGCU 5830 AGCAAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCACCUG 7327
    595 ACGUCCUU G CUCGGGGA 5831 UCCCCGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGACGU 7328
    599 CCUUGCUC G GGGAGCUG 6902 CAGCUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGCAAGG 7329
    600 CUUGCUCG G GGAGCUGC 6903 GCAGCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGCAAG 7330
    601 UUGCUCGG G GAGCUGCA 6904 UGCAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGAGCAA 7331
    602 UGCUCGGG G AGCUGCAG 6905 CUGCAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGAGCA 7332
    604 CUCGGGGA G CUGCAGGA 5832 UCCUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCCGAG 7333
    607 GGGGAGCU G CAGGAGAG 5833 CUCUCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUCCCC 7334
    610 GAGCUGCA G GAGAGCCA 6906 UGGCUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGCUC 7335
    611 AGCUGCAG G AGAGCCAG 6907 CUGGCUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCAGCU 7336
    613 CUGCAGGA G AGCCAGAG 6908 CUCUGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGCAG 7337
    615 GCAGGAGA G CCAGAGUC 5834 GACUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCCUGC 7338
    619 GAGAGCCA G AGUCGCUU 6909 AAGCGACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUCUC 7339
    621 GAGCCAGA G UCGCUUGG 5835 CCAAGCGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGCUC 7340
    624 CCAGAGUC G CUUGGAGG 5836 CCUCCAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GACUCUGG 7341
    628 AGUCGCUU G GAGGCUGC 6910 GCAGCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGCGACU 7342
    629 GUCGCUUG G AGGCUGCC 6911 GGCAGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGCGAC 7343
    631 CGCUUGGA G GCUGCCAC 6912 GUGGCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAAGCG 7344
    632 GCUUGGAG G CUGCCACU 5837 AGUGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCAAGC 7345
    635 UGGAGGCU G CCACUAAG 5838 CUUAGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUCCA 7346
    643 GCCACUAA G GAAUGCCA 6913 UGGCAUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAGUGGC 7347
    644 CCACUAAG G AAUGCCAG 6914 CUGGCAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUAGUGG 7348
    648 UAAGGAAU G CCAGGCUC 5839 GAGCCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUCCUUA 7349
    652 GAAUGCCA G GCUCUGGA 6915 UCCAGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCAUUC 7350
    653 AAUGCCAG G CUCUGGAG 5840 CUCCAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGCAUU 7351
    658 CAGGCUCU G GAGGGUCG 6916 CGACCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGCCUG 7352
    659 AGGCUCUG G AGGGUCGG 6917 CCGACCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGCCU 7353
    661 GCUCUGGA G GGUCGGGC 6918 GCCCGACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGAGC 7354
    662 CUCUGGAG G GUCGGGCC 6919 GGCCCGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCAGAG 7355
    663 UCUGGAGG G UCGGGCCC 5841 GGGCCCGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCCAGA 7356
    666 GGAGGGUC G GGCCCGGG 6920 CCCGGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GACCCUCC 7357
    667 GAGGGUCG G GCCCGGGC 6921 GCCCGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGACCCUC 7358
    668 AGGGUCGG G CCCGGGCG 5842 CGCCCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGACCCU 7359
    672 UCGGGCCC G GGCGGCCA 6922 UGGCCGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCCCGA 7360
    673 CGGGCCCG G GCGGCCAG 6923 CUGGCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGCCCG 7361
    674 GGGCCCGG G CGGCCAGC 5843 GCUGGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGGCCC 7362
    676 GCCCGGGC G GCCAGCGA 6924 UCGCUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCCGGGC 7363
    677 CCCGGGCG G CCAGCGAG 5844 CUCGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCCGGG 7364
    681 GGCGGCCA G CGAGCAGG 5845 CCUGCUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCGCC 7365
    683 CGGCCAGC G AGCAGGCG 6925 CGCCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGGCCG 7366
    685 GCCAGCGA G CAGGCGCG 5846 CGCGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGCUGGC 7367
    688 AGCGAGCA G GCGCGGCA 6926 UGCCGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCGCU 7368
    689 GCGAGCAG G CGCGGCAG 5847 CUGCCGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCUCGC 7369
    691 GAGCAGGC G CGGCAGCU 5848 AGCUGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUGCUC 7370
    693 GCAGGCGC G GCAGCUGG 6927 CCAGCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGCCUGC 7371
    694 CAGGCGCG G CAGCUGGA 5849 UCCAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCGCCUG 7372
    697 GCGCGGCA G CUGGAGAG 5850 CUCUCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCGCGC 7373
    700 CGGCAGCU G GAGAGUGA 6928 UCACUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGCCG 7374
    701 GGCAGCUG G AGAGUGAG 6929 CUCACUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUGCC 7375
    703 CAGCUGGA G AGUGAGCG 6930 CGCUCACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGCUG 7376
    705 GCUGGAGA G UGAGCGCG 5851 CGCGCUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCCAGC 7377
    707 UGGAGAGU G AGCGCGAG 6931 CUCGCGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUCUCCA 7378
    709 GAGAGUGA G CGCGAGGC 5852 GCCUCGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCACUCUC 7379
    711 GAGUGAGC G CGAGGCGC 5853 GCGCCUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUCACUC 7380
    713 GUGAGCGC G AGGCGCUG 6932 CAGCGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGCUCAC 7381
    715 GAGCGCGA G GCGCUGCA 6933 UGCAGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGCGCUC 7382
    716 AGCGCGAG G CGCUGCAG 5854 CUGCAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGCGCU 7383
    718 CGCGAGGC G CUGCAGCA 5855 UGCUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUCGCG 7384
    721 GAGGCGCU G CAGCAGCA 5856 UGCUGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGCCUC 7385
    724 GCGCUGCA G CAGCAGCA 5857 UGCUGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGCGC 7386
    727 CUGCAGCA G CAGCACAG 5858 CUGUGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGCAG 7387
    730 CAGCAGCA G CACAGCGU 5859 ACGCUGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGCUG 7388
    735 GCAGCACA G CGUGCAGG 5860 CCUGCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGCUGC 7389
    737 AGCACAGC G UGCAGGUG 5861 CACCUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGUGCU 7390
    739 CACAGCGU G CAGGUGGA 5862 UCCACCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCUGUG 7391
    742 AGCGUGCA G GUGGACCA 6934 UGGUCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCACGCU 7392
    743 GCGUGCAG G UGGACCAG 5863 CUGGUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCACGC 7393
    745 GUGCAGGU G GACCAGCU 6935 AGCUGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUGCAC 7394
    746 UGCAGGUG G ACCAGCUG 6936 CAGCUGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCUGCA 7395
    751 GUGGACCA G CUGCGCAU 5864 AUGCGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUCCAC 7396
    754 GACCAGCU G CGCAUGCA 5865 UGCAUGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGGUC 7397
    756 CCAGCUGC G CAUGCAGG 5866 CCUGCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGCUGG 7398
    760 CUGCGCAU G CAGGGCCA 5867 UGGCCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCGCAG 7399
    763 CGCAUGCA G GGCCAGAG 6937 CUCUGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAUGCG 7400
    764 GCAUGCAG G GCCAGAGC 6938 GCUCUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCAUGC 7401
    765 CAUGCAGG G CCAGAGCG 5868 CGCUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGCAUG 7402
    769 CAGGGCCA G AGCGUGGA 6939 UCCACGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCCUG 7403
    771 GGGCCAGA G CGUGGAGG 5869 CCUCCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGCCC 7404
    773 GCCAGAGC G UGGAGGCC 5870 GGCCUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUCUGGC 7405
    775 CAGAGCGU G GAGGCCGC 6940 GCGGCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCUCUG 7406
    776 AGAGCGUG G AGGCCGCG 6941 CGCGGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACGCUCU 7407
    778 AGCGUGGA G GCCGCGCU 6942 AGCGCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCACGCU 7408
    779 GCGUGGAG G CCGCGCUC 5871 GAGCGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCACGC 7409
    782 UGGAGGCC G CGCUCCGC 5872 GCGGAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCUCCA 7410
    784 GAGGCCGC G CUCCGCAU 5873 AUGCGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGCCUC 7411
    789 CGCGCUCC G CAUGGAGC 5874 GCUCCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAGCGCG 7412
    793 CUCCGCAU G GAGCGCCA 6943 UGGCGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCGGAG 7413
    794 UCCGCAUG G AGCGCCAG 6944 CUGGCGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGCGGA 7414
    796 CGCAUGGA G CGCCAGGC 5875 GCCUGGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAUGCG 7415
    798 CAUGGAGC G CCAGGCCG 5876 CGGCCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUCCAUG 7416
    802 GAGCGCCA G GCCGCCUC 6945 GAGGCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCGCUC 7417
    803 AGCGCCAG G CCGCCUCG 5877 CGAGGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGCGCU 7418
    806 GCCAGGCC G CCUCGGAG 5878 CUCCGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCUGGC 7419
    811 GCCGCCUC G GAGGAGAA 6946 UUCUCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGGCGGC 7420
    812 CCGCCUCG G AGGAGAAG 6947 CUUCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGGCGG 7421
    814 GCCUCGGA G GAGAAGAG 6948 CUCUUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCGAGGC 7422
    815 CCUCGGAG G AGAAGAGG 6949 CCUCUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCGAGG 7423
    817 UCGGAGGA G AAGAGGAA 6950 UUCCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCCGA 7424
    820 GAGGAGAA G AGGAAGCU 6951 AGCUUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUCCUC 7425
    822 GGAGAAGA G GAAGCUGG 6952 CCAGCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCUCC 7426
    823 GAGAAGAG G AAGCUGGC 6953 GCCAGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUUCUC 7427
    826 AAGAGGAA G CUGGCCCA 5879 UGGGCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCUCUU 7428
    829 AGGAAGCU G GCCCAGUU 6954 AACUGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUUCCU 7429
    830 GGAAGCUG G CCCAGUUG 5880 CAACUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUUCC 7430
    835 CUGGCCCA G UUGCAGGU 5881 ACCUGCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCCAG 7431
    838 GCCCAGUU G CAGGUGGC 5882 GCCACCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACUGGGC 7432
    841 CAGUUGCA G GUGGCCUA 6955 UAGGCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAACUG 7433
    842 AGUUGCAG G UGGCCUAU 5883 AUAGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCAACU 7434
    844 UUGCAGGU G GCCUAUCA 6956 UGAUAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUGCAA 7435
    845 UGCAGGUG G CCUAUCAC 5884 GUGAUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCUGCA 7436
    856 UAUCACCA G CUCUUCCA 5885 UGGAAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUGAUA 7437
    866 UCUUCCAA G AAUACGAC 6957 GUCGUAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGAAGA 7438
    872 AAGAAUAC G ACAACCAC 6958 GUGGUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAUUCUU 7439
    886 CACAUCAA G AGCAGCGU 6959 ACGCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAUGUG 7440
    888 CAUCAAGA G CAGCGUGG 5886 CCACGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUGAUG 7441
    891 CAAGAGCA G CGUGGUGG 5887 CCACCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCUUG 7442
    893 AGAGCAGC G UGGUGGGC 5888 GCCCACCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGCUCU 7443
    895 AGCAGCGU G GUGGGCAG 6960 CUGCCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCUGCU 7444
    896 GCAGCGUG G UGGGCAGU 5889 ACUGCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACGCUGC 7445
    898 AGCGUGGU G GGCAGUGA 6961 UCACUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCACGCU 7446
    899 GCGUGGUG G GCAGUGAG 6962 CUCACUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCACGC 7447
    900 CGUGGUGG G CAGUGAGC 5890 GCUCACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACCACG 7448
    903 GGUGGGCA G UGAGCGGA 5891 UCCGCUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCCACC 7449
    905 UGGGCAGU G AGCGGAAG 6963 CUUCCGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGCCCA 7450
    907 GGCAGUGA G CGGAAGCG 5892 CGCUUCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCACUGCC 7451
    909 CAGUGAGC G GAAGCGAG 6964 CUCGCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUCACUG 7452
    910 AGUGAGCG G AAGCGAGG 6965 CCUCGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCUCACU 7453
    913 GAGCGGAA G CGAGGAAU 5893 AUUCCUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCGCUC 7454
    915 GCGGAAGC G AGGAAUGC 6966 GCAUUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUUCCGC 7455
    917 GGAAGCGA G GAAUGCAG 6967 CUGCAUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGCUUCC 7456
    918 GAAGCGAG G AAUGCAGC 6968 GCUGCAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGCUUC 7457
    922 CGAGGAAU G CAGCUGGA 5894 UCCAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUCCUCG 7458
    925 GGAAUGCA G CUGGAAGA 5895 UCUUCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAUUCC 7459
    928 AUGCAGCU G GAAGAUCU 6969 AGAUCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGCAU 7460
    929 UGCAGCUG G AAGAUCUC 6970 GAGAUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUGCA 7461
    932 AGCUGGAA G AUCUCAAA 6971 UUUGAGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCAGCU 7462
    943 CUCAAACA G CAGCUCCA 5896 UGGAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUUGAG 7463
    946 AAACAGCA G CUCCAGCA 5897 UGCUGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGUUU 7464
    952 CAGCUCCA G CAGGCCGA 5898 UCGGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAGCUG 7465
    955 CUCCAGCA G GCCGAGGA 6972 UCCUCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGGAG 7466
    956 UCCAGCAG G CCGAGGAG 5899 CUCCUCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCUGGA 7467
    959 AGCAGGCC G AGGAGGCC 6973 GGCCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCUGCU 7468
    961 CAGGCCGA G GAGGCCCU 6974 AGGGCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGCCUG 7469
    962 AGGCCGAG G AGGCCCUG 6975 CAGGGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGGCCU 7470
    964 GCCGAGGA a GCCCUGGU 6976 ACCAGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCGGC 7471
    965 CCGAGGAG G CCCUGGUG 5900 CACCAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUCGG 7472
    970 GAGGCCCU G GUGGCCAA 6977 UUGGCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGCCUC 7473
    971 AGGCCCUG G UGGCCAAA 5901 UUUGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGCCU 7474
    973 GCCCUGGU G GCCAAACA 6978 UGUUUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCAGGGC 7475
    974 CCCUGGUG G CCAAACAG 5902 CUGUUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCAGGG 7476
    982 GCCAAACA G GAGGUGAU 6979 AUCACCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUUGGC 7477
    983 CCAAACAG G AGGUGAUC 6980 GAUCACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUUUGG 7478
    985 AAACAGGA G GUGAUCGA 6981 UCGAUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGUUU 7479
    986 AACAGGAG G UGAUCGAU 5903 AUCGAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUGUU 7480
    988 CAGGAGGU G AUCGAUAA 6982 UUAUCGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUCCUG 7481
    992 AGGUGAUC G AUAAGCUG 6983 CAGCUUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUCACCU 7482
    997 AUCGAUAA G CUGAAGGA 5904 UCCUUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAUCGAU 7483
    1000 GAUAAGCU G AAGGAGGA 6984 UCCUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUUAUC 7484
    1003 AAGCUGAA G GAGGAGGC 6985 GCCUCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGCUU 7485
    1004 AGCUGAAG G AGGAGGCC 6986 GGCCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCAGCU 7486
    1006 CUGAAGGA G GAGGCCGA 6987 UCGGCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUUCAG 7487
    1007 UGAAGGAG G AGGCCGAG 6988 CUCGGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUUCA 7488
    1009 AAGGAGGA G GCCGAGCA 6989 UGCUCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCCUU 7489
    1010 AGGAGGAG G CCGAGCAG 5905 CUGCUCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUCCU 7490
    1013 AGGAGGCC G AGCAGCAC 6990 GUGCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCUCCU 7491
    1015 GAGGCCGA G CAGCACAA 5906 UUGUGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGCCUC 7492
    1018 GCCGAGCA G CACAAGAU 5907 AUCUUGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCGGC 7493
    1024 CAGCACAA G AUUGUGAU 6991 AUCACAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUGCUG 7494
    1028 ACAAGAUU G UGAUGGAG 5908 CUCCAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUCUUGU 7495
    1030 AAGAUUGU G AUGGAGAC 6992 GUCUCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAUCUU 7496
    1033 AUUGUGAU G GAGACCGU 6993 ACGGUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCACAAU 7497
    1034 UUGUGAUG G AGACCGUU 6994 AACGGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCACAA 7498
    1036 GUGAUGGA G ACCGUUCC 6995 GGAACGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAUCAC 7499
    1040 UGGAGACC G UUCCGGUG 5909 CACCGGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUCUCCA 7500
    1045 ACCGUUCC G GUGCUGAA 6996 UUCAGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAACGGU 7501
    1046 CCGUUCCG G UGCUGAAG 5910 CUUCAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGAACGG 7502
    1048 GUUCCGGU G CUGAAGGC 5911 GCCUUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCGGAAC 7503
    1051 CCGGUGCU G AAGGCCCA 6997 UGGGCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCACCGG 7504
    1054 GUGCUGAA G GCCCAGGC 6998 GCCUGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGCAC 7505
    1055 UGCUGAAG G CCCAGGCG 5912 CGCCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCAGCA 7506
    1060 AAGGCCCA G GCGGAUAU 6999 AUAUCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCCUU 7507
    1061 AGGCCCAG G CGGAUAUC 5913 GAUAUCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGCCU 7508
    1063 GCCCAGGC G GAUAUCUA 7000 UAGAUAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUGGGC 7509
    1064 CCCAGGCG G AUAUCUAC 7001 GUAGAUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCUGGG 7510
    1075 AUCUACAA G GCGGACUU 7002 AAGUCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUAGAU 7511
    1076 UCUACAAG G CGGACUUC 5914 GAAGUCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGUAGA 7512
    1078 UACAAGGC G GACUUCCA 7003 UGGAAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUUGUA 7513
    1079 ACAAGGCG G ACUUCCAG 7004 CUGGAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCUUGU 7514
    1087 GACUUCCA G GCUGAGAG 7005 CUCUCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAAGUC 7515
    1088 ACUUCCAG G CUGAGAGG 5915 CCUCUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGAAGU 7516
    1091 UCCAGGCU G AGAGGCAG 7006 CUGCCUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUGGA 7517
    1093 CAGGCUGA G AGGCAGGC 7007 GCCUGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGCCUG 7518
    1095 GGCUGAGA G GCAGGCCC 7008 GGGCCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCAGCC 7519
    1096 GCUGAGAG G CAGGCCCG 5916 CGGGCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUCAGC 7520
    1099 GAGAGGCA G GCCCGGGA 7009 UCCCGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUCUC 7521
    1100 AGAGGCAG G CCCGGGAG 5917 CUCCCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCCUCU 7522
    1104 GCAGGCCC G GGAGAAGC 7010 GCUUCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCCUGC 7523
    1105 CAGGCCCG G GAGAAGCU 7011 AGCUUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGCCUG 7524
    1106 AGGCCCGG G AGAAGCUG 7012 CAGCUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGGCCU 7525
    1108 GCCCGGGA G AAGCUGGC 7013 GCCAGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCGGGC 7526
    1111 CGGGAGAA G CUGGCCGA 5918 UCGGCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUCCCG 7527
    1114 GAGAAGCU G GCCGAGAA 7014 UUCUCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUUCUC 7528
    1115 AGAAGCUG G CCGAGAAG 5919 CUUCUCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUUCU 7529
    1118 AGCUGGCC G AGAAGAAG 7015 CUUCUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCAGCU 7530
    1120 CUGGCCGA G AAGAAGGA 7016 UCCUUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGCCAG 7531
    1123 GCCGAGAA G AAGGAGCU 7017 AGCUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUCGGC 7532
    1126 GAGAAGAA G GAGCUCCU 7018 AGGAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUUCUC 7533
    1127 AGAAGAAG G AGCUCCUG 7019 CAGGAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUUCU 7534
    1129 AAGAAGGA G CUCCUGCA 5920 UGCAGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUUCUU 7535
    1135 GAGCUCCU G CAGGAGCA 5921 UGCUCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGCUC 7536
    1138 CUCCUGCA G GAGCAGCU 7020 AGCUGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGGAG 7537
    1139 UCCUGCAG G AGCAGCUG 7021 CAGCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCAGGA 7538
    1141 CUGCAGGA G CAGCUGGA 5922 UCCAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGCAG 7539
    1144 CAGGAGCA G CUGGAGCA 5923 UGCUCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCCUG 7540
    1147 GAGCAGCU G GAGCAGCU 7022 AGCUGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGCUC 7541
    1148 AGCAGCUG G AGCAGCUG 7023 CAGCUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUGCU 7542
    1150 CAGCUGGA G CAGCUGCA 5924 UGCAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGCUG 7543
    1153 CUGGAGCA G CUGCAGAG 5925 CUCUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCCAG 7544
    1156 GAGCAGCU G CAGAGGGA 5926 UCCCUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGCUC 7545
    1159 CAGCUGCA G AGGGAGUA 7024 UACUCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGCUG 7546
    1161 GCUGCAGA G GGAGUACA 7025 UGUACUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGCAGC 7547
    1162 CUGCAGAG G GAGUACAG 7026 CUGUACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUGCAG 7548
    1163 UGCAGAGG G AGUACAGC 7027 GCUGUACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCUGCA 7549
    1165 CAGAGGGA G UACAGCAA 5927 UUGCUGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCUCUG 7550
    1170 GGAGUACA G CAAACUGA 5928 UCAGUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUACUCC 7551
    1177 AGCAAACU G AAGGCCAG 7028 CUGGCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUUGCU 7552
    1180 AAACUGAA G GCCAGCUG 7029 CAGCUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGUUU 7553
    1181 AACUGAAG G CCAGCUGU 5929 ACAGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCAGUU 7554
    1185 GAAGGCCA G CUGUCAGG 5930 CCUGACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCUUC 7555
    1188 GGCCAGCU G UCAGGAGU 5931 ACUCCUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGGCC 7556
    1192 AGCUGUCA G GAGUCGGC 7030 GCCGACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACAGCU 7557
    1193 GCUGUCAG G AGUCGGCC 7031 GGCCGACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGACAGC 7558
    1195 UGUCAGGA G UCGGCCAG 5932 CUGGCCGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGACA 7559
    1198 CAGGAGUC G GCCAGGAU 7032 AUCCUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GACUCCUG 7560
    1199 AGGAGUCG G CCAGGAUC 5933 GAUCCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGACUCCU 7561
    1203 GUCGGCCA G GAUCGAGG 7033 CCUCGAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCGAC 7562
    1204 UCGGCCAG G AUCGAGGA 7034 UCCUCGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGCCGA 7563
    1208 CCAGGAUC G AGGACAUG 7035 CAUGUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUCCUGG 7564
    1210 AGGAUCGA G GACAUGAG 7036 CUCAUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGAUCCU 7565
    1211 GGAUCGAG G ACAUGAGG 7037 CCUCAUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGAUCC 7566
    1216 GAGGACAU G AGGAAGCG 7038 CGCUUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGUCCUC 7567
    1218 GGACAUGA G GAAGCGGC 7039 GCCGCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUGUCC 7568
    1219 GACAUGAG G AAGCGGCA 7040 UGCCGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCAUGUC 7569
    1222 AUGAGGAA G CGGCAUGU 5934 ACAUGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCUCAU 7570
    1224 GAGGAAGC G GCAUGUCG 7041 CGACAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUUCCUC 7571
    1225 AGGAAGCG G CAUGUCGA 5935 UCGACAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCUUCCU 7572
    1229 AGCGGCAU G UCGAGGUC 5936 GACCUCGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCCGCU 7573
    1232 GGCAUGUC G AGGUCUCC 7042 GGAGACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GACAUGCC 7574
    1234 CAUGUCGA G GUCUCCCA 7043 UGGGAGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGACAUG 7575
    1235 AUGUCGAG G UCUCCCAG 5937 CUGGGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGACAU 7576
    1243 GUCUCCCA G GCCCCCUU 7044 AAGGGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGAGAC 7577
    1244 UCUCCCAG G CCCCCUUG 5938 CAAGGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGAGA 7578
    1252 GCCCCCUU G CCCCCCGC 5939 GCGGGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGGGGC 7579
    1259 UGCCCCCC G CCCCUGCC 5940 GGCAGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGGGGCA 7580
    1265 CCGCCCCU G CCUACCUC 5941 GAGGUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGCGG 7581
    1285 UCUCCCCU G GCCCUGCC 7045 GGCAGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGAGA 7582
    1286 CUCCCCUG G CCCUGCCC 5942 GGGCAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGGAG 7583
    1291 CUGGCCCU G CCCAGCCA 5943 UGGCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGCCAG 7584
    1296 CCUGCCCA G CCAGAGGA 5944 UCCUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCAGG 7585
    1300 CCCAGCCA G AGGAGGAG 7046 CUCCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUGGG 7586
    1302 CAGCCAGA G GAGGAGCC 7047 GGCUCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGCUG 7587
    1303 AGCCAGAG G AGGAGCCC 7048 GGGCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUGGCU 7588
    1305 CCAGAGGA G GAGCCCCC 7049 GGGGGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCUGG 7589
    1306 CAGAGGAG G AGCCCCCC 7050 GGGGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUCUG 7590
    1308 GAGGAGGA G CCCCCCCG 5945 CGGGGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCCUC 7591
    1316 GCCCCCCC G AGGAGCCA 7051 UGGCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGGGGGC 7592
    1318 CCCCCCGA G GAGCCACC 7052 GGUGGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGGGGG 7593
    1319 CCCCCGAG G AGCCACCU 7053 AGGUGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGGGGG 7594
    1321 CCCGAGGA G CCACCUGA 5946 UCAGGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCGGG 7595
    1328 AGCCACCU G ACUUCUGC 7054 GCAGAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUGGCU 7596
    1335 UGACUUCU G CUGUCCCA 5947 UGGGACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGUCA 7597
    1338 CUUCUGCU G UCCCAAGU 5948 ACUUGGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAGAAG 7598
    1345 UGUCCCAA G UGCCAGUA 5949 UACUGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGGACA 7599
    1347 UCCCAAGU G CCAGUAUC 5950 GAUACUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUGGGA 7600
    1351 AAGUGCCA G UAUCAGGC 5951 GCCUGAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCACUU 7601
    1357 CAGUAUCA G GCCCCUGA 7055 UCAGGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUACUG 7602
    1358 AGUAUCAG G CCCCUGAU 5952 AUCAGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAUACU 7603
    1364 AGGCCCCU G AUAUGGAC 7056 GUCCAUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGCCU 7604
    1369 CCUGAUAU G GACACCCU 7057 AGGGUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAUCAGG 7605
    1370 CUGAUAUG G ACACCCUG 7058 CAGGGUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUAUCAG 7606
    1378 GACACCCU G CAGAUACA 5953 UGUAUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGUGUC 7607
    1381 ACCCUGCA G AUACAUGU 7059 ACAUGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGGGU 7608
    1388 AGAUACAU G UCAUGGAG 5954 CUCCAUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGUAUCU 7609
    1393 CAUGUCAU G GAGUGCAU 7060 AUGCACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGACAUG 7610
    1394 AUGUCAUG G AGUGCAUU 7061 AAUGCACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGACAU 7611
    1396 GUCAUGGA G UGCAUUGA 5955 UCAAUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAUGAC 7612
    1398 CAUGGAGU G CAUUGAGU 5956 ACUCAAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUCCAUG 7613
    1403 AGUGCAUU G AGUAGGGC 7062 GCCCUACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUGCACU 7614
    1405 UGCAUUGA G UAGGGCCG 5957 CGGCCCUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAAUGCA 7615
    1408 AUUGAGUA G GGCCGGCC 7063 GGCCGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACUCAAU 7616
    1409 UUGAGUAG G GCCGGCCA 7064 UGGCCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUACUCAA 7617
    1410 UGAGUAGG G CCGGCCAG 5958 CUGGCCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUACUCA 7618
    1413 GUAGGGCC G GCCAGUGC 7065 GCACUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCCUAC 7619
    1414 UAGGGCCG G CCAGUGCA 5959 UGCACUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGCCCUA 7620
    1418 GCCGGCCA G UGCAAGGC 5960 GCCUUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCGGC 7621
    1420 CGGCCAGU G CAAGGCCA 5961 UGGCCUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGGCCG 7622
    1424 CAGUGCAA G GCCACUGC 7066 GCAGUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGCACUG 7623
    1425 AGUGCAAG G CCACUGCC 5962 GGCAGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGCACU 7624
    1431 AGGCCACU G CCUGCCCG 5963 CGGGCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGGCCU 7625
    1435 CACUGCCU G CCCGAGGA 5964 UCCUCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCAGUG 7626
    1439 GCCUGCCC G AGGACGUG 7067 CACGUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCAGGC 7627
    1441 CUGCCCGA G GACGUGCC 7068 GGCACGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGGCAG 7628
    1442 UGCCCGAG G ACGUGCCC 7069 GGGCACGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGGGCA 7629
    1445 CCGAGGAC G UGCCCGGG 5965 CCCGGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCCUCGG 7630
    1447 GAGGACGU G CCCGGGAC 5966 GUCCCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGUCCUC 7631
    1451 ACGUGCCC G GGACCGUG 7070 CACGGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCACGU 7632
    1452 CGUGCCCG G GACCGUGC 7071 GCACGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGCACG 7633
    1453 GUGCCCGG G ACCGUGCA 7072 UGCACGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGGCAC 7634
    1457 CCGGGACC G UGCAGUCU 5967 AGACUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUCCCGG 7635
    1459 GGGACCGU G CAGUCUGC 5968 GCAGACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGGUCCC 7636
    1462 ACCGUGCA G UCUGCGCU 5969 AGCGCAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCACGGU 7637
    1466 UGCAGUCU G CGCUUUCC 5970 GGAAAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGACUGCA 7638
    1468 CAGUCUGC G CUUUCCUC 5971 GAGGAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGACUG 7639
    1481 CCUCUCCC G CCUGCCUA 5972 UAGGCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGAGAGG 7640
    1485 UCCCGCCU G CCUAGCCC 5973 GGGCUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCGGGA 7641
    1490 CCUGCCUA G CCCAGGAU 5974 AUCCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAGGCAGG 7642
    1495 CUAGCCCA G GAUGAAGG 7073 CCUUCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCUAG 7643
    1496 UAGCCCAG G AUGAAGGG 7074 CCCUUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGCUA 7644
    1499 CCCAGGAU G AAGGGCUG 7075 CAGCCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCUGGG 7645
    1502 AGGAUGAA G GGCUGGGU 7076 ACCCAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAUCCU 7646
    1503 GGAUGAAG G GCUGGGUG 7077 CACCCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCAUCC 7647
    1504 GAUGAAGG G CUGGGUGG 5975 CCACCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUUCAUC 7648
    1507 GAAGGGCU G GGUGGCCA 7078 UGGCCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCCUUC 7649
    1508 AAGGGCUG G GUGGCCAC 7079 GUGGCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCCUU 7650
    1509 AGGGCUGG G UGGCCACA 5976 UGUGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGCCCU 7651
    1511 GGCUGGGU G GCCACAAC 7080 GUUGUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCAGCC 7652
    1512 GCUGGGUG G CCACAACU 5977 AGUUGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCCAGC 7653
    1521 CCACAACU G GGAUGCCA 7081 UGGCAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUGUGG 7654
    1522 CACAACUG G GAUGCCAC 7082 GUGGCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUUGUG 7655
    1523 ACAACUGG G AUGCCACC 7083 GGUGGCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGUUGU 7656
    1526 ACUGGGAU G CCACCUGG 5978 CCAGGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCCAGU 7657
    1533 UGCCACCU G GAGCCCCA 7084 UGGGGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUGGCA 7658
    1534 GCCACCUG G AGCCCCAC 7085 GUGGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGUGGC 7659
    1536 CACCUGGA G CCCCACCC 5979 GGGUGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGGUG 7660
    1546 CCCACCCA G GAGCUGGC 7086 GCCAGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGUGGG 7661
    1547 CCACCCAG G AGCUGGCC 7087 GGCCAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGUGG 7662
    1549 ACCCAGGA G CUGGCCGC 5980 GCGGCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGGGU 7663
    1552 CAGGAGCU 0 GCCGCGGC 7088 GCCGCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUCCUG 7664
    1553 AGGAGCUG G CCGCGGCA 5981 UGCCGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUCCU 7665
    1556 AGCUGGCC G CGGCACCU 5982 AGGUGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCAGCU 7666
    1558 CUGGCCGC G GCACCUUA 7089 UAAGGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGCCAG 7667
    1559 UGGCCGCG G CACCUUAC 5983 GUAAGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCGGCCA 7668
    1568 CACCUUAC G CUUCAGCU 5984 AGCUGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAAGGUG 7669
    1574 ACGCUUCA G CUGUUGAU 5985 AUCAACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAGCGU 7670
    1577 CUUCAGCU G UUGAUCCG 5986 CGGAUCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGAAG 7671
    1580 CAGCUGUU G AUCCGCUG 7090 CAGCGGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACAGCUG 7672
    1585 GUUGAUCC G CUGGUCCC 5987 GGGACCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAUCAAC 7673
    1588 GAUCCGCU G GUCCCCUC 7091 GAGGGGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGGAUC 7674
    1589 AUCCGCUG G UCCCCUCU 5988 AGAGGGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCGGAU 7675
    1601 CCUCUUUU G GGGUAGAU 7092 AUCUACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAGAGG 7676
    1602 CUCUUUUG G GGUAGAUG 7093 CAUCUACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAAGAG 7677
    1603 UCUUUUGG G GUAGAUGC 7094 GCAUCUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAAAAGA 7678
    1604 CUUUUGGG G UAGAUGCG 5989 CGCAUCUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAAAAG 7679
    1607 UUGGGGUA G AUGCGGCC 7095 GGCCGCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACCCCAA 7680
    1610 GGGUAGAU G CGGCCCCG 5990 CGGGGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUACCC 7681
    1612 GUAGAUGC G GCCCCGAU 7096 AUCGGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAUCUAC 7682
    1613 UAGAUGCG G CCCCGAUC 5991 GAUCGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCAUCUA 7683
    1618 GCGGCCCC G AUCAGGCC 7097 GGCCUGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGGCCGC 7684
    1623 CCCGAUCA G GCCUGACU 7098 AGUCAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUCGGG 7685
    1624 CCGAUCAG G CCUGACUC 5992 GAGUCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAUCGG 7686
    1628 UCAGGCCU G ACUCGCUG 7099 CAGCGAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCCUGA 7687
    1633 CCUGACUC G CUGCUCUU 5993 AAGAGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGUCAGG 7688
    1636 GACUCGCU G CUCUUUUU 5994 AAAAAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGAGUC 7689
    1645 CUCUUUUU G UUCCCUUC 5995 GAAGGGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAAGAG 7690
    1655 UCCCUUCU G UCUGCUCG 5996 CGAGCAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGGGA 7691
    1659 UUCUGUCU G CUCGAACC 5997 GGUUCGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGACAGAA 7692
    1663 GUCUGCUC G AACCACUU 7100 AAGUGGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGCAGAC 7693
    1672 AACCACUU G CCUCGGGC 5998 GCCCGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGUGGUU 7694
    1677 CUUGCCUC G GGCUAAUC 7101 GAUUAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGGCAAG 7695
    1678 UUGCCUCG G GCUAAUCC 7102 GGAUUAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGGCAA 7696
    1679 UGCCUCGG G CUAAUCCC 5999 GGGAUUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGAGGCA 7697
    1705 CUCCACCC G GCACUGGG 7103 CCCAGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGUGGAG 7698
    1706 UCCACCCG G CACUGGGG 6000 CCCCAGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGUGGA 7699
    1711 CCGGCACU G GGGAAGUC 7104 GACUUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGCCGG 7700
    1712 CGGCACUG G GGAAGUCA 7105 UGACUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUGCCG 7701
    1713 GGCACUGG G GAAGUCAA 7106 UUGACUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGUGCC 7702
    1714 GCACUGGG G AAGUCAAG 7107 CUUGACUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGUGC 7703
    1717 CUGGGGAA G UCAAGAAU 6001 AUUCUUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCCAG 7704
    1722 GAAGUCAA G AAUGGGGC 7108 GCCCCAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGACUUC 7705
    1726 UCAAGAAU G GGGCCUGG 7109 CCAGGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUCUUGA 7706
    1727 CAAGAAUG G GGCCUGGG 7110 CCCAGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUCUUG 7707
    1728 AAGAAUGG G GCCUGGGG 7111 CCCCAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAUUCUU 7708
    1729 AGAAUGGG G CCUGGGGC 6002 GCCCCAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAUUCU 7709
    1733 UGGGGCCU G GGGCUCUC 7112 GAGAGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGCCCCA 7710
    1734 GGGGCCUG G GGCUCUCA 7113 UGAGAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGCCCC 7711
    1735 GGGCCUGG G GCUCUCAG 7114 CUGAGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGGCCC 7712
    1736 GGCCUGGG G CUCUCAGG 6003 CCUGAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGGCC 7713
    1743 GGCUCUCA G GGAGAACU 7115 AGUUCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGAGCC 7714
    1744 GCUCUCAG G GAGAACUG 7116 CAGUUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAGAGC 7715
    1745 CUCUCAGG G AGAACUGC 7117 GCAGUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGAGAG 7716
    1747 CUCAGGGA G AACUGCUU 7118 AAGCAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCUGAG 7717
    1752 GGAGAACU G CUUCCCCU 6004 AGGGGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUCUCC 7718
    1761 CUUCCCCU G GCAGAGCU 7119 AGCUCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGGAAG 7719
    1762 UUCCCCUG G CAGAGCUG 6005 CAGCUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGGAA 7720
    1765 CCCUGGCA G AGCUGGGU 7120 ACCCAGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCAGGG 7721
    1767 CUGGCAGA G CUGGGUGG 6006 CCACCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGCCAG 7722
    1770 GCAGAGCU G GGUGGCAG 7121 CUGCCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUCUGC 7723
    1771 CAGAGCUG G GUGGCAGC 7122 GCUGCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCUCUG 7724
    1772 AGAGCUGG G UGGCAGCU 6007 AGCUGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGCUCU 7725
    1774 AGCUGGGU G GCAGCUCU 7123 AGAGCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCAGCU 7726
    1775 GCUGGGUG G CAGCUCUU 6008 AAGAGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCCAGC 7727
    1778 GGGUGGCA G CUCUUCCU 6009 AGGAAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCACCC 7728
    1793 CUCCCACC G GACACCGA 7124 UCGGUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUGGGAG 7729
    1794 UCCCACCG G ACACCGAC 7125 GUCGGUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGUGGGA 7730
    1800 CGGACACC G ACCCGCCC 7126 GGGCGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUGUCCG 7731
    1805 ACCGACCC G CCCGCCGC 6010 GCGGCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGUCGGU 7732
    1809 ACCCGCCC G CCGCUGUG 6011 CACAGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCGGGU 7733
    1812 CGCCCGCC G CUGUGCCC 6012 GGGCACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCGGGCG 7734
    1815 CCGCCGCU G UGCCCUGG 6013 CCAGGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGGCGG 7735
    1817 GCCGCUGU G CCCUGGGA 6014 UCCCAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGCGGC 7736
    1822 UGUGCCCU G GGAGUGCU 7127 AGCACUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGCACA 7737
    1823 GUGCCCUG G GAGUGCUG 7128 CAGCACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGCAC 7738
    1824 UGCCCUGG G AGUGCUGC 7129 GCAGCACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGGGCA 7739
    1826 CCCUGGGA G UGCUGCCC 6015 GGGCAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCAGGG 7740
    1828 CUGGGAGU G CUGCCCUC 6016 GAGGGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUCCCAG 7741
    1831 GGAGUGCU G CCCUCUUA 6017 UAAGAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCACUCC 7742
    1844 CUUACCAU G CACACGGG 6018 CCCGUGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGUAAG 7743
    1850 AUGCACAC G GGUGCUCU 7130 AGAGCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGUGCAU 7744
    1851 UGCACACG G GUGCUCUC 7131 GAGAGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUGUGCA 7745
    1852 GCACACGG G UGCUCUCC 6019 GGAGAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGUGUGC 7746
    1854 ACACGGGU G CUCUCCUU 6020 AAGGAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCGUGU 7747
    1865 CUCCUUUU G GGCUGCAU 7132 AUGCAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAGGAG 7748
    1866 UCCUUUUG G GCUGCAUG 7133 CAUGCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGCG CAAAAGGA 7749
    1867 CCUUUUGG G CUGCAUGC 6021 GCAUGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAAAAGG 7750
    1870 UUUGGGCU G CAUGCUAU 6022 AUAGCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCCAAA 7751
    1874 GGCUGCAU G CUAUUCCA 6023 UGGAAUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCAGCC 7752
    1887 UCCAUUUU G CAGCCAGA 6024 UCUGGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAUGGA 7753
    1890 AUUUUGCA G CCAGACCG 6025 CGGUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAAAAU 7754
    1894 UGCAGCCA G ACCGAUGU 7134 ACAUCGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUGCA 7755
    1898 GCCAGACC G AUGUGUAU 7135 AUACACAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUCUGGC 7756
    1901 AGACCGAU G UGUAUUUA 6026 UAAAUACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCGGUCU 7757
    1903 ACCGAUGU G UAUUUAAC 6027 GUUAAAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAUCGGU 7758
    1914 UUUAACCA G UCACUAUU 6028 AAUAGUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUUAAA 7759
    1923 UCACUAUU G AUGGACAU 7136 AUGUCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUAGUGA 7760
    1926 CUAUUGAU G GACAUUUG 7137 CAAAUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAAUAG 7761
    1927 UAUUGAUG G ACAUUUGG 7138 CCAAAUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCAAUA 7762
    1934 GGACAUUU G GGUUGUUU 7139 AAACAACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAUGUCC 7763
    1935 GACAUUUG G GUUGUUUC 7140 GAAACAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAUGUC 7764
    1936 ACAUUUGG G UUGUUUCC 6029 GGAAACAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAAAUGU 7765
    1939 UUUGGGUU G UUUCCCAU 6030 AUGGGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACCCAAA 7766
    1954 AUCUUUUU G UUACCAUA 6031 UAUGGUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAAGAU 7767
    1969 UAAAUAAU G GCAUAGUA 7141 UACUAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUAUUUA 7768
    1970 AAAUAAUG G CAUAGUAA 6032 UUACUAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUAUUU 7769
    1975 AUGGCAUA G UAAAAAAA 6033 UUUUUUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUGCCAU 7770

    Input Sequence = NM_003639. Cut Site = G/.

    Arm Length = 8. Core Sequence GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG

    NM_003639 (Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase (IKBKG), mRNA.; 1994 bp)
  • TABLE VIII
    Human PKR Hammerhead and Substrate Sequence
    Seq Seq
    Pos Substrate ID Hammerhead ID
    20 GGCGCAGU U UGCUCAUA 1 UAUGAGCA CUGAUGAGGCCGUUAGGCCGAA ACUGCGCC 632
    21 GCGCAGUU U GCUCAUAC 2 GUAUGAGC CUGAUGAGGCCGUUAGGCCGAA AACUGCGC 633
    25 AGUUUGCU C AUACUUUG 3 CAAAGUAU CUGAUGAGGCCGUUAGGCCGAA AGCAAACU 634
    28 UUGCUCAU A CUUUGUGA 4 UCACAAAG CUGAUGAGGCCGUUAGGCCGAA AUGAGCAA 635
    31 CUCAUACU U UGUGACUU 5 AAGUCACA CUGAUGAGGCCGUUAGGCCGAA AGUAUGAG 636
    32 UCAUACUU U GUGACUUG 6 CAAGUCAC CUGAUGAGGCCGUUAGGCCGAA AAGUAUGA 637
    39 UUGUGACU U GCGGUCAC 7 GUGACCGC CUGAUGAGGCCGUUAGGCCGAA AGUCACAA 638
    45 CUUGCGGU C ACAGUGGC 8 GCCACUGU CUGAUGAGGCCGUUAGGCCGAA ACCGCAAG 639
    56 AGUGGCAU U CAGCUCCA 9 UGGAGCUG CUGAUGAGGCCGUUAGGCCGAA AUGCCACU 640
    57 GUGGCAUU C AGCUCCAC 10 GUGGAGCU CUGAUGAGGCCGUUAGGCCGAA AAUGCCAC 641
    62 AUUCAGCU C CACACUUG 11 CAAGUGUG CUGAUGAGGCCGUUAGGCCGAA AGCUGAAU 642
    69 UCCACACU U GGUAGAAC 12 GUUCUACC CUGAUGAGGCCGUUAGGCCGAA AGUGUGGA 643
    73 CACUUGGU A GAACCACA 13 UGUGGUUC CUGAUGAGGCCGUUAGGCCGAA ACCAAGUG 644
    96 ACAAGCAU A GAAACAUC 14 GAUGUUUC CUGAUGAGGCCGUUAGGCCGAA AUGCUUGU 645
    104 AGAAACAU C CUAAACAA 15 UUGUUUAG CUGAUGAGGCCGUUAGGCCGAA AUGUUUCU 646
    107 AACAUCCU A AACAAUCU 16 AGAUUGUU CUGAUGAGGCCGUUAGGCCGAA AGGAUGUU 647
    114 UAAACAAU C UUCAUCGA 17 UCGAUGAA CUGAUGAGGCCGUUAGGCCGAA AUUGUUUA 648
    116 AACAAUCU U CAUCGAGG 18 CCUCGAUG CUGAUGAGGCCGUUAGGCCGAA AGAUUGUU 649
    117 ACAAUCUU C AUCGAGGC 19 GCCUCGAU CUGAUGAGGCCGUUAGGCCGAA AAGAUUGU 650
    120 AUCUUCAU C GAGGCAUC 20 GAUGCCUC CUGAUGAGGCCGUUAGGCCGAA AUGAAGAU 651
    128 CGAGGCAU C GAGGUCCA 21 UGGACCUC CUGAUGAGGCCGUUAGGCCGAA AUGCCUCG 652
    134 AUCGAGGU C CAUCCCAA 22 UUGGGAUG CUGAUGAGGCCGUUAGGCCGAA ACCUCGAU 653
    138 AGGUCCAU C CCAAUAAA 23 UUUAUUGG CUGAUGAGGCCGUUAGGCCGAA AUGGACCU 654
    144 AUCCCAAU A AAAAUCAG 24 CUGAUUUU CUGAUGAGGCCGUUAGGCCGAA AUUGGGAU 655
    150 AUAAAAAU C AGGAGACC 25 GGUCUCCU CUGAUGAGGCCGUUAGGCCGAA AUUUUUAU 656
    165 CCCUGGCU A UCAUAGAC 26 GUCUAUGA CUGAUGAGGCCGUUAGGCCGAA AGCCAGGG 657
    167 CUGGCUAU C AUAGACCU 27 AGGUCUAU CUGAUGAGGCCGUUAGGCCGAA AUAGCCAG 658
    170 GCUAUCAU A GACCUUAG 28 CUAAGGUC CUGAUGAGGCCGUUAGGCCGAA AUGAUAGC 659
    176 AUAGACCU U AGUCUUCG 29 CGAAGACU CUGAUGAGGCCGUUAGGCCGAA AGGUCUAU 660
    177 UAGACCUU A GUCUUCGC 30 GCGAAGAC CUGAUGAGGCCGUUAGGCCGAA AAGGUCUA 661
    180 ACCUUAGU C UUCGCUGG 31 CCAGCGAA CUGAUGAGGCCGUUAGGCCGAA ACUAAGGU 662
    182 CUUAGUCU U CGCUGGUA 32 UACCAGCG CUGAUGAGGCCGUUAGGCCGAA AGACUAAG 663
    183 UUAGUCUU C GCUGGUAU 33 AUACCAGC CUGAUGAGGCCGUUAGGCCGAA AAGACUAA 664
    190 UCGCUGGU A UACUCGCU 34 AGCGAGUA CUGAUGAGGCCGUUAGGCCGAA ACCAGCGA 665
    192 GCUGGUAU A CUCGCUGU 35 ACAGCGAG CUGAUGAGGCCGUUAGGCCGAA AUACCAGC 666
    195 GGUAUACU C GCUGUCUG 36 CAGACAGC CUGAUGAGGCCGUUAGGCCGAA AGUAUACC 667
    201 CUCGCUGU C UGUCAACC 37 GGUUGACA CUGAUGAGGCCGUUAGGCCGAA ACAGCGAG 668
    205 CUGUCUGU C AACCAGCG 38 CGCUGGUU CUGAUGAGGCCGUUAGGCCGAA ACAGACAG 669
    216 CCAGCGGU U GACUUUUU 39 AAAAAGUC CUGAUGAGGCCGUUAGGCCGAA ACCGCUGG 670
    221 GGUUGACU U UUUUUAAG 40 CUUAAAAA CUGAUGAGGCCGUUAGGCCGAA AGUCAACC 671
    222 GUUGACUU U UUUUAAGC 41 GCUUAAAA CUGAUGAGGCCGUUAGGCCGAA AAGUCAAC 672
    223 UUGACUUU U UUUAAGCC 42 GGCUUAAA CUGAUGAGGCCGUUAGGCCGAA AAAGUCAA 673
    224 UGACUUUU U UUAAGCCU 43 AGGCUUAA CUGAUGAGGCCGUUAGGCCGAA AAAAGUCA 674
    225 GACUUUUU U UAAGCCUU 44 AAGGCUUA CUGAUGAGGCCGUUAGGCCGAA AAAAAGUC 675
    226 ACUUUUUU U AAGCCUUC 45 GAAGGCUU CUGAUGAGGCCGUUAGGCCGAA AAAAAAGU 676
    227 CUUUUUUU A AGCCUUCU 46 AGAAGGCU CUGAUGAGGCCGUUAGGCCGAA AAAAAAAG 677
    233 UUAAGCCU U CUUUUUUC 47 GAAAAAAG CUGAUGAGGCCGUUAGGCCGAA AGGCUUAA 678
    234 UAAGCCUU C UUUUUUCU 48 AGAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAGGCUUA 679
    236 AGCCUUCU U UUUUCUCU 49 AGAGAAAA CUGAUGAGGCCGUUAGGCCGAA AGAAGGCU 680
    237 GCCUUCUU U UUUCUCUU 50 AAGAGAAA CUGAUGAGGCCGUUAGGCCGAA AAGAAGGC 681
    238 CCUUCUUU U UUCUCUUU 51 AAAGAGAA CUGAUGAGGCCGUUAGGCCGAA AAAGAAGG 682
    239 CUUCUUUU U UCUCUUUU 52 AAAAGAGA CUGAUGAGGCCGUUAGGCCGAA AAAAGAAG 683
    240 UUCUUUUU U CUCUUUUA 53 UAAAAGAG CUGAUGAGGCCGUUAGGCCGAA AAAAAGAA 684
    241 UCUUUUUU C UCUUUUAC 54 GUAAAAGA CUGAUGAGGCCGUUAGGCCGAA AAAAAAGA 685
    243 UUUUUUCU C UUUUACCA 55 UGGUAAAA CUGAUGAGGCCGUUAGGCCGAA AGAAAAAA 686
    245 UUUUCUCU U UUACCAGU 56 ACUGGUAA CUGAUGAGGCCGUUAGGCCGAA AGAGAAAA 687
    246 UUUCUCUU U UACCAGUU 57 AACUGGUA CUGAUGAGGCCGUUAGGCCGAA AAGAGAAA 688
    247 UUCUCUUU U ACCAGUUU 58 AAACUGGU CUGAUGAGGCCGUUAGGCCGAA AAAGAGAA 689
    248 UCUCUUUU A CCAGUUUC 59 GAAACUGG CUGAUGAGGCCGUUAGGCCGAA AAAAGAGA 690
    254 UUACCAGU U UCUGGAGC 60 GCUCCAGA CUGAUGAGGCCGUUAGGCCGAA ACUGGUAA 691
    255 UACCAGUU U CUGGAGCA 61 UGCUCCAG CUGAUGAGGCCGUUAGGCCGAA AACUGGUA 692
    256 ACCAGUUU C UGGAGCAA 62 UUGCUCCA CUGAUGAGGCCGUUAGGCCGAA AAACUGGU 693
    267 GAGCAAAU U CAGUUUGC 63 GCAAACUG CUGAUGAGGCCGUUAGGCCGAA AUUUGCUC 694
    268 AGCAAAUU C AGUUUGCC 64 GGCAAACU CUGAUGAGGCCGUUAGGCCGAA AAUUUGCU 695
    272 AAUUCAGU U UGCCUUCC 65 GGAAGGCA CUGAUGAGGCCGUUAGGCCGAA ACUGAAUU 696
    273 AUUCAGUU U GCCUUCCU 66 AGGAAGGC CUGAUGAGGCCGUUAGGCCGAA AACUGAAU 697
    278 GUUUGCCU U CCUGGAUU 67 AAUCCAGG CUGAUGAGGCCGUUAGGCCGAA AGGCAAAC 698
    279 UUUGCCUU C CUGGAUUU 68 AAAUCCAG CUGAUGAGGCCGUUAGGCCGAA AAGGCAAA 699
    286 UCCUGGAU U UGUAAAUU 69 AAUUUACA CUGAUGAGGCCGUUAGGCCGAA AUCCAGGA 700
    287 CCUGGAUU U GUAAAUUG 70 CAAUUUAC CUGAUGAGGCCGUUAGGCCGAA AAUCCAGG 701
    290 GGAUUUGU A AAUUGUAA 71 UUACAAUU CUGAUGAGGCCGUUAGGCCGAA ACAAAUCC 702
    294 UUGUAAAU U GUAAUGAC 72 GUCAUUAC CUGAUGAGGCCGUUAGGCCGAA AUUUACAA 703
    297 UAAAUUGU A AUGACCUC 73 GAGGUCAU CUGAUGAGGCCGUUAGGCCGAA ACAAUUUA 704
    305 AAUGACCU C AAAACUUU 74 AAAGUUUU CUGAUGAGGCCGUUAGGCCGAA AGGUCAUU 705
    312 UCAAAACU U UAGCAGUU 75 AACUGCUA CUGAUGAGGCCGUUAGGCCGAA AGUUUUGA 706
    313 CAAAACUU U AGCAGUUC 76 GAACUGCU CUGAUGAGGCCGUUAGGCCGAA AAGUUUUG 707
    314 AAAACUUU A GCAGUUCU 77 AGAACUGC CUGAUGAGGCCGUUAGGCCGAA AAAGUUUU 708
    320 UUAGCAGU U CUUCCAUC 78 GAUGGAAG CUGAUGAGGCCGUUAGGCCGAA ACUGCUAA 709
    321 UAGCAGUU C UUCCAUCU 79 AGAUGGAA CUGAUGAGGCCGUUAGGCCGAA AACUGCUA 710
    323 GCAGUUCU U CCAUCUGA 80 UCAGAUGG CUGAUGAGGCCGUUAGGCCGAA AGAACUGC 711
    324 CAGUUCUU C CAUCUGAC 81 GUCAGAUG CUGAUGAGGCCGUUAGGCCGAA AAGAACUG 712
    328 UCUUCCAU C UGACUCAG 82 CUGAGUCA CUGAUGAGGCCGUUAGGCCGAA AUGGAAGA 713
    334 AUCUGACU C AGGUUUGC 83 GCAAACCU CUGAUGAGGCCGUUAGGCCGAA AGUCAGAU 714
    339 ACUCAGGU U UGCUUCUC 84 GAGAAGCA CUGAUGAGGCCGUUAGGCCGAA ACCUGAGU 715
    340 CUCAGGUU U GCUUCUCU 85 AGAGAAGC CUGAUGAGGCCGUUAGGCCGAA AACCUGAG 716
    344 GGUUUGCU U CUCUGGCG 86 CGCCAGAG CUGAUGAGGCCGUUAGGCCGAA AGCAAACC 717
    345 GUUUGCUU C UCUGGCGG 87 CCGCCAGA CUGAUGAGGCCGUUAGGCCGAA AAGCAAAC 718
    347 UUGCUUCU C UGGCGGUC 88 GACCGCCA CUGAUGAGGCCGUUAGGCCGAA AGAAGCAA 719
    355 CUGGCGGU C UUCAGAAU 89 AUUCUGAA CUGAUGAGGCCGUUAGGCCGAA ACCGCCAG 720
    357 GGCGGUCU U CAGAAUCA 90 UGAUUCUG CUGAUGAGGCCGUUAGGCCGAA AGACCGCC 721
    358 GCGGUCUU C AGAAUCAA 91 UUGAUUCU CUGAUGAGGCCGUUAGGCCGAA AAGACCGC 722
    364 UUCAGAAU C AACAUCCA 92 UGGAUGUU CUGAUGAGGCCGUUAGGCCGAA AUUCUGAA 723
    370 AUCAACAU C CACACUUC 93 GAAGUGUG CUGAUGAGGCCGUUAGGCCGAA AUGUUGAU 724
    377 UCCACACU U CCGUGAUU 94 AAUCACGG CUGAUGAGGCCGUUAGGCCGAA AGUGUGGA 725
    378 CCACACUU C CGUGAUUA 95 UAAUCACG CUGAUGAGGCCGUUAGGCCGAA AAGUGUGG 726
    385 UCCGUGAU U AUCUGCGU 96 ACGCAGAU CUGAUGAGGCCGUUAGGCCGAA AUCACGGA 727
    386 CCGUGAUU A UCUGCGUG 97 CACGCAGA CUGAUGAGGCCGUUAGGCCGAA AAUCACGG 728
    388 GUGAUUAU C UGCGUGCA 98 UGCACGCA CUGAUGAGGCCGUUAGGCCGAA AUAAUCAC 729
    398 GCGUGCAU U UUGGACAA 99 UUGUCCAA CUGAUGAGGCCGUUAGGCCGAA AUGCACGC 730
    399 CGUGCAUU U UGGACAAA 100 UUUGUCCA CUGAUGAGGCCGUUAGGCCGAA AAUGCACG 731
    400 GUGCAUUU U GGACAAAG 101 CUUUGUCC CUGAUGAGGCCGUUAGGCCGAA AAAUGCAC 732
    411 ACAAAGCU U CCAACCAG 102 CUGGUUGG CUGAUGAGGCCGUUAGGCCGAA AGCUUUGU 733
    412 CAAAGCUU C CAACCAGG 103 CCUGGUUG CUGAUGAGGCCGUUAGGCCGAA AAGCUUUG 734
    423 ACCAGGAU A CGGGAAGA 104 UCUUCCCG CUGAUGAGGCCGUUAGGCCGAA AUCCUGGU 735
    448 CUGGUGAU C UUUCAGCA 105 UGCUGAAA CUGAUGAGGCCGUUAGGCCGAA AUCACCAG 736
    450 GGUGAUCU U UCAGCAGG 106 CCUGCUGA CUGAUGAGGCCGUUAGGCCGAA AGAUCACC 737
    451 GUGAUCUU U CAGCAGGU 107 ACCUGCUG CUGAUGAGGCCGUUAGGCCGAA AAGAUCAC 738
    452 UGAUCUUU C AGCAGGUU 108 AACCUGCU CUGAUGAGGCCGUUAGGCCGAA AAAGAUCA 739
    460 CAGCAGGU U UCUUCAUG 109 CAUGAAGA CUGAUGAGGCCGUUAGGCCGAA ACCUGCUG 740
    461 AGCAGGUU U CUUCAUGG 110 CCAUGAAG CUGAUGAGGCCGUUAGGCCGAA AACCUGCU 741
    462 GCAGGUUU C UUCAUGGA 111 UCCAUGAA CUGAUGAGGCCGUUAGGCCGAA AAACCUGC 742
    464 AGGUUUCU U CAUGGAGG 112 CCUCCAUG CUGAUGAGGCCGUUAGGCCGAA AGAAACCU 743
    465 GGUUUCUU C AUGGAGGA 113 UCCUCCAU CUGAUGAGGCCGUUAGGCCGAA AAGAAACC 744
    477 GAGGAACU U AAUACAUA 114 UAUGUAUU CUGAUGAGGCCGUUAGGCCGAA AGUUCCUC 745
    478 AGGAACUU A AUACAUAC 115 GUAUGUAU CUGAUGAGGCCGUUAGGCCGAA AAGUUCCU 746
    481 AACUUAAU A CAUACCGU 116 ACGGUAUG CUGAUGAGGCCGUUAGGCCGAA AUUAAGUU 747
    485 UAAUACAU A CCGUCAGA 117 UCUGACGG CUGAUGAGGCCGUUAGGCCGAA AUGUAUUA 748
    490 CAUACCGU C AGAAGCAG 118 CUGCUUCU CUGAUGAGGCCGUUAGGCCGAA ACGGUAUG 749
    504 CAGGGAGU A GUACUUAA 119 UUAAGUAC CUGAUGAGGCCGUUAGGCCGAA ACUCCCUG 750
    507 GGAGUAGU A CUUAAAUA 120 UAUUUAAG CUGAUGAGGCCGUUAGGCCGAA ACUACUCC 751
    510 GUAGUACU U AAAUAUCA 121 UGAUAUUU CUGAUGAGGCCGUUAGGCCGAA AGUACUAC 752
    511 UAGUACUU A AAUAUCAA 122 UUGAUAUU CUGAUGAGGCCGUUAGGCCGAA AAGUACUA 753
    515 ACUUAAAU A UCAAGAAC 123 GUUCUUGA CUGAUGAGGCCGUUAGGCCGAA AUUUAAGU 754
    517 UUAAAUAU C AAGAACUG 124 CAGUUCUU CUGAUGAGGCCGUUAGGCCGAA AUAUUUAA 755
    529 AACUGCCU A AUUCAGGA 125 UCCUGAAU CUGAUGAGGCCGUUAGGCCGAA AGGCAGUU 756
    532 UGCCUAAU U CAGGACCU 126 AGGUCCUG CUGAUGAGGCCGUUAGGCCGAA AUUAGGCA 757
    533 GCCUAAUU C AGGACCUC 127 GAGGUCCU CUGAUGAGGCCGUUAGGCCGAA AAUUAGGC 758
    541 CAGGACCU C CACAUGAU 128 AUCAUGUG CUGAUGAGGCCGUUAGGCCGAA AGGUCCUG 759
    550 CACAUGAU A GGAGGUUU 129 AAACCUCC CUGAUGAGGCCGUUAGGCCGAA AUCAUGUG 760
    557 UAGGAGGU U UACAUUUC 130 GAAAUGUA CUGAUGAGGCCGUUAGGCCGAA ACCUCCUA 761
    558 AGGAGGUU U ACAUUUCA 131 UGAAAUGU CUGAUGAGGCCGUUAGGCCGAA AACCUCCU 762
    559 GGAGGUUU A CAUUUCAA 132 UUGAAAUG CUGAUGAGGCCGUUAGGCCGAA AAACCUCC 763
    563 GUUUACAU U UCAAGUUA 133 UAACUUGA CUGAUGAGGCCGUUAGGCCGAA AUGUAAAC 764
    564 UUUACAUU U CAAGUUAU 134 AUAACUUG CUGAUGAGGCCGUUAGGCCGAA AAUGUAAA 765
    565 UUACAUUU C AAGUUAUA 135 UAUAACUU CUGAUGAGGCCGUUAGGCCGAA AAAUGUAA 766
    570 UUUCAAGU U AUAAUAGA 136 UCUAUUAU CUGAUGAGGCCGUUAGGCCGAA ACUUGAAA 767
    571 UUCAAGUU A UAAUAGAU 137 AUCUAUUA CUGAUGAGGCCGUUAGGCCGAA AACUUGAA 768
    573 CAAGUUAU A AUAGAUGG 138 CCAUCUAU CUGAUGAGGCCGUUAGGCCGAA AUAACUUG 769
    576 GUUAUAAU A GAUGGAAG 139 CUUCCAUC CUGAUGAGGCCGUUAGGCCGAA AUUAUAAC 770
    590 AAGAGAAU U UCCAGAAG 140 CUUCUGGA CUGAUGAGGCCGUUAGGCCGAA AUUCUCUU 771
    591 AGAGAAUU U CCAGAAGG 141 CCUUCUGG CUGAUGAGGCCGUUAGGCCGAA AAUUCUCU 772
    592 GAGAAUUU C CAGAAGGU 142 ACCUUCUG CUGAUGAGGCCGUUAGGCCGAA AAAUUCUC 773
    607 GUGAAGGU A GAUCAAAG 143 CUUUGAUC CUGAUGAGGCCGUUAGGCCGAA ACCUUCAC 774
    611 AGGUAGAU C AAAGAAGG 144 CCUUCUUU CUGAUGAGGCCGUUAGGCCGAA AUCUACCU 775
    644 AGCCAAAU U AGCUGUUG 145 CAACAGCU CUGAUGAGGCCGUUAGGCCGAA AUUUGGCU 776
    645 GCCAAAUU A GCUGUUGA 146 UCAACAGC CUGAUGAGGCCGUUAGGCCGAA AAUUUGGC 777
    651 UUAGCUGU U GAGAUACU 147 AGUAUCUC CUGAUGAGGCCGUUAGGCCGAA ACAGCUAA 778
    657 GUUGAGAU A CUUAAUAA 148 UUAUUAAG CUGAUGAGGCCGUUAGGCCGAA AUCUCAAC 779
    660 GAGAUACU U AAUAAGGA 149 UCCUUAUU CUGAUGAGGCCGUUAGGCCGAA AGUAUCUC 780
    661 AGAUACUU A AUAAGGAA 150 UUCCUUAU CUGAUGAGGCCGUUAGGCCGAA AAGUAUCU 781
    664 UACUUAAU A AGGAAAAG 151 CUUUUCCU CUGAUGAGGCCGUUAGGCCGAA AUUAAGUA 782
    681 AAGGCAGU U AGUCCUUU 152 AAAGGACU CUGAUGAGGCCGUUAGGCCGAA ACUGCCUU 783
    682 AGGCAGUU A GUCCUUUA 153 UAAAGGAC CUGAUGAGGCCGUUAGGCCGAA AACUGCCU 784
    685 CAGUUAGU C CUUUAUUA 154 UAAUAAAG CUGAUGAGGCCGUUAGGCCGAA ACUAACUG 785
    688 UUAGUCCU U UAUUAUUG 155 CAAUAAUA CUGAUGAGGCCGUUAGGCCGAA AGGACUAA 786
    689 UAGUCCUU U AUUAUUGA 156 UCAAUAAU CUGAUGAGGCCGUUAGGCCGAA AAGGACUA 787
    690 AGUCCUUU A UUAUUGAC 157 GUCAAUAA CUGAUGAGGCCGUUAGGCCGAA AAAGGACU 788
    692 UCCUUUAU U AUUGACAA 158 UUGUCAAU CUGAUGAGGCCGUUAGGCCGAA AUAAAGGA 789
    693 CCUUUAUU A UUGACAAC 159 GUUGUCAA CUGAUGAGGCCGUUAGGCCGAA AAUAAAGG 790
    695 UUUAUUAU U GACAACAA 160 UUGUUGUC CUGAUGAGGCCGUUAGGCCGAA AUAAUAAA 791
    709 CAACGAAU U CUUCAGAA 161 UUCUGAAG CUGAUGAGGCCGUUAGGCCGAA AUUCGUUG 792
    710 AACGAAUU C UUCAGAAG 162 CUUCUGAA CUGAUGAGGCCGUUAGGCCGAA AAUUCGUU 793
    712 CGAAUUCU U CAGAAGGA 163 UCCUUCUG CUGAUGAGGCCGUUAGGCCGAA AGAAUUCG 794
    713 GAAUUCUU C AGAAGGAU 164 AUCCUUCU CUGAUGAGGCCGUUAGGCCGAA AAGAAUUC 795
    722 AGAAGGAU U AUCCAUGG 165 CCAUGGAU CUGAUGAGGCCGUUAGGCCGAA AUCCUUCU 796
    723 GAAGGAUU A UCCAUGGG 166 CCCAUGGA CUGAUGAGGCCGUUAGGCCGAA AAUCCUUC 797
    725 AGGAUUAU C CAUGGGGA 167 UCCCCAUG CUGAUGAGGCCGUUAGGCCGAA AUAAUCCU 798
    736 UGGGGAAU U ACAUAGGC 168 GCCUAUGU CUGAUGAGGCCGUUAGGCCGAA AUUCCCCA 799
    737 GGGGAAUU A CAUAGGCC 169 GGCCUAUG CUGAUGAGGCCGUUAGGCCGAA AAUUCCCC 800
    741 AAUUACAU A GGCCUUAU 170 AUAAGGCC CUGAUGAGGCCGUUAGGCCGAA AUGUAAUU 801
    747 AUAGGCCU U AUCAAUAG 171 CUAUUGAU CUGAUGAGGCCGUUAGGCCGAA AGGCCUAU 802
    748 UAGGCCUU A UCAAUAGA 172 UCUAUUGA CUGAUGAGGCCGUUAGGCCGAA AAGGCCUA 803
    750 GGCCUUAU C AAUAGAAU 173 AUUCUAUU CUGAUGAGGCCGUUAGGCCGAA AUAAGGCC 804
    754 UUAUCAAU A GAAUUGCC 174 GGCAAUUC CUGAUGAGGCCGUUAGGCCGAA AUUGAUAA 805
    759 AAUAGAAU U GCCCAGAA 175 UUCUGGGC CUGAUGAGGCCGUUAGGCCGAA AUUCUAUU 806
    777 AAAAGACU A ACUGUAAA 176 UUUACAGU CUGAUGAGGCCGUUAGGCCGAA AGUCUUUU 807
    783 CUAACUGU A AAUUAUGA 177 UCAUAAUU CUGAUGAGGCCGUUAGGCCGAA ACAGUUAG 808
    787 CUGUAAAU U AUGAACAG 178 CUGUUCAU CUGAUGAGGCCGUUAGGCCGAA AUUUACAG 809
    788 UGUAAAUU A UGAACAGU 179 ACUGUUCA CUGAUGAGGCCGUUAGGCCGAA AAUUUACA 810
    803 GUGUGCAU C GGGGGUGC 180 GCACCCCC CUGAUGAGGCCGUUAGGCCGAA AUGCACAC 811
    827 AGAAGGAU U UCAUUAUA 181 UAUAAUGA CUGAUGAGGCCGUUAGGCCGAA AUCCUUCU 812
    828 GAAGGAUU U CAUUAUAA 182 UUAUAAUG CUGAUGAGGCCGUUAGGCCGAA AAUCCUUC 813
    829 AAGGAUUU C AUUAUAAA 183 UUUAUAAU CUGAUGAGGCCGUUAGGCCGAA AAAUCCUU 814
    832 GAUUUCAU U AUAAAUGC 184 GCAUUUAU CUGAUGAGGCCGUUAGGCCGAA AUGAAAUC 815
    833 AUUUCAUU A UAAAUGCA 185 UGCAUUUA CUGAUGAGGCCGUUAGGCCGAA AAUGAAAU 816
    835 UUCAUUAU A AAUGCAAA 186 UUUGCAUU CUGAUGAGGCCGUUAGGCCGAA AUAAUGAA 817
    860 GAAAGAAU A UAGUAUUG 187 CAAUACUA CUGAUGAGGCCGUUAGGCCGAA AUUCUUUC 818
    862 AAGAAUAU A GUAUUGGU 188 ACCAAUAC CUGAUGAGGCCGUUAGGCCGAA AUAUUCUU 819
    865 AAUAUAGU A UUGGUACA 189 UGUACCAA CUGAUGAGGCCGUUAGGCCGAA ACUAUAUU 820
    867 UAUAGUAU U GGUACAGG 190 CCUGUACC CUGAUGAGGCCGUUAGGCCGAA AUACUAUA 821
    871 GUAUUGGU A CAGGUUCU 191 AGAACCUG CUGAUGAGGCCGUUAGGCCGAA ACCAAUAC 822
    877 GUACAGGU U CUACUAAA 192 UUUAGUAG CUGAUGAGGCCGUUAGGCCGAA ACCUGUAC 823
    878 UACAGGUU C UACUAAAC 193 GUUUAGUA CUGAUGAGGCCGUUAGGCCGAA AACCUGUA 824
    880 CAGGUUCU A CUAAACAG 194 CUGUUUAG CUGAUGAGGCCGUUAGGCCGAA AGAACCUG 825
    883 GUUCUACU A AACAGGAA 195 UUCCUGUU CUGAUGAGGCCGUUAGGCCGAA AGUAGAAC 826
    902 AAAACAAU U GGCCGCUA 196 UAGCGGCC CUGAUGAGGCCGUUAGGCCGAA AUUGUUUU 827
    910 UGGCCGCU A AACUUGCA 197 UGCAAGUU CUGAUGAGGCCGUUAGGCCGAA AGCGGCCA 828
    915 GCUAAACU U GCAUAUCU 198 AGAUAUGC CUGAUGAGGCCGUUAGGCCGAA AGUUUAGC 829
    920 ACUUGCAU A UCUUCAGA 199 UCUGAAGA CUGAUGAGGCCGUUAGGCCGAA AUGCAAGU 830
    922 UUGCAUAU C UUCAGAUA 200 UAUCUGAA CUGAUGAGGCCGUUAGGCCGAA AUAUGCAA 831
    924 GCAUAUCU U CAGAUAUU 201 AAUAUCUG CUGAUGAGGCCGUUAGGCCGAA AGAUAUGC 832
    925 CAUAUCUU C AGAUAUUA 202 UAAUAUCU CUGAUGAGGCCGUUAGGCCGAA AAGAUAUG 833
    930 CUUCAGAU A UUAUCAGA 203 UCUGAUAA CUGAUGAGGCCGUUAGGCCGAA AUCUGAAG 834
    932 UCAGAUAU U AUCAGAAG 204 CUUCUGAU CUGAUGAGGCCGUUAGGCCGAA AUAUCUGA 835
    933 CAGAUAUU A UCAGAAGA 205 UCUUCUGA CUGAUGAGGCCGUUAGGCCGAA AAUAUCUG 836
    935 GAUAUUAU C AGAAGAAA 206 UUUCUUCU CUGAUGAGGCCGUUAGGCCGAA AUAAUAUC 837
    947 AGAAACCU C AGUGAAAU 207 AUUUCACU CUGAUGAGGCCGUUAGGCCGAA AGGUUUCU 838
    956 AGUGAAAU C UGACUACC 208 GGUAGUCA CUGAUGAGGCCGUUAGGCCGAA AUUUCACU 839
    962 AUCUGACU A CCUGUCCU 209 AGGACAGG CUGAUGAGGCCGUUAGGCCGAA AGUCAGAU 840
    968 CUACCUGU C CUCUGGUU 210 AACCAGAG CUGAUGAGGCCGUUAGGCCGAA ACAGGUAG 841
    971 CCUGUCCU C UGGUUCUU 211 AAGAACCA CUGAUGAGGCCGUUAGGCCGAA AGGACAGG 842
    976 CCUCUGGU U CUUUUGCU 212 AGCAAAAG CUGAUGAGGCCGUUAGGCCGAA ACCAGAGG 843
    977 CUCUGGUU C UUUUGCUA 213 UAGCAAAA CUGAUGAGGCCGUUAGGCCGAA AACCAGAG 844
    979 CUGGUUCU U UUGCUACU 214 AGUAGCAA CUGAUGAGGCCGUUAGGCCGAA AGAACCAG 845
    980 UGGUUCUU U UGCUACUA 215 UAGUAGCA CUGAUGAGGCCGUUAGGCCGAA AAGAACCA 846
    981 GGUUCUUU U GCUACUAC 216 GUAGUAGC CUGAUGAGGCCGUUAGGCCGAA AAAGAACC 847
    985 CUUUUGCU A CUACGUGU 217 ACACGUAG CUGAUGAGGCCGUUAGGCCGAA AGCAAAAG 848
    988 UUGCUACU A CGUGUGAG 218 CUCACACG CUGAUGAGGCCGUUAGGCCGAA AGUAGCAA 849
    998 GUGUGAGU C CCAAAGCA 219 UGCUUUGG CUGAUGAGGCCGUUAGGCCGAA ACUCACAC 850
    1010 AAGCAACU C UUUAGUGA 220 UCACUAAA CUGAUGAGGCCGUUAGGCCGAA AGUUGCUU 851
    1012 GCAACUCU U UAGUGACC 221 GGUCACUA CUGAUGAGGCCGUUAGGCCGAA AGAGUUGC 852
    1013 CAACUCUU U AGUGACCA 222 UGGUCACU CUGAUGAGGCCGUUAGGCCGAA AAGAGUUG 853
    1014 AACUCUUU A GUGACCAG 223 CUGGUCAC CUGAUGAGGCCGUUAGGCCGAA AAAGAGUU 854
    1029 AGCACACU C GCUUCUGA 224 UCAGAAGC CUGAUGAGGCCGUUAGGCCGAA AGUGUGCU 855
    1033 CACUCGCU U CUGAAUCA 225 UGAUUCAG CUGAUGAGGCCGUUAGGCCGAA AGCGAGUG 856
    1034 ACUCGCUU C UGAAUCAU 226 AUGAUUCA CUGAUGAGGCCGUUAGGCCGAA AAGCGAGU 857
    1040 UUCUGAAU C AUCAUCUG 227 CAGAUGAU CUGAUGAGGCCGUUAGGCCGAA AUUCAGAA 858
    1043 UGAAUCAU C AUCUGAAG 228 CUUCAGAU CUGAUGAGGCCGUUAGGCCGAA AUGAUUCA 859
    1046 AUCAUCAU C UGAAGGUG 229 CACCUUCA CUGAUGAGGCCGUUAGGCCGAA AUGAUGAU 860
    1058 AGGUGACU U CUCAGCAG 230 CUGCUGAG CUGAUGAGGCCGUUAGGCCGAA AGUCACCU 861
    1059 GGUGACUU C UCAGCAGA 231 UCUGCUGA CUGAUGAGGCCGUUAGGCCGAA AAGUCACC 862
    1061 UGACUUCU C AGCAGAUA 232 UAUCUGCU CUGAUGAGGCCGUUAGGCCGAA AGAAGUCA 863
    1069 CAGCAGAU A CAUCAGAG 233 CUCUGAUG CUGAUGAGGCCGUUAGGCCGAA AUCUGCUG 864
    1073 AGAUACAU C AGAGAUAA 234 UUAUCUCU CUGAUGAGGCCGUUAGGCCGAA AUGUAUCU 865
    1080 UCAGAGAU A AAUUCUAA 235 UUAGAAUU CUGAUGAGGCCGUUAGGCCGAA AUCUCUGA 866
    1084 AGAUAAAU U CUAACAGU 236 ACUGUUAG CUGAUGAGGCCGUUAGGCCGAA AUUUAUCU 867
    1085 GAUAAAUU C UAACAGUG 237 CACUGUUA CUGAUGAGGCCGUUAGGCCGAA AAUUUAUC 868
    1087 UAAAUUCU A ACAGUGAC 238 GUCACUGU CUGAUGAGGCCGUUAGGCCGAA AGAAUUUA 869
    1099 GUGACAGU U UAAACAGU 239 ACUGUUUA CUGAUGAGGCCGUUAGGCCGAA ACUGUCAC 870
    1100 UGACAGUU U AAACAGUU 240 AACUGUUU CUGAUGAGGCCGUUAGGCCGAA AACUGUCA 871
    1101 GACAGUUU A AACAGUUC 241 GAACUGUU CUGAUGAGGCCGUUAGGCCGAA AAACUGUC 872
    1108 UAAACAGU U CUUCGUUG 242 CAACGAAG CUGAUGAGGCCGUUAGGCCGAA ACUGUUUA 873
    1109 AAACAGUU C UUCGUUGC 243 GCAACGAA CUGAUGAGGCCGUUAGGCCGAA AACUGUUU 874
    1111 ACAGUUCU U CGUUGCUU 244 AAGCAACG CUGAUGAGGCCGUUAGGCCGAA AGAACUGU 875
    1112 CAGUUCUU C GUUGCUUA 245 UAAGCAAC CUGAUGAGGCCGUUAGGCCGAA AAGAACUG 876
    1115 UUCUUCGU U GCUUAUGA 246 UCAUAAGC CUGAUGAGGCCGUUAGGCCGAA ACGAAGAA 877
    1119 UCGUUGCU U AUGAAUGG 247 CCAUUCAU CUGAUGAGGCCGUUAGGCCGAA AGCAACGA 878
    1120 CGUUGCUU A UGAAUGGU 248 ACCAUUCA CUGAUGAGGCCGUUAGGCCGAA AAGCAACG 879
    1129 UGAAUGGU C UCAGAAAU 249 AUUUCUGA CUGAUGAGGCCGUUAGGCCGAA ACCAUUCA 880
    1131 AAUGGUCU C AGAAAUAA 250 UUAUUUCU CUGAUGAGGCCGUUAGGCCGAA AGACCAUU 881
    1138 UCAGAAAU A AUCAAAGG 251 CCUUUGAU CUGAUGAGGCCGUUAGGCCGAA AUUUCUGA 882
    1141 GAAAUAAU C AAAGGAAG 252 CUUCCUUU CUGAUGAGGCCGUUAGGCCGAA AUUAUUUC 883
    1160 AAAAAGAU C UUUGGCAC 253 GUGCCAAA CUGAUGAGGCCGUUAGGCCGAA AUCUUUUU 884
    1162 AAAGAUCU U UGGCACCC 254 GGGUGCCA CUGAUGAGGCCGUUAGGCCGAA AGAUCUUU 885
    1163 AAGAUCUU U GGCACCCA 255 UGGGUGCC CUGAUGAGGCCGUUAGGCCGAA AAGAUCUU 886
    1175 ACCCAGAU U UGACCUUC 256 GAAGGUCA CUGAUGAGGCCGUUAGGCCGAA AUCUGGGU 887
    1176 CCCAGAUU U GACCUUCC 257 GGAAGGUC CUGAUGAGGCCGUUAGGCCGAA AAUCUGGG 888
    1182 UUUGACCU U CCUGACAU 258 AUGUCAGG CUGAUGAGGCCGUUAGGCCGAA AGGUCAAA 889
    1183 UUGACCUU C CUGACAUG 259 CAUGUCAG CUGAUGAGGCCGUUAGGCCGAA AAGGUCAA 890
    1205 AACAAAGU A UACUGUGG 260 CCACAGUA CUGAUGAGGCCGUUAGGCCGAA ACUUUGUU 891
    1207 CAAAGUAU A CUGUGGAC 261 GUCCACAG CUGAUGAGGCCGUUAGGCCGAA AUACUUUG 892
    1223 CAAGAGGU U UGGCAUGG 262 CCAUGCCA CUGAUGAGGCCGUUAGGCCGAA ACCUCUUG 893
    1224 AAGAGGUU U GGCAUGGA 263 UCCAUGCC CUGAUGAGGCCGUUAGGCCGAA AACCUCUU 894
    1234 GCAUGGAU U UUAAAGAA 264 UUCUUUAA CUGAUGAGGCCGUUAGGCCGAA AUCCAUGC 895
    1235 CAUGGAUU U UAAAGAAA 265 UUUCUUUA CUGAUGAGGCCGUUAGGCCGAA AAUCCAUG 896
    1236 AUGGAUUU U AAAGAAAU 266 AUUUCUUU CUGAUGAGGCCGUUAGGCCGAA AAAUCCAU 897
    1237 UGGAUUUU A AAGAAAUA 267 UAUUUCUU CUGAUGAGGCCGUUAGGCCGAA AAAAUCCA 898
    1245 AAAGAAAU A GAAUUAAU 268 AUUAAUUC CUGAUGAGGCCGUUAGGCCGAA AUUUCUUU 899
    1250 AAUAGAAU U AAUUGGCU 269 AGCCAAUU CUGAUGAGGCCGUUAGGCCGAA AUUCUAUU 900
    1251 AUAGAAUU A AUUGGCUC 270 GAGCCAAU CUGAUGAGGCCGUUAGGCCGAA AAUUCUAU 901
    1254 GAAUUAAU U GGCUCAGG 271 CCUGAGCC CUGAUGAGGCCGUUAGGCCGAA AUUAAUUC 902
    1259 AAUUGGCU C AGGUGGAU 272 AUCCACCU CUGAUGAGGCCGUUAGGCCGAA AGCCAAUU 903
    1268 AGGUGGAU U UGGCCAAG 273 CUUGGCCA CUGAUGAGGCCGUUAGGCCGAA AUCCACCU 904
    1269 GGUGGAUU U GGCCAAGU 274 ACUUGGCC CUGAUGAGGCCGUUAGGCCGAA AAUCCACC 905
    1278 GGCCAAGU U UUCAAAGC 275 GCUUUGAA CUGAUGAGGCCGUUAGGCCGAA ACUUGGCC 906
    1279 GCCAAGUU U UCAAAGCA 276 UGCUUUGA CUGAUGAGGCCGUUAGGCCGAA AACUUGGC 907
    1280 CCAAGUUU U CAAAGCAA 277 UUGCUUUG CUGAUGAGGCCGUUAGGCCGAA AAACUUGG 908
    1281 CAAGUUUU C AAAGCAAA 278 UUUGCUUU CUGAUGAGGCCGUUAGGCCGAA AAAACUUG 909
    1299 CACAGAAU U GACGGAAA 279 UUUCCGUC CUGAUGAGGCCGUUAGGCCGAA AUUCUGUG 910
    1312 GAAAGACU U ACGUUAUU 280 AAUAACGU CUGAUGAGGCCGUUAGGCCGAA AGUCUUUC 911
    1313 AAAGACUU A CGUUAUUA 281 UAAUAACG CUGAUGAGGCCGUUAGGCCGAA AAGUCUUU 912
    1317 ACUUACGU U AUUAAACG 282 CGUUUAAU CUGAUGAGGCCGUUAGGCCGAA ACGUAAGU 913
    1318 CUUACGUU A UUAAACGU 283 ACGUUUAA CUGAUGAGGCCGUUAGGCCGAA AACGUAAG 914
    1320 UACGUUAU U AAACGUGU 284 ACACGUUU CUGAUGAGGCCGUUAGGCCGAA AUAACGUA 915
    1321 ACGUUAUU A AACGUGUU 285 AACACGUU CUGAUGAGGCCGUUAGGCCGAA AAUAACGU 916
    1329 AAACGUGU U AAAUAUAA 286 UUAUAUUU CUGAUGAGGCCGUUAGGCCGAA ACACGUUU 917
    1330 AACGUGUU A AAUAUAAU 287 AUUAUAUU CUGAUGAGGCCGUUAGGCCGAA AACACGUU 918
    1334 UGUUAAAU A UAAUAACG 288 CGUUAUUA CUGAUGAGGCCGUUAGGCCGAA AUUUAACA 919
    1336 UUAAAUAU A AUAACGAG 289 CUCGUUAU CUGAUGAGGCCGUUAGGCCGAA AUAUUUAA 920
    1339 AAUAUAAU A ACGAGAAG 290 CUUCUCGU CUGAUGAGGCCGUUAGGCCGAA AUUAUAUU 921
    1362 CGUGAAGU A AAAGCAUU 291 AAUGCUUU CUGAUGAGGCCGUUAGGCCGAA ACUUCACG 922
    1370 AAAAGCAU U GGCAAAAC 292 GUUUUGCC CUGAUGAGGCCGUUAGGCCGAA AUGCUUUU 923
    1380 GCAAAACU U GAUCAUGU 293 ACAUGAUC CUGAUGAGGCCGUUAGGCCGAA AGUUUUGC 924
    1384 AACUUGAU C AUGUAAAU 294 AUUUACAU CUGAUGAGGCCGUUAGGCCGAA AUCAAGUU 925
    1389 GAUCAUGU A AAUAUUGU 295 ACAAUAUU CUGAUGAGGCCGUUAGGCCGAA ACAUGAUC 926
    1393 AUGUAAAU A UUGUUCAC 296 GUGAACAA CUGAUGAGGCCGUUAGGCCGAA AUUUACAU 927
    1395 GUAAAUAU U GUUCACUA 297 UAGUGAAC CUGAUGAGGCCGUUAGGCCGAA AUAUUUAC 928
    1398 AAUAUUGU U CACUACAA 298 UUGUAGUG CUGAUGAGGCCGUUAGGCCGAA ACAAUAUU 929
    1399 AUAUUGUU C ACUACAAU 299 AUUGUAGU CUGAUGAGGCCGUUAGGCCGAA AACAAUAU 930
    1403 UGUUCACU A CAAUGGCU 300 AGCCAUUG CUGAUGAGGCCGUUAGGCCGAA AGUGAACA 931
    1414 AUGGCUGU U GGGAUGGA 301 UCCAUCCC CUGAUGAGGCCGUUAGGCCGAA ACAGCCAU 932
    1424 GGAUGGAU U UGAUUAUG 302 CAUAAUCA CUGAUGAGGCCGUUAGGCCGAA AUCCAUCC 933
    1425 GAUGGAUU U GAUUAUGA 303 UCAUAAUC CUGAUGAGGCCGUUAGGCCGAA AAUCCAUC 934
    1429 GAUUUGAU U AUGAUCCU 304 AGGAUCAU CUGAUGAGGCCGUUAGGCCGAA AUCAAAUC 935
    1430 AUUUGAUU A UGAUCCUG 305 CAGGAUCA CUGAUGAGGCCGUUAGGCCGAA AAUCAAAU 936
    1435 AUUAUGAU C CUGAGACC 306 GGUCUCAG CUGAUGAGGCCGUUAGGCCGAA AUCAUAAU 937
    1453 GUGAUGAU U CUCUUGAG 307 CUCAAGAG CUGAUGAGGCCGUUAGGCCGAA AUCAUCAC 938
    1454 UGAUGAUU C UCUUGAGA 308 UCUCAAGA CUGAUGAGGCCGUUAGGCCGAA AAUCAUCA 939
    1456 AUGAUUCU C UUGAGAGC 309 GCUCUCAA CUGAUGAGGCCGUUAGGCCGAA AGAAUCAU 940
    1458 GAUUCUCU U GAGAGCAG 310 CUGCUCUC CUGAUGAGGCCGUUAGGCCGAA AGAGAAUC 941
    1471 GCAGUGAU U AUGAUCCU 311 AGGAUCAU CUGAUGAGGCCGUUAGGCCGAA AUCACUGC 942
    1472 CAGUGAUU A UGAUCCUG 312 CAGGAUCA CUGAUGAGGCCGUUAGGCCGAA AAUCACUG 943
    1477 AUUAUGAU C CUGAGAAC 313 GUUCUCAG CUGAUGAGGCCGUUAGGCCGAA AUCAUAAU 944
    1495 GCAAAAAU A GUUCAAGG 314 CCUUGAAC CUGAUGAGGCCGUUAGGCCGAA AUUUUUGC 945
    1498 AAAAUAGU U CAAGGUCA 315 UGACCUUG CUGAUGAGGCCGUUAGGCCGAA ACUAUUUU 946
    1499 AAAUAGUU C AAGGUCAA 316 UUGACCUU CUGAUGAGGCCGUUAGGCCGAA AACUAUUU 947
    1505 UUCAAGGU C AAAGACUA 317 UAGUCUUU CUGAUGAGGCCGUUAGGCCGAA ACCUUGAA 948
    1513 CAAAGACU A AGUGCCUU 318 AAGGCACU CUGAUGAGGCCGUUAGGCCGAA AGUCUUUG 949
    1521 AAGUGCCU U UUCAUCCA 319 UGGAUGAA CUGAUGAGGCCGUUAGGCCGAA AGGCACUU 950
    1522 AGUGCCUU U UCAUCCAA 320 UUGGAUGA CUGAUGAGGCCGUUAGGCCGAA AAGGCACU 951
    1523 GUGCCUUU U CAUCCAAA 321 UUUGGAUG CUGAUGAGGCCGUUAGGCCGAA AAAGGCAC 952
    1524 UGCCUUUU C AUCCAAAU 322 AUUUGGAU CUGAUGAGGCCGUUAGGCCGAA AAAAGGCA 953
    1527 CUUUUCAU C CAAAUGGA 323 UCCAUUUG CUGAUGAGGCCGUUAGGCCGAA AUGAAAAG 954
    1538 AAUGGAAU U CUGUGAUA 324 UAUCACAG CUGAUGAGGCCGUUAGGCCGAA AUUCCAUU 955
    1539 AUGGAAUU C UGUGAUAA 325 UUAUCACA CUGAUGAGGCCGUUAGGCCGAA AAUUCCAU 956
    1546 UCUGUGAU A AAGGGACC 326 GGUCCCUU CUGAUGAGGCCGUUAGGCCGAA AUCACAGA 957
    1556 AGGGACCU U GGAACAAU 327 AUUGUUCC CUGAUGAGGCCGUUAGGCCGAA AGGUCCCU 958
    1569 CAAUGGAU U GAAAAAAG 328 CUUUUUUC CUGAUGAGGCCGUUAGGCCGAA AUCCAUUG 959
    1593 GAGAAACU A GACAAAGU 329 ACUUUGUC CUGAUGAGGCCGUUAGGCCGAA AGUUUCUC 960
    1602 GACAAAGU U UUGGCUUU 330 AAAGCCAA CUGAUGAGGCCGUUAGGCCGAA ACUUUGUC 961
    1603 ACAAAGUU U UGGCUUUG 331 CAAAGCCA CUGAUGAGGCCGUUAGGCCGAA AACUUUGU 962
    1604 CAAAGUUU U GGCUUUGG 332 CCAAAGCC CUGAUGAGGCCGUUAGGCCGAA AAACUUUG 963
    1609 UUUUGGCU U UGGAACUC 333 GAGUUCCA CUGAUGAGGCCGUUAGGCCGAA AGCCAAAA 964
    1610 UUUGGCUU U GGAACUCU 334 AGAGUUCC CUGAUGAGGCCGUUAGGCCGAA AAGCCAAA 965
    1617 UUGGAACU C UUUGAACA 335 UGUUCAAA CUGAUGAGGCCGUUAGGCCGAA AGUUCCAA 966
    1619 GGAACUCU U UGAACAAA 336 UUUGUUCA CUGAUGAGGCCGUUAGGCCGAA AGAGUUCC 967
    1620 GAACUCUU U GAACAAAU 337 AUUUGUUC CUGAUGAGGCCGUUAGGCCGAA AAGAGUUC 968
    1629 GAACAAAU A ACAAAAGG 338 CCUUUUGU CUGAUGAGGCCGUUAGGCCGAA AUUUGUUC 969
    1645 GGGUGGAU U AUAUACAU 339 AUGUAUAU CUGAUGAGGCCGUUAGGCCGAA AUCCACCC 970
    1646 GGUGGAUU A UAUACAUU 340 AAUGUAUA CUGAUGAGGCCGUUAGGCCGAA AAUCCACC 971
    1648 UGGAUUAU A UACAUUCA 341 UGAAUGUA CUGAUGAGGCCGUUAGGCCGAA AUAAUCCA 972
    1650 GAUUAUAU A CAUUCAAA 342 UUUGAAUG CUGAUGAGGCCGUUAGGCCGAA AUAUAAUC 973
    1654 AUAUACAU U CAAAAAAA 343 UUUUUUUG CUGAUGAGGCCGUUAGGCCGAA AUGUAUAU 974
    1655 UAUACAUU C AAAAAAAU 344 AUUUUUUU CUGAUGAGGCCGUUAGGCCGAA AAUGUAUA 975
    1664 AAAAAAAU U AAUUCAUA 345 UAUGAAUU CUGAUGAGGCCGUUAGGCCGAA AUUUUUUU 976
    1665 AAAAAAUU A AUUCAUAG 346 CUAUGAAU CUGAUGAGGCCGUUAGGCCGAA AAUUUUUU 977
    1668 AAAUUAAU U CAUAGAGA 347 UCUCUAUG CUGAUGAGGCCGUUAGGCCGAA AUUAAUUU 978
    1669 AAUUAAUU C AUAGAGAU 348 AUCUCUAU CUGAUGAGGCCGUUAGGCCGAA AAUUAAUU 979
    1672 UAAUUCAU A GAGAUCUU 349 AAGAUCUC CUGAUGAGGCCGUUAGGCCGAA AUGAAUUA 980
    1678 AUAGAGAU C UUAAGCCA 350 UGGCUUAA CUGAUGAGGCCGUUAGGCCGAA AUCUCUAU 981
    1680 AGAGAUCU U AAGCCAAG 351 CUUGGCUU CUGAUGAGGCCGUUAGGCCGAA AGAUCUCU 982
    1681 GAGAUCUU A AGCCAAGU 352 ACUUGGCU CUGAUGAGGCCGUUAGGCCGAA AAGAUCUC 983
    1690 AGCCAAGU A AUAUAUUC 353 GAAUAUAU CUGAUGAGGCCGUUAGGCCGAA ACUUGGCU 984
    1693 CAAGUAAU A UAUUCUUA 354 UAAGAAUA CUGAUGAGGCCGUUAGGCCGAA AUUACUUG 985
    1695 AGUAAUAU A UUCUUAGU 355 ACUAAGAA CUGAUGAGGCCGUUAGGCCGAA AUAUUACU 986
    1697 UAAUAUAU U CUUAGUAG 356 CUACUAAG CUGAUGAGGCCGUUAGGCCGAA AUAUAUUA 987
    1698 AAUAUAUU C UUAGUAGA 357 UCUACUAA CUGAUGAGGCCGUUAGGCCGAA AAUAUAUU 988
    1700 UAUAUUCU U AGUAGAUA 358 UAUCUACU CUGAUGAGGCCGUUAGGCCGAA AGAAUAUA 989
    1701 AUAUUCUU A GUAGAUAC 359 GUAUCUAC CUGAUGAGGCCGUUAGGCCGAA AAGAAUAU 990
    1704 UUCUUAGU A GAUACAAA 360 UUUGUAUC CUGAUGAGGCCGUUAGGCCGAA ACUAAGAA 991
    1708 UAGUAGAU A CAAAACAA 361 UUGUUUUG CUGAUGAGGCCGUUAGGCCGAA AUCUACUA 992
    1719 AAACAAGU A AAGAUUGG 362 CCAAUCUU CUGAUGAGGCCGUUAGGCCGAA ACUUGUUU 993
    1725 GUAAAGAU U GGAGACUU 363 AAGUCUCC CUGAUGAGGCCGUUAGGCCGAA AUCUUUAC 994
    1733 UGGAGACU U UGGACUUG 364 CAAGUCCA CUGAUGAGGCCGUUAGGCCGAA AGUCUCCA 995
    1734 GGAGACUU U GGACUUGU 365 ACAAGUCC CUGAUGAGGCCGUUAGGCCGAA AAGUCUCC 996
    1740 UUUGGACU U GUAACAUC 366 GAUGUUAC CUGAUGAGGCCGUUAGGCCGAA AGUCCAAA 997
    1743 GGACUUGU A ACAUCUCU 367 AGAGAUGU CUGAUGAGGCCGUUAGGCCGAA ACAAGUCC 998
    1748 UGUAACAU C UCUGAAAA 368 UUUUCAGA CUGAUGAGGCCGUUAGGCCGAA AUGUUACA 999
    1750 UAACAUCU C UGAAAAAU 369 AUUUUUCA CUGAUGAGGCCGUUAGGCCGAA AGAUGUUA 1000
    1780 CAAGGAGU A AGGGAACU 370 AGUUCCCU CUGAUGAGGCCGUUAGGCCGAA ACUCCUUG 1001
    1789 AGGGAACU U UGCGAUAC 371 GUAUCGCA CUGAUGAGGCCGUUAGGCCGAA AGUUCCCU 1002
    1790 GGGAACUU U GCGAUACA 372 UGUAUCGC CUGAUGAGGCCGUUAGGCCGAA AAGUUCCC 1003
    1796 UUUGCGAU A CAUGAGCC 373 GGCUCAUG CUGAUGAGGCCGUUAGGCCGAA AUCGCAAA 1004
    1815 GAACAGAU U UCUUCGCA 374 UGCGAAGA CUGAUGAGGCCGUUAGGCCGAA AUCUGUUC 1005
    1816 AACAGAUU U CUUCGCAA 375 UUGCGAAG CUGAUGAGGCCGUUAGGCCGAA AAUCUGUU 1006
    1817 ACAGAUUU C UUCGCAAG 376 CUUGCGAA CUGAUGAGGCCGUUAGGCCGAA AAAUCUGU 1007
    1819 AGAUUUCU U CGCAAGAC 377 GUCUUGCG CUGAUGAGGCCGUUAGGCCGAA AGAAAUCU 1008
    1820 GAUUUCUU C GCAAGACU 378 AGUCUUGC CUGAUGAGGCCGUUAGGCCGAA AAGAAAUC 1009
    1829 GCAAGACU A UGGAAAGG 379 CCUUUCCA CUGAUGAGGCCGUUAGGCCGAA AGUCUUGC 1010
    1848 GUGGACCU C UACGCUUU 380 AAAGCGUA CUGAUGAGGCCGUUAGGCCGAA AGGUCCAC 1011
    1850 GGACCUCU A CGCUUUGG 381 CCAAAGCG CUGAUGAGGCCGUUAGGCCGAA AGAGGUCC 1012
    1855 UCUACGCU U UGGGGCUA 382 UAGCCCCA CUGAUGAGGCCGUUAGGCCGAA AGCGUAGA 1013
    1856 CUACGCUU U GGGGCUAA 383 UUAGCCCC CUGAUGAGGCCGUUAGGCCGAA AAGCGUAG 1014
    1863 UUGGGGCU A AUUCUUGC 384 GCAAGAAU CUGAUGAGGCCGUUAGGCCGAA AGCCCCAA 1015
    1866 GGGCUAAU U CUUGCUGA 385 UCAGCAAG CUGAUGAGGCCGUUAGGCCGAA AUUAGCCC 1016
    1867 GGCUAAUU C UUGCUGAA 386 UUCAGCAA CUGAUGAGGCCGUUAGGCCGAA AAUUAGCC 1017
    1869 CUAAUUCU U GCUGAACU 387 AGUUCAGC CUGAUGAGGCCGUUAGGCCGAA AGAAUUAG 1018
    1878 GCUGAACU U CUUCAUGU 388 ACAUGAAG CUGAUGAGGCCGUUAGGCCGAA AGUUCAGC 1019
    1879 CUGAACUU C UUCAUGUA 389 UACAUGAA CUGAUGAGGCCGUUAGGCCGAA AAGUUCAG 1020
    1881 GAACUUCU U CAUGUAUG 390 CAUACAUG CUGAUGAGGCCGUUAGGCCGAA AGAAGUUC 1021
    1882 AACUUCUU C AUGUAUGU 391 ACAUACAU CUGAUGAGGCCGUUAGGCCGAA AAGAAGUU 1022
    1887 CUUCAUGU A UGUGACAC 392 GUGUCACA CUGAUGAGGCCGUUAGGCCGAA ACAUGAAG 1023
    1900 ACACUGCU U UUGAAACA 393 UGUUUCAA CUGAUGAGGCCGUUAGGCCGAA AGCAGUGU 1024
    1901 CACUGCUU U UGAAACAU 394 AUGUUUCA CUGAUGAGGCCGUUAGGCCGAA AAGCAGUG 1025
    1902 ACUGCUUU U GAAACAUC 395 GAUGUUUC CUGAUGAGGCCGUUAGGCCGAA AAAGCAGU 1026
    1910 UGAAACAU C AAAGUUUU 396 AAAACUUU CUGAUGAGGCCGUUAGGCCGAA AUGUUUCA 1027
    1916 AUCAAAGU U UUUCACAG 397 CUGUGAAA CUGAUGAGGCCGUUAGGCCGAA ACUUUGAU 1028
    1917 UCAAAGUU U UUCACAGA 398 UCUGUGAA CUGAUGAGGCCGUUAGGCCGAA AACUUUGA 1029
    1918 CAAAGUUU U UCACAGAC 399 GUCUGUGA CUGAUGAGGCCGUUAGGCCGAA AAACUUUG 1030
    1919 AAAGUUUU U CACAGACC 400 GGUCUGUG CUGAUGAGGCCGUUAGGCCGAA AAAACUUU 1031
    1920 AAGUUUUU C ACAGACCU 401 AGGUCUGU CUGAUGAGGCCGUUAGGCCGAA AAAAACUU 1032
    1929 ACAGACCU A CGGGAUGG 402 CCAUCCCG CUGAUGAGGCCGUUAGGCCGAA AGGUCUGU 1033
    1941 GAUGGCAU C AUCUCAGA 403 UCUGAGAU CUGAUGAGGCCGUUAGGCCGAA AUGCCAUC 1034
    1944 GGCAUCAU C UCAGAUAU 404 AUAUCUGA CUGAUGAGGCCGUUAGGCCGAA AUGAUGCC 1035
    1946 CAUCAUCU C AGAUAUAU 405 AUAUAUCU CUGAUGAGGCCGUUAGGCCGAA AGAUGAUG 1036
    1951 UCUCAGAU A UAUUUGAU 406 AUCAAAUA CUGAUGAGGCCGUUAGGCCGAA AUCUGAGA 1037
    1953 UCAGAUAU A UUUGAUAA 407 UUAUCAAA CUGAUGAGGCCGUUAGGCCGAA AUAUCUGA 1038
    1955 AGAUAUAU U UGAUAAAA 408 UUUUAUCA CUGAUGAGGCCGUUAGGCCGAA AUAUAUCU 1039
    1956 GAUAUAUU U GAUAAAAA 409 UUUUUAUC CUGAUGAGGCCGUUAGGCCGAA AAUAUAUC 1040
    1960 UAUUUGAU A AAAAAGAA 410 UUCUUUUU CUGAUGAGGCCGUUAGGCCGAA AUCAAAUA 1041
    1975 AAAAAACU C UUCUACAG 411 CUGUAGAA CUGAUGAGGCCGUUAGGCCGAA AGUUUUUU 1042
    1977 AAAACUCU U CUACAGAA 412 UUCUGUAG CUGAUGAGGCCGUUAGGCCGAA AGAGUUUU 1043
    1978 AAACUCUU C UACAGAAA 413 UUUCUGUA CUGAUGAGGCCGUUAGGCCGAA AAGAGUUU 1044
    1980 ACUCUUCU A CAGAAAUU 414 AAUUUCUG CUGAUGAGGCCGUUAGGCCGAA AGAAGAGU 1045
    1988 ACAGAAAU U ACUCUCAA 415 UUGAGAGU CUGAUGAGGCCGUUAGGCCGAA AUUUCUGU 1046
    1989 CAGAAAUU A CUCUCAAA 416 UUUGAGAG CUGAUGAGGCCGUUAGGCCGAA AAUUUCUG 1047
    1992 AAAUUACU C UCAAAGAA 417 UUCUUUGA CUGAUGAGGCCGUUAGGCCGAA AGUAAUUU 1048
    1994 AUUACUCU C AAAGAAAC 418 GUUUCUUU CUGAUGAGGCCGUUAGGCCGAA AGAGUAAU 1049
    2011 CUGAGGAU C GACCUAAC 419 GUUAGGUC CUGAUGAGGCCGUUAGGCCGAA AUCCUCAG 1050
    2017 AUCGACCU A ACACAUCU 420 AGAUGUGU CUGAUGAGGCCGUUAGGCCGAA AGGUCGAU 1051
    2024 UAACACAU C UGAAAUAC 421 GUAUUUCA CUGAUGAGGCCGUUAGGCCGAA AUGUGUUA 1052
    2031 UCUGAAAU A CUAAGGAC 422 GUCCUUAG CUGAUGAGGCCGUUAGGCCGAA AUUUCAGA 1053
    2034 GAAAUACU A AGGACCUU 423 AAGGUCCU CUGAUGAGGCCGUUAGGCCGAA AGUAUUUC 1054
    2042 AAGGACCU U GACUGUGU 424 ACACAGUC CUGAUGAGGCCGUUAGGCCGAA AGGUCCUU 1055
    2089 ACACAUGU U AGAGCCCU 425 AGGGCUCU CUGAUGAGGCCGUUAGGCCGAA ACAUGUGU 1056
    2090 CACAUGUU A GAGCCCUU 426 AAGGGCUC CUGAUGAGGCCGUUAGGCCGAA AACAUGUG 1057
    2098 AGAGCCCU U CUGAAAAA 427 UUUUUCAG CUGAUGAGGCCGUUAGGCCGAA AGGGCUCU 1058
    2099 GAGCCCUU C UGAAAAAG 428 CUUUUUCA CUGAUGAGGCCGUUAGGCCGAA AAGGGCUC 1059
    2109 GAAAAAGU A UCCUGCUU 429 AAGCAGGA CUGAUGAGGCCGUUAGGCCGAA ACUUUUUC 1060
    2111 AAAAGUAU C CUGCUUCU 430 AGAAGCAG CUGAUGAGGCCGUUAGGCCGAA AUACUUUU 1061
    2117 AUCCUGCU U CUGAUAUG 431 CAUAUCAG CUGAUGAGGCCGUUAGGCCGAA AGCAGGAU 1062
    2118 UCCUGCUU C UGAUAUGC 432 GCAUAUCA CUGAUGAGGCCGUUAGGCCGAA AAGCAGGA 1063
    2123 CUUCUGAU A UGCAGUUU 433 AAACUGCA CUGAUGAGGCCGUUAGGCCGAA AUCAGAAG 1064
    2130 UAUGCAGU U UUCCUUAA 434 UUAAGGAA CUGAUGAGGCCGUUAGGCCGAA ACUGCAUA 1065
    2131 AUGCAGUU U UCCUUAAA 435 UUUAAGGA CUGAUGAGGCCGUUAGGCCGAA AACUGCAU 1066
    2132 UGCAGUUU U CCUUAAAU 436 AUUUAAGG CUGAUGAGGCCGUUAGGCCGAA AAACUGCA 1067
    2133 GCAGUUUU C CUUAAAUU 437 AAUUUAAG CUGAUGAGGCCGUUAGGCCGAA AAAACUGC 1068
    2136 GUUUUCCU U AAAUUAUC 438 GAUAAUUU CUGAUGAGGCCGUUAGGCCGAA AGGAAAAC 1069
    2137 UUUUCCUU A AAUUAUCU 439 AGAUAAUU CUGAUGAGGCCGUUAGGCCGAA AAGGAAAA 1070
    2141 CCUUAAAU U AUCUAAAA 440 UUUUAGAU CUGAUGAGGCCGUUAGGCCGAA AUUUAAGG 1071
    2142 CUUAAAUU A UCUAAAAU 441 AUUUUAGA CUGAUGAGGCCGUUAGGCCGAA AAUUUAAG 1072
    2144 UAAAUUAU C UAAAAUCU 442 AGAUUUUA CUGAUGAGGCCGUUAGGCCGAA AUAAUUUA 1073
    2146 AAUUAUCU A AAAUCUGC 443 GCAGAUUU CUGAUGAGGCCGUUAGGCCGAA AGAUAAUU 1074
    2151 UCUAAAAU C UGCUAGGG 444 CCCUAGCA CUGAUGAGGCCGUUAGGCCGAA AUUUUAGA 1075
    2156 AAUCUGCU A GGGAAUAU 445 AUAUUCCC CUGAUGAGGCCGUUAGGCCGAA AGCAGAUU 1076
    2163 UAGGGAAU A UCAAUAGA 446 UCUAUUGA CUGAUGAGGCCGUUAGGCCGAA AUUCCCUA 1077
    2165 GGGAAUAU C AAUAGAUA 447 UAUCUAUU CUGAUGAGGCCGUUAGGCCGAA AUAUUCCC 1078
    2169 AUAUCAAU A GAUAUUUA 448 UAAAUAUC CUGAUGAGGCCGUUAGGCCGAA AUUGAUAU 1079
    2173 CAAUAGAU A UUUACCUU 449 AAGGUAAA CUGAUGAGGCCGUUAGGCCGAA AUCUAUUG 1080
    2175 AUAGAUAU U UACCUUUU 450 AAAAGGUA CUGAUGAGGCCGUUAGGCCGAA AUAUCUAU 1081
    2176 UAGAUAUU U ACCUUUUA 451 UAAAAGGU CUGAUGAGGCCGUUAGGCCGAA AAUAUCUA 1082
    2177 AGAUAUUU A CCUUUUAU 452 AUAAAAGG CUGAUGAGGCCGUUAGGCCGAA AAAUAUCU 1083
    2181 AUUUACCU U UUAUUUUA 453 UAAAAUAA CUGAUGAGGCCGUUAGGCCGAA AGGUAAAU 1084
    2182 UUUACCUU U UAUUUUAA 454 UUAAAAUA CUGAUGAGGCCGUUAGGCCGAA AAGGUAAA 1085
    2183 UUACCUUU U AUUUUAAU 455 AUUAAAAU CUGAUGAGGCCGUUAGGCCGAA AAAGGUAA 1086
    2184 UACCUUUU A UUUUAAUG 456 CAUUAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAGGUA 1087
    2186 CCUUUUAU U UUAAUGUU 457 AACAUUAA CUGAUGAGGCCGUUAGGCCGAA AUAAAAGG 1088
    2187 CUUUUAUU U UAAUGUUU 458 AAACAUUA CUGAUGAGGCCGUUAGGCCGAA AAUAAAAG 1089
    2188 UUUUAUUU U AAUGUUUC 459 GAAACAUU CUGAUGAGGCCGUUAGGCCGAA AAAUAAAA 1090
    2189 UUUAUUUU A AUGUUUCC 460 GGAAACAU CUGAUGAGGCCGUUAGGCCGAA AAAAUAAA 1091
    2194 UUUAAUGU U UCCUUUAA 461 UUAAAGGA CUGAUGAGGCCGUUAGGCCGAA ACAUUAAA 1092
    2195 UUAAUGUU U CCUUUAAU 462 AUUAAAGG CUGAUGAGGCCGUUAGGCCGAA AACAUUAA 1093
    2196 UAAUGUUU C CUUUAAUU 463 AAUUAAAG CUGAUGAGGCCGUUAGGCCGAA AAACAUUA 1094
    2199 UGUUUCCU U UAAUUUUU 464 AAAAAUUA CUGAUGAGGCCGUUAGGCCGAA AGGAAACA 1095
    2200 GUUUCCUU U AAUUUUUU 465 AAAAAAUU CUGAUGAGGCCGUUAGGCCGAA AAGGAAAC 1096
    2201 UUUCCUUU A AUUUUUUA 466 UAAAAAAU CUGAUGAGGCCGUUAGGCCGAA AAAGGAAA 1097
    2204 CCUUUAAU U UUUUACUA 467 UAGUAAAA CUGAUGAGGCCGUUAGGCCGAA AUUAAAGG 1098
    2205 CUUUAAUU U UUUACUAU 468 AUAGUAAA CUGAUGAGGCCGUUAGGCCGAA AAUUAAAG 1099
    2206 UUUAAUUU U UUACUAUU 469 AAUAGUAA CUGAUGAGGCCGUUAGGCCGAA AAAUUAAA 1100
    2207 UUAAUUUU U UACUAUUU 470 AAAUAGUA CUGAUGAGGCCGUUAGGCCGAA AAAAUUAA 1101
    2208 UAAUUUUU U ACUAUUUU 471 AAAAUAGU CUGAUGAGGCCGUUAGGCCGAA AAAAAUUA 1102
    2209 AAUUUUUU A CUAUUUUU 472 AAAAAUAG CUGAUGAGGCCGUUAGGCCGAA AAAAAAUU 1103
    2212 UUUUUACU A UUUUUACU 473 AGUAAAAA CUGAUGAGGCCGUUAGGCCGAA AGUAAAAA 1104
    2214 UUUACUAU U UUUACUAA 474 UUAGUAAA CUGAUGAGGCCGUUAGGCCGAA AUAGUAAA 1105
    2215 UUACUAUU U UUACUAAU 475 AUUAGUAA CUGAUGAGGCCGUUAGGCCGAA AAUAGUAA 1106
    2216 UACUAUUU U UACUAAUC 476 GAUUAGUA CUGAUGAGGCCGUUAGGCCGAA AAAUAGUA 1107
    2217 ACUAUUUU U ACUAAUCU 477 AGAUUAGU CUGAUGAGGCCGUUAGGCCGAA AAAAUAGU 1108
    2218 CUAUUUUU A CUAAUCUU 478 AAGAUUAG CUGAUGAGGCCGUUAGGCCGAA AAAAAUAG 1109
    2221 UUUUUACU A AUCUUUCU 479 AGAAAGAU CUGAUGAGGCCGUUAGGCCGAA AGUAAAAA 1110
    2224 UUACUAAU C UUUCUGCA 480 UGCAGAAA CUGAUGAGGCCGUUAGGCCGAA AUUAGUAA 1111
    2226 ACUAAUCU U UCUGCAGA 481 UCUGCAGA CUGAUGAGGCCGUUAGGCCGAA AGAUUAGU 1112
    2227 CUAAUCUU U CUGCAGAA 482 UUCUGCAG CUGAUGAGGCCGUUAGGCCGAA AAGAUUAG 1113
    2228 UAAUCUUU C UGCAGAAA 483 UUUCUGCA CUGAUGAGGCCGUUAGGCCGAA AAAGAUUA 1114
    2246 AGAAAGGU U UUCUUCUU 484 AAGAAGAA CUGAUGAGGCCGUUAGGCCGAA ACCUUUCU 1115
    2247 GAAAGGUU U UCUUCUUU 485 AAAGAAGA CUGAUGAGGCCGUUAGGCCGAA AACCUUUC 1116
    2248 AAAGGUUU U CUUCUUUU 486 AAAAGAAG CUGAUGAGGCCGUUAGGCCGAA AAACCUUU 1117
    2249 AAGGUUUU C UUCUUUUU 487 AAAAAGAA CUGAUGAGGCCGUUAGGCCGAA AAAACCUU 1118
    2251 GGUUUUCU U CUUUUUGC 488 GCAAAAAG CUGAUGAGGCCGUUAGGCCGAA AGAAAACC 1119
    2252 GUUUUCUU C UUUUUGCU 489 AGCAAAAA CUGAUGAGGCCGUUAGGCCGAA AAGAAAAC 1120
    2254 UUUCUUCU U UUUGCUUC 490 GAAGCAAA CUGAUGAGGCCGUUAGGCCGAA AGAAGAAA 1121
    2255 UUCUUCUU U UUGCUUCA 491 UGAAGCAA CUGAUGAGGCCGUUAGGCCGAA AAGAAGAA 1122
    2256 UCUUCUUU U UGCUUCAA 492 UUGAAGCA CUGAUGAGGCCGUUAGGCCGAA AAAGAAGA 1123
    2257 CUUCUUUU U GCUUCAAA 493 UUUGAAGC CUGAUGAGGCCGUUAGGCCGAA AAAAGAAG 1124
    2261 UUUUUGCU U CAAAAACA 494 UGUUUUUG CUGAUGAGGCCGUUAGGCCGAA AGCAAAAA 1125
    2262 UUUUGCUU C AAAAACAU 495 AUGUUUUU CUGAUGAGGCCGUUAGGCCGAA AAGCAAAA 1126
    2271 AAAAACAU U CUUACAUU 496 AAUGUAAG CUGAUGAGGCCGUUAGGCCGAA AUGUUUUU 1127
    2272 AAAACAUU C UUACAUUU 497 AAAUGUAA CUGAUGAGGCCGUUAGGCCGAA AAUGUUUU 1128
    2274 AACAUUCU U ACAUUUUA 498 UAAAAUGU CUGAUGAGGCCGUUAGGCCGAA AGAAUGUU 1129
    2275 ACAUUCUU A CAUUUUAC 499 GUAAAAUG CUGAUGAGGCCGUUAGGCCGAA AAGAAUGU 1130
    2279 UCUUACAU U UUACUUUU 500 AAAAGUAA CUGAUGAGGCCGUUAGGCCGAA AUGUAAGA 1131
    2280 CUUACAUU U UACUUUUU 501 AAAAAGUA CUGAUGAGGCCGUUAGGCCGAA AAUGUAAG 1132
    2281 UUACAUUU U ACUUUUUC 502 GAAAAAGU CUGAUGAGGCCGUUAGGCCGAA AAAUGUAA 1133
    2282 UACAUUUU A CUUUUUCC 503 GGAAAAAG CUGAUGAGGCCGUUAGGCCGAA AAAAUGUA 1134
    2285 AUUUUACU U UUUCCUGG 504 CCAGGAAA CUGAUGAGGCCGUUAGGCCGAA AGUAAAAU 1135
    2286 UUUUACUU U UUCCUGGC 505 GCCAGGAA CUGAUGAGGCCGUUAGGCCGAA AAGUAAAA 1136
    2287 UUUACUUU U UCCUGGCU 506 AGCCAGGA CUGAUGAGGCCGUUAGGCCGAA AAAGUAAA 1137
    2288 UUACUUUU U CCUGGCUC 507 GAGCCAGG CUGAUGAGGCCGUUAGGCCGAA AAAAGUAA 1138
    2289 UACUUUUU C CUGGCUCA 508 UGAGCCAG CUGAUGAGGCCGUUAGGCCGAA AAAAAGUA 1139
    2296 UCCUGGCU C AUCUCUUU 509 AAAGAGAU CUGAUGAGGCCGUUAGGCCGAA AGCCAGGA 1140
    2299 UGGCUCAU C UCUUUAUU 510 AAUAAAGA CUGAUGAGGCCGUUAGGCCGAA AUGAGCCA 1141
    2301 GCUCAUCU C UUUAUUCU 511 AGAAUAAA CUGAUGAGGCCGUUAGGCCGAA AGAUGAGC 1142
    2303 UCAUCUCU U UAUUCUUU 512 AAAGAAUA CUGAUGAGGCCGUUAGGCCGAA AGAGAUGA 1143
    2304 CAUCUCUU U AUUCUUUU 513 AAAAGAAU CUGAUGAGGCCGUUAGGCCGAA AAGAGAUG 1144
    2305 AUCUCUUU A UUCUUUUU 514 AAAAAGAA CUGAUGAGGCCGUUAGGCCGAA AAAGAGAU 1145
    2307 CUCUUUAU U CUUUUUUU 515 AAAAAAAG CUGAUGAGGCCGUUAGGCCGAA AUAAAGAG 1146
    2308 UCUUUAUU C UUUUUUUU 516 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAUAAAGA 1147
    2310 UUUAUUCU U UUUUUUUU 517 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AGAAUAAA 1148
    2311 UUAUUCUU U UUUUUUUU 518 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAGAAUAA 1149
    2312 UAUUCUUU U UUUUUUUU 519 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAGAAUA 1150
    2313 AUUCUUUU U UUUUUUUU 520 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAGAAU 1151
    2314 UUCUUUUU U UUUUUUUU 521 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAGAA 1152
    2315 UCUUUUUU U UUUUUUUA 522 UAAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAGA 1153
    2316 CUUUUUUU U UUUUUUAA 523 UUAAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAG 1154
    2317 UUUUUUUU U UUUUUAAA 524 UUUAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 1155
    2318 UUUUUUUU U UUUUAAAG 525 CUUUAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 1156
    2319 UUUUUUUU U UUUAAAGA 526 UCUUUAAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 1157
    2320 UUUUUUUU U UUAAAGAC 527 GUCUUUAA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 1158
    2321 UUUUUUUU U UAAAGACA 528 UGUCUUUA CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 1159
    2322 UUUUUUUU U AAAGACAG 529 CUGUCUUU CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 1160
    2323 UUUUUUUU A AAGACAGA 530 UCUGUCUU CUGAUGAGGCCGUUAGGCCGAA AAAAAAAA 1161
    2334 GACAGAGU C UCGCUCUG 531 CAGAGCGA CUGAUGAGGCCGUUAGGCCGAA ACUCUGUC 1162
    2336 CAGAGUCU C GCUCUGUU 532 AACAGAGC CUGAUGAGGCCGUUAGGCCGAA AGACUCUG 1163
    2340 GUCUCGCU C UGUUGCCC 533 GGGCAACA CUGAUGAGGCCGUUAGGCCGAA AGCGAGAC 1164
    2344 CGCUCUGU U GCCCAGGC 534 GCCUGGGC CUGAUGAGGCCGUUAGGCCGAA ACAGAGCG 1165
    2372 GACACAGU C UUGGCUCA 535 UGAGCCAA CUGAUGAGGCCGUUAGGCCGAA ACUGUGUC 1166
    2374 CACAGUCU U GGCUCACU 536 AGUGAGCC CUGAUGAGGCCGUUAGGCCGAA AGACUGUG 1167
    2379 UCUUGGCU C ACUGCAAC 537 GUUGCAGU CUGAUGAGGCCGUUAGGCCGAA AGCCAAGA 1168
    2389 CUGCAACU U CUGCCUCU 538 AGAGGCAG CUGAUGAGGCCGUUAGGCCGAA AGUUGCAG 1169
    2390 UGCAACUU C UGCCUCUU 539 AAGAGGCA CUGAUGAGGCCGUUAGGCCGAA AAGUUGCA 1170
    2396 UUCUGCCU C UUGGGUUC 540 GAACCCAA CUGAUGAGGCCGUUAGGCCGAA AGGCAGAA 1171
    2398 CUGCCUCU U GGGUUCAA 541 UUGAACCC CUGAUGAGGCCGUUAGGCCGAA AGAGGCAG 1172
    2403 UCUUGGGU U CAAGUGAU 542 AUCACUUG CUGAUGAGGCCGUUAGGCCGAA ACCCAAGA 1173
    2404 CUUGGGUU C AAGUGAUU 543 AAUCACUU CUGAUGAGGCCGUUAGGCCGAA AACCCAAG 1174
    2412 CAAGUGAU U CUCCUGCC 544 GGCAGGAG CUGAUGAGGCCGUUAGGCCGAA AUCACUUG 1175
    2413 AAGUGAUU C UCCUGCCU 545 AGGCAGGA CUGAUGAGGCCGUUAGGCCGAA AAUCACUU 1176
    2415 GUGAUUCU C CUGCCUCA 546 UGAGGCAG CUGAUGAGGCCGUUAGGCCGAA AGAAUCAC 1177
    2422 UCCUGCCU C AGCCUCCU 547 AGGAGGCU CUGAUGAGGCCGUUAGGCCGAA AGGCAGGA 1178
    2428 CUCAGCCU C CUGAGUAG 548 CUACUCAG CUGAUGAGGCCGUUAGGCCGAA AGGCUGAG 1179
    2435 UCCUGAGU A GCUGGAUU 549 AAUCCAGC CUGAUGAGGCCGUUAGGCCGAA ACUCAGGA 1180
    2443 AGCUGGAU U ACAGGCAU 550 AUGCCUGU CUGAUGAGGCCGUUAGGCCGAA AUCCAGCU 1181
    2444 GCUGGAUU A CAGGCAUG 551 CAUGCCUG CUGAUGAGGCCGUUAGGCCGAA AAUCCAGC 1182
    2469 ACCCAACU A AUUUUUGU 552 ACAAAAAU CUGAUGAGGCCGUUAGGCCGAA AGUUGGGU 1183
    2472 CAACUAAU U UUUGUGUU 553 AACACAAA CUGAUGAGGCCGUUAGGCCGAA AUUAGUUG 1184
    2473 AACUAAUU U UUGUGUUU 554 AAACACAA CUGAUGAGGCCGUUAGGCCGAA AAUUAGUU 1185
    2474 ACUAAUUU U UGUGUUUU 555 AAAACACA CUGAUGAGGCCGUUAGGCCGAA AAAUUAGU 1186
    2475 CUAAUUUU U GUGUUUUU 556 AAAAACAC CUGAUGAGGCCGUUAGGCCGAA AAAAUUAG 1187
    2480 UUUUGUGU U UUUAAUAA 557 UUAUUAAA CUGAUGAGGCCGUUAGGCCGAA ACACAAAA 1188
    2481 UUUGUGUU U UUAAUAAA 558 UUUAUUAA CUGAUGAGGCCGUUAGGCCGAA AACACAAA 1189
    2482 UUGUGUUU U UAAUAAAG 559 CUUUAUUA CUGAUGAGGCCGUUAGGCCGAA AAACACAA 1190
    2483 UGUGUUUU U AAUAAAGA 560 UCUUUAUU CUGAUGAGGCCGUUAGGCCGAA AAAACACA 1191
    2484 GUGUUUUU A AUAAAGAC 561 GUCUUUAU CUGAUGAGGCCGUUAGGCCGAA AAAAACAC 1192
    2487 UUUUUAAU A AAGACAGG 562 CCUGUCUU CUGAUGAGGCCGUUAGGCCGAA AUUAAAAA 1193
    2498 GACAGGGU U UCACCAUG 563 CAUGGUGA CUGAUGAGGCCGUUAGGCCGAA ACCCUGUC 1194
    2499 ACAGGGUU U CACCAUGU 564 ACAUGGUG CUGAUGAGGCCGUUAGGCCGAA AACCCUGU 1195
    2500 CAGGGUUU C ACCAUGUU 565 AACAUGGU CUGAUGAGGCCGUUAGGCCGAA AAACCCUG 1196
    2508 CACCAUGU U GGCCAGGC 566 GCCUGGCC CUGAUGAGGCCGUUAGGCCGAA ACAUGGUG 1197
    2521 AGGCUGGU C UCAAACUC 567 GAGUUUGA CUGAUGAGGCCGUUAGGCCGAA ACCAGCCU 1198
    2523 GCUGGUCU C AAACUCCU 568 AGGAGUUU CUGAUGAGGCCGUUAGGCCGAA AGACCAGC 1199
    2529 CUCAAACU C CUGACCUC 569 GAGGUCAG CUGAUGAGGCCGUUAGGCCGAA AGUUUGAG 1200
    2537 CCUGACCU C AAGUAAUC 570 GAUUACUU CUGAUGAGGCCGUUAGGCCGAA AGGUCAGG 1201
    2542 CCUCAAGU A AUCCACCU 571 AGGUGGAU CUGAUGAGGCCGUUAGGCCGAA ACUUGAGG 1202
    2545 CAAGUAAU C CACCUGCC 572 GGCAGGUG CUGAUGAGGCCGUUAGGCCGAA AUUACUUG 1203
    2555 ACCUGCCU C GGCCUCCC 573 GGGAGGCC CUGAUGAGGCCGUUAGGCCGAA AGGCAGGU 1204
    2561 CUCGGCCU C CCAAAGUG 574 CACUUUGG CUGAUGAGGCCGUUAGGCCGAA AGGCCGAG 1205
    2577 GCUGGGAU U ACAGGGAU 575 AUCCCUGU CUGAUGAGGCCGUUAGGCCGAA AUCCCAGC 1206
    2578 CUGGGAUU A CAGGGAUG 576 CAUCCCUG CUGAUGAGGCCGUUAGGCCGAA AAUCCCAG 1207
    2605 CCCAGCCU C AUCUCUUU 577 AAAGAGAU CUGAUGAGGCCGUUAGGCCGAA AGGCUGGG 1208
    2608 AGCCUCAU C UCUUUGUU 578 AACAAAGA CUGAUGAGGCCGUUAGGCCGAA AUGAGGCU 1209
    2610 CCUCAUCU C UUUGUUCU 579 AGAACAAA CUGAUGAGGCCGUUAGGCCGAA AGAUGAGG 1210
    2612 UCAUCUCU U UGUUCUAA 580 UUAGAACA CUGAUGAGGCCGUUAGGCCGAA AGAGAUGA 1211
    2613 CAUCUCUU U GUUCUAAA 581 UUUAGAAC CUGAUGAGGCCGUUAGGCCGAA AAGAGAUG 1212
    2616 CUCUUUGU U CUAAAGAU 582 AUCUUUAG CUGAUGAGGCCGUUAGGCCGAA ACAAAGAG 1213
    2617 UCUUUGUU C UAAAGAUG 583 CAUCUUUA CUGAUGAGGCCGUUAGGCCGAA AACAAAGA 1214
    2619 UUUGUUCU A AAGAUGGA 584 UCCAUCUU CUGAUGAGGCCGUUAGGCCGAA AGAACAAA 1215
    2644 CCCCAAAU U UUCUUUUU 585 AAAAAGAA CUGAUGAGGCCGUUAGGCCGAA AUUUGGGG 1216
    2645 CCCAAAUU U UCUUUUUA 586 UAAAAAGA CUGAUGAGGCCGUUAGGCCGAA AAUUUGGG 1217
    2646 CCAAAUUU U CUUUUUAU 587 AUAAAAAG CUGAUGAGGCCGUUAGGCCGAA AAAUUUGG 1218
    2647 CAAAUUUU C UUUUUAUA 588 UAUAAAAA CUGAUGAGGCCGUUAGGCCGAA AAAAUUUG 1219
    2649 AAUUUUCU U UUUAUACU 589 AGUAUAAA CUGAUGAGGCCGUUAGGCCGAA AGAAAAUU 1220
    2650 AUUUUCUU U UUAUACUA 590 UAGUAUAA CUGAUGAGGCCGUUAGGCCGAA AAGAAAAU 1221
    2651 UUUUCUUU U UAUACUAU 591 AUAGUAUA CUGAUGAGGCCGUUAGGCCGAA AAAGAAAA 1222
    2652 UUUCUUUU U AUACUAUU 592 AAUAGUAU CUGAUGAGGCCGUUAGGCCGAA AAAAGAAA 1223
    2653 UUCUUUUU A UACUAUUA 593 UAAUAGUA CUGAUGAGGCCGUUAGGCCGAA AAAAAGAA 1224
    2655 CUUUUUAU A CUAUUAAU 594 AUUAAUAG CUGAUGAGGCCGUUAGGCCGAA AUAAAAAG 1225
    2658 UUUAUACU A UUAAUGAA 595 UUCAUUAA CUGAUGAGGCCGUUAGGCCGAA AGUAUAAA 1226
    2660 UAUACUAU U AAUGAAUC 596 GAUUCAUU CUGAUGAGGCCGUUAGGCCGAA AUAGUAUA 1227
    2661 AUACUAUU A AUGAAUCA 597 UGAUUCAU CUGAUGAGGCCGUUAGGCCGAA AAUAGUAU 1228
    2668 UAAUGAAU C AAUCAAUU 598 AAUUGAUU CUGAUGAGGCCGUUAGGCCGAA AUUCAUUA 1229
    2672 GAAUCAAU C AAUUCAUA 599 UAUGAAUU CUGAUGAGGCCGUUAGGCCGAA AUUGAUUC 1230
    2676 CAAUCAAU U CAUAUCUA 600 UAGAUAUG CUGAUGAGGCCGUUAGGCCGAA AUUGAUUG 1231
    2677 AAUCAAUU C AUAUCUAU 601 AUAGAUAU CUGAUGAGGCCGUUAGGCCGAA AAUUGAUU 1232
    2680 CAAUUCAU A UCUAUUUA 602 UAAAUAGA CUGAUGAGGCCGUUAGGCCGAA AUGAAUUG 1233
    2682 AUUCAUAU C UAUUUAUU 603 AAUAAAUA CUGAUGAGGCCGUUAGGCCGAA AUAUGAAU 1234
    2684 UCAUAUCU A UUUAUUAA 604 UUAAUAAA CUGAUGAGGCCGUUAGGCCGAA AGAUAUGA 1235
    2686 AUAUCUAU U UAUUAAAU 605 AUUUAAUA CUGAUGAGGCCGUUAGGCCGAA AUAGAUAU 1236
    2687 UAUCUAUU U AUUAAAUU 606 AAUUUAAU CUGAUGAGGCCGUUAGGCCGAA AAUAGAUA 1237
    2688 AUCUAUUU A UUAAAUUU 607 AAAUUUAA CUGAUGAGGCCGUUAGGCCGAA AAAUAGAU 1238
    2690 CUAUUUAU U AAAUUUCU 608 AGAAAUUU CUGAUGAGGCCGUUAGGCCGAA AUAAAUAG 1239
    2691 UAUUUAUU A AAUUUCUA 609 UAGAAAUU CUGAUGAGGCCGUUAGGCCGAA AAUAAAUA 1240
    2695 UAUUAAAU U UCUACCGC 610 GCGGUAGA CUGAUGAGGCCGUUAGGCCGAA AUUUAAUA 1241
    2696 AUUAAAUU U CUACCGCU 611 AGCGGUAG CUGAUGAGGCCGUUAGGCCGAA AAUUUAAU 1242
    2697 UUAAAUUU C UACCGCUU 612 AAGCGGUA CUGAUGAGGCCGUUAGGCCGAA AAAUUUAA 1243
    2699 AAAUUUCU A CCGCUUUU 613 AAAAGCGG CUGAUGAGGCCGUUAGGCCGAA AGAAAUUU 1244
    2705 CUACCGCU U UUAGGCCA 614 UGGCCUAA CUGAUGAGGCCGUUAGGCCGAA AGCGGUAG 1245
    2706 UACCGCUU U UAGGCCAA 615 UUGGCCUA CUGAUGAGGCCGUUAGGCCGAA AAGCGGUA 1246
    2707 ACCGCUUU U AGGCCAAA 616 UUUGGCCU CUGAUGAGGCCGUUAGGCCGAA AAAGCGGU 1247
    2708 CCGCUUUU A GGCCAAAA 617 UUUUGGCC CUGAUGAGGCCGUUAGGCCGAA AAAAGCGG 1248
    2723 AAAAAUGU A AGAUCGUU 618 AACGAUCU CUGAUGAGGCCGUUAGGCCGAA ACAUUUUU 1249
    2728 UGUAAGAU C GUUCUCUG 619 CAGAGAAC CUGAUGAGGCCGUUAGGCCGAA AUCUUACA 1250
    2731 AAGAUCGU U CUCUGCCU 620 AGGCAGAG CUGAUGAGGCCGUUAGGCCGAA ACGAUCUU 1251
    2732 AGAUCGUU C UCUGCCUC 621 GAGGCAGA CUGAUGAGGCCGUUAGGCCGAA AACGAUCU 1252
    2734 AUCGUUCU C UGCCUCAC 622 GUGAGGCA CUGAUGAGGCCGUUAGGCCGAA AGAACGAU 1253
    2740 CUCUGCCU C ACAUAGCU 623 AGCUAUGU CUGAUGAGGCCGUUAGGCCGAA AGGCAGAG 1254
    2745 CCUCACAU A GCUUACAA 624 UUGUAAGC CUGAUGAGGCCGUUAGGCCGAA AUGUGAGG 1255
    2749 ACAUAGCU U ACAAGCCA 625 UGGCUUGU CUGAUGAGGCCGUUAGGCCGAA AGCUAUGU 1256
    2750 CAUAGCUU A CAAGCCAG 626 CUGGCUUG CUGAUGAGGCCGUUAGGCCGAA AAGCUAUG 1257
    2769 GGAGAAAU A UGGUACUC 627 GAGUACCA CUGAUGAGGCCGUUAGGCCGAA AUUUCUCC 1258
    2774 AAUAUGGU A CUCAUUAA 628 UUAAUGAG CUGAUGAGGCCGUUAGGCCGAA ACCAUAUU 1259
    2777 AUGGUACU C AUUAAAAA 629 UUUUUAAU CUGAUGAGGCCGUUAGGCCGAA AGUACCAU 1260
    2780 GUACUCAU U AAAAAAAA 630 UUUUUUUU CUGAUGAGGCCGUUAGGCCGAA AUGAGUAC 1261
    2781 UACUCAUU A AAAAAAAA 631 UUUUUUUU CUGAUGAGGCCGUUAGGCCGAA AAUGAGUA 1262

    Input Sequence = NM_002759. Cut Site = UH/.

    Arm Length = 8. Core Sequence = CUGAUGAG GCCGUUAGGC CGAA

    NM_002759 (Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)

    Underlined region can be any X sequence or linker, as described herein.
  • TABLE IX
    Human PKR Inozyme and Substrate Sequence
    Seq Seq
    Pos Substrate ID Inozyme ID
    17 GGCGGCGC A GUUUGCUC 1263 GAGCAAAC CUGAUGAGGCCGUUAGGCCGAA ICGCCGCC 1762
    24 CAGUUUGC U CAUACUUU 1264 AAAGUAUG CUGAUGAGGCCGUUAGGCCGAA ICAAACUG 1763
    26 GUUUGCUC A UACUUUGU 1265 ACAAAGUA CUGAUGAGGCCGUUAGGCCGAA IAGCAAAC 1764
    30 GCUCAUAC U UUGUGACU 1266 AGUCACAA CUGAUGAGGCCGUUAGGCCGAA IUAUGAGC 1765
    38 UUUGUGAC U UGCGGUCA 1267 UGACCGCA CUGAUGAGGCCGUUAGGCCGAA IUCACAAA 1766
    46 UUGCGGUC A CAGUGGCA 1268 UGCCACUG CUGAUGAGGCCGUUAGGCCGAA IACCGCAA 1767
    48 GCGGUCAC A GUGGCAUU 1269 AAUGCCAC CUGAUGAGGCCGUUAGGCCGAA IUGACCGC 1768
    54 ACAGUGGC A UUCAGCUC 1270 GAGCUGAA CUGAUGAGGCCGUUAGGCCGAA ICCACUGU 1769
    58 UGGCAUUC A GCUCCACA 1271 UGUGGAGC CUGAUGAGGCCGUUAGGCCGAA IAAUGCCA 1770
    61 CAUUCAGC U CCACACUU 1272 AAGUGUGG CUGAUGAGGCCGUUAGGCCGAA ICUGAAUG 1771
    63 UUCAGCUC C ACACUUGG 1273 CCAAGUGU CUGAUGAGGCCGUUAGGCCGAA IAGCUGAA 1772
    64 UCAGCUCC A CACUUGGU 1274 ACCAAGUG CUGAUGAGGCCGUUAGGCCGAA IGAGCUGA 1773
    66 AGCUCCAC A CUUGGUAG 1275 CUACCAAG CUGAUGAGGCCGUUAGGCCGAA IUGGAGCU 1774
    68 CUCCACAC U UGGUAGAA 1276 UUCUACCA CUGAUGAGGCCGUUAGGCCGAA IUGUGGAG 1775
    78 GGUAGAAC C ACAGGCAC 1277 GUGCCUGU CUGAUGAGGCCGUUAGGCCGAA IUUCUACC 1776
    79 GUAGAACC A CAGGCACG 1278 CGUGCCUG CUGAUGAGGCCGUUAGGCCGAA IGUUCUAC 1777
    81 AGAACCAC A GGCACGAC 1279 GUCGUGCC CUGAUGAGGCCGUUAGGCCGAA IUGGUUCU 1778
    85 CCACAGGC A CGACAAGC 1280 GCUUGUCG CUGAUGAGGCCGUUAGGCCGAA ICCUGUGG 1779
    90 GGCACGAC A AGCAUAGA 1281 UCUAUGCU CUGAUGAGGCCGUUAGGCCGAA IUCGUGCC 1780
    94 CGACAAGC A UAGAAACA 1282 UGUUUCUA CUGAUGAGGCCGUUAGGCCGAA ICUUGUCG 1781
    102 AUAGAAAC A UCCUAAAC 1283 GUUUAGGA CUGAUGAGGCCGUUAGGCCGAA IUUUCUAU 1782
    105 GAAACAUC C UAAACAAU 1284 AUUGUUUA CUGAUGAGGCCGUUAGGCCGAA IAUGUUUC 1783
    106 AAACAUCC U AAACAAUC 1285 GAUUGUUU CUGAUGAGGCCGUUAGGCCGAA IGAUGUUU 1784
    111 UCCUAAAC A AUCUUCAU 1286 AUGAAGAU CUGAUGAGGCCGUUAGGCCGAA IUUUAGGA 1785
    115 AAACAAUC U UCAUCGAG 1287 CUCGAUGA CUGAUGAGGCCGUUAGGCCGAA IAUUGUUU 1786
    118 CAAUCUUC A UCGAGGCA 1288 UGCCUCGA CUGAUGAGGCCGUUAGGCCGAA IAAGAUUG 1787
    126 AUCGAGGC A UCGAGGUC 1289 GACCUCGA CUGAUGAGGCCGUUAGGCCGAA ICCUCGAU 1788
    135 UCGAGGUC C AUCCCAAU 1290 AUUGGGAU CUGAUGAGGCCGUUAGGCCGAA IACCUCGA 1789
    136 CGAGGUCC A UCCCAAUA 1291 UAUUGGGA CUGAUGAGGCCGUUAGGCCGAA IGACCUCG 1790
    139 GGUCCAUC C CAAUAAAA 1292 UUUUAUUG CUGAUGAGGCCGUUAGGCCGAA IAUGGACC 1791
    140 GUCCAUCC C AAUAAAAA 1293 UUUUUAUU CUGAUGAGGCCGUUAGGCCGAA IGAUGGAC 1792
    141 UCCAUCCC A AUAAAAAU 1294 AUUUUUAU CUGAUGAGGCCGUUAGGCCGAA IGGAUGGA 1793
    151 UAAAAAUC A GGAGACCC 1295 GGGUCUCC CUGAUGAGGCCGUUAGGCCGAA IAUUUUUA 1794
    158 CAGGAGAC C CUGGCUAU 1296 AUAGCCAG CUGAUGAGGCCGUUAGGCCGAA IUCUCCUG 1795
    159 AGGAGACC C UGGCUAUC 1297 GAUAGCCA CUGAUGAGGCCGUUAGGCCGAA IGUCUCCU 1796
    160 GGAGACCC U GGCUAUCA 1298 UGAUAGCC CUGAUGAGGCCGUUAGGCCGAA IGGUCUCC 1797
    164 ACCCUGGC U AUCAUAGA 1299 UCUAUGAU CUGAUGAGGCCGUUAGGCCGAA ICCAGGGU 1798
    168 UGGCUAUC A UAGACCUU 1300 AAGGUCUA CUGAUGAGGCCGUUAGGCCGAA IAUAGCCA 1799
    174 UCAUAGAC C UUAGUCUU 1301 AAGACUAA CUGAUGAGGCCGUUAGGCCGAA IUCUAUGA 1800
    175 CAUAGACC U UAGUCUUC 1302 GAAGACUA CUGAUGAGGCCGUUAGGCCGAA IGUCUAUG 1801
    181 CCUUAGUC U UCGCUGGU 1303 ACCAGCGA CUGAUGAGGCCGUUAGGCCGAA IACUAAGG 1802
    186 GUCUUCGC U GGUAUACU 1304 AGUAUACC CUGAUGAGGCCGUUAGGCCGAA ICGAAGAC 1803
    194 UGGUAUAC U CGCUGUCU 1305 AGACAGCG CUGAUGAGGCCGUUAGGCCGAA IUAUACCA 1804
    198 AUACUCGC U GUCUGUCA 1306 UGACAGAC CUGAUGAGGCCGUUAGGCCGAA ICGAGUAU 1805
    202 UCGCUGUC U GUCAACCA 1307 UGGUUGAC CUGAUGAGGCCGUUAGGCCGAA IACAGCGA 1806
    206 UGUCUGUC A ACCAGCGG 1308 CCGCUGGU CUGAUGAGGCCGUUAGGCCGAA IACAGACA 1807
    209 CUGUCAAC C AGCGGUUG 1309 CAACCGCU CUGAUGAGGCCGUUAGGCCGAA IUUGACAG 1808
    210 UGUCAACC A GCGGUUGA 1310 UCAACCGC CUGAUGAGGCCGUUAGGCCGAA IGUUGACA 1809
    220 CGGUUGAC U UUUUUUAA 1311 UUAAAAAA CUGAUGAGGCCGUUAGGCCGAA IUCAACCG 1810
    231 UUUUAAGC C UUCUUUUU 1312 AAAAAGAA CUGAUGAGGCCGUUAGGCCGAA ICUUAAAA 1811
    232 UUUAAGCC U UCUUUUUU 1313 AAAAAAGA CUGAUGAGGCCGUUAGGCCGAA IGCUUAAA 1812
    235 AAGCCUUC U UUUUUCUC 1314 GAGAAAAA CUGAUGAGGCCGUUAGGCCGAA IAAGGCUU 1813
    242 CUUUUUUC U CUUUUACC 1315 GGUAAAAG CUGAUGAGGCCGUUAGGCCGAA IAAAAAAG 1814
    244 UUUUUCUC U UUUACCAG 1316 CUGGUAAA CUGAUGAGGCCGUUAGGCCGAA IAGAAAAA 1815
    250 UCUUUUAC C AGUUUCUG 1317 CAGAAACU CUGAUGAGGCCGUUAGGCCGAA IUAAAAGA 1816
    251 CUUUUACC A GUUUCUGG 1318 CCAGAAAC CUGAUGAGGCCGUUAGGCCGAA IGUAAAAG 1817
    257 CCAGUUUC U GGAGCAAA 1319 UUUGCUCC CUGAUGAGGCCGUUAGGCCGAA IAAACUGG 1818
    263 UCUGGAGC A AAUUCAGU 1320 ACUGAAUU CUGAUGAGGCCGUUAGGCCGAA ICUCCAGA 1819
    269 GCAAAUUC A GUUUGCCU 1321 AGGCAAAC CUGAUGAGGCCGUUAGGCCGAA IAAUUUGC 1820
    276 CAGUUUGC C UUCCUGGA 1322 UCCAGGAA CUGAUGAGGCCGUUAGGCCGAA ICAAACUG 1821
    277 AGUUUGCC U UCCUGGAU 1323 AUCCAGGA CUGAUGAGGCCGUUAGGCCGAA IGCAAACU 1822
    280 UUGCCUUC C UGGAUUUG 1324 CAAAUCCA CUGAUGAGGCCGUUAGGCCGAA IAAGGCAA 1823
    281 UGCCUUCC U GGAUUUGU 1325 ACAAAUCC CUGAUGAGGCCGUUAGGCCGAA IGAAGGCA 1824
    303 GUAAUGAC C UCAAAACU 1326 AGUUUUGA CUGAUGAGGCCGUUAGGCCGAA IUCAUUAC 1825
    304 UAAUGACC U CAAAACUU 1327 AAGUUUUG CUGAUGAGGCCGUUAGGCCGAA IGUCAUUA 1826
    306 AUGACCUC A AAACUUUA 1328 UAAAGUUU CUGAUGAGGCCGUUAGGCCGAA IAGGUCAU 1827
    311 CUCAAAAC U UUAGCAGU 1329 ACUGCUAA CUGAUGAGGCCGUUAGGCCGAA IUUUUGAG 1828
    317 ACUUUAGC A GUUCUUCC 1330 GGAAGAAC CUGAUGAGGCCGUUAGGCCGAA ICUAAAGU 1829
    322 AGCAGUUC U UCCAUCUG 1331 CAGAUGGA CUGAUGAGGCCGUUAGGCCGAA IAACUGCU 1830
    325 AGUUCUUC C AUCUGACU 1332 AGUCAGAU CUGAUGAGGCCGUUAGGCCGAA IAAGAACU 1831
    326 GUUCUUCC A UCUGACUC 1333 GAGUCAGA CUGAUGAGGCCGUUAGGCCGAA IGAAGAAC 1832
    329 CUUCCAUC U GACUCAGG 1334 CCUGAGUC CUGAUGAGGCCGUUAGGCCGAA IAUGGAAG 1833
    333 CAUCUGAC U CAGGUUUG 1335 CAAACCUG CUGAUGAGGCCGUUAGGCCGAA IUCAGAUG 1834
    335 UCUGACUC A GGUUUGCU 1336 AGCAAACC CUGAUGAGGCCGUUAGGCCGAA IAGUCAGA 1835
    343 AGGUUUGC U UCUCUGGC 1337 GCCAGAGA CUGAUGAGGCCGUUAGGCCGAA ICAAACCU 1836
    346 UUUGCUUC U CUGGCGGU 1338 ACCGCCAG CUGAUGAGGCCGUUAGGCCGAA IAAGCAAA 1837
    348 UGCUUCUC U GGCGGUCU 1339 AGACCGCC CUGAUGAGGCCGUUAGGCCGAA IAGAAGCA 1838
    356 UGGCGGUC U UCAGAAUC 1340 GAUUCUGA CUGAUGAGGCCGUUAGGCCGAA IACCGCCA 1839
    359 CGGUCUUC A GAAUCAAC 1341 GUUGAUUC CUGAUGAGGCCGUUAGGCCGAA IAAGACCG 1840
    365 UCAGAAUC A ACAUCCAC 1342 GUGGAUGU CUGAUGAGGCCGUUAGGCCGAA IAUUCUGA 1841
    368 GAAUCAAC A UCCACACU 1343 AGUGUGGA CUGAUGAGGCCGUUAGGCCGAA IUUGAUUC 1842
    371 UCAACAUC C ACACUUCC 1344 GGAAGUGU CUGAUGAGGCCGUUAGGCCGAA IAUGUUGA 1843
    372 CAACAUCC A CACUUCCG 1345 CGGAAGUG CUGAUGAGGCCGUUAGGCCGAA IGAUGUUG 1844
    374 ACAUCCAC A CUUCCGUG 1346 CACGGAAG CUGAUGAGGCCGUUAGGCCGAA IUGGAUGU 1845
    376 AUCCACAC U UCCGUGAU 1347 AUCACGGA CUGAUGAGGCCGUUAGGCCGAA IUGUGGAU 1846
    379 CACACUUC C GUGAUUAU 1348 AUAAUCAC CUGAUGAGGCCGUUAGGCCGAA IAAGUGUG 1847
    389 UGAUUAUC U GCGUGCAU 1349 AUGCACGC CUGAUGAGGCCGUUAGGCCGAA IAUAAUCA 1848
    396 CUGCGUGC A UUUUGGAC 1350 GUCCAAAA CUGAUGAGGCCGUUAGGCCGAA ICACGCAG 1849
    405 UUUUGGAC A AAGCUUCC 1351 GGAAGCUU CUGAUGAGGCCGUUAGGCCGAA IUCCAAAA 1850
    410 GACAAAGC U UCCAACCA 1352 UGGUUGGA CUGAUGAGGCCGUUAGGCCGAA ICUUUGUC 1851
    413 AAAGCUUC C AACCAGGA 1353 UCCUGGUU CUGAUGAGGCCGUUAGGCCGAA IAAGCUUU 1852
    414 AAGCUUCC A ACCAGGAU 1354 AUCCUGGU CUGAUGAGGCCGUUAGGCCGAA IGAAGCUU 1853
    417 CUUCCAAC C AGGAUACG 1355 CGUAUCCU CUGAUGAGGCCGUUAGGCCGAA IUUGGAAG 1854
    418 UUCCAACC A GGAUACGG 1356 CCGUAUCC CUGAUGAGGCCGUUAGGCCGAA IGUUGGAA 1855
    441 GAAAUGGC U GGUGAUCU 1357 AGAUCACC CUGAUGAGGCCGUUAGGCCGAA ICCAUUUC 1856
    449 UGGUGAUC U UUCAGCAG 1358 CUGCUGAA CUGAUGAGGCCGUUAGGCCGAA IAUCACCA 1857
    453 GAUCUUUC A GCAGGUUU 1359 AAACCUGC CUGAUGAGGCCGUUAGGCCGAA IAAAGAUC 1858
    456 CUUUCAGC A GGUUUCUU 1360 AAGAAACC CUGAUGAGGCCGUUAGGCCGAA ICUGAAAG 1859
    463 CAGGUUUC U UCAUGGAG 1361 CUCCAUGA CUGAUGAGGCCGUUAGGCCGAA IAAACCUG 1860
    466 GUUUCUUC A UGGAGGAA 1362 UUCCUCCA CUGAUGAGGCCGUUAGGCCGAA IAAGAAAC 1861
    476 GGAGGAAC U UAAUACAU 1363 AUGUAUUA CUGAUGAGGCCGUUAGGCCGAA IUUCCUCC 1862
    483 CUUAAUAC A UACCGUCA 1364 UGACGGUA CUGAUGAGGCCGUUAGGCCGAA IUAUUAAG 1863
    487 AUACAUAC C GUCAGAAG 1365 CUUCUGAC CUGAUGAGGCCGUUAGGCCGAA IUAUGUAU 1864
    491 AUACCGUC A GAAGCAGG 1366 CCUGCUUC CUGAUGAGGCCGUUAGGCCGAA IACGGUAU 1865
    497 UCAGAAGC A GGGAGUAG 1367 CUACUCCC CUGAUGAGGCCGUUAGGCCGAA ICUUCUGA 1866
    509 AGUAGUAC U UAAAUAUC 1368 GAUAUUUA CUGAUGAGGCCGUUAGGCCGAA IUACUACU 1867
    518 UAAAUAUC A AGAACUGC 1369 GCAGUUCU CUGAUGAGGCCGUUAGGCCGAA IAUAUUUA 1868
    524 UCAAGAAC U GCCUAAUU 1370 AAUUAGGC CUGAUGAGGCCGUUAGGCCGAA IUUCUUGA 1869
    527 AGAACUGC C UAAUUCAG 1371 CUGAAUUA CUGAUGAGGCCGUUAGGCCGAA ICAGUUCU 1870
    528 GAACUGCC U AAUUCAGG 1372 CCUGAAUU CUGAUGAGGCCGUUAGGCCGAA IGCAGUUC 1871
    534 CCUAAUUC A GGACCUCC 1373 GGAGGUCC CUGAUGAGGCCGUUAGGCCGAA IAAUUAGG 1872
    539 UUCAGGAC C UCCACAUG 1374 CAUGUGGA CUGAUGAGGCCGUUAGGCCGAA IUCCUGAA 1873
    540 UCAGGACC U CCACAUGA 1375 UCAUGUGG CUGAUGAGGCCGUUAGGCCGAA IGUCCUGA 1874
    542 AGGACCUC C ACAUGAUA 1376 UAUCAUGU CUGAUGAGGCCGUUAGGCCGAA IAGGUCCU 1875
    543 GGACCUCC A CAUGAUAG 1377 CUAUCAUG CUGAUGAGGCCGUUAGGCCGAA IGAGGUCC 1876
    545 ACCUCCAC A UGAUAGGA 1378 UCCUAUCA CUGAUGAGGCCGUUAGGCCGAA IUGGAGGU 1877
    561 AGGUUUAC A UUUCAAGU 1379 ACUUGAAA CUGAUGAGGCCGUUAGGCCGAA IUAAACCU 1878
    566 UACAUUUC A AGUUAUAA 1380 UUAUAACU CUGAUGAGGCCGUUAGGCCGAA IAAAUGUA 1879
    593 AGAAUUUC C AGAAGGUG 1381 CACCUUCU CUGAUGAGGCCGUUAGGCCGAA IAAAUUCU 1880
    594 GAAUUUCC A GAAGGUGA 1382 UCACCUUC CUGAUGAGGCCGUUAGGCCGAA IGAAAUUC 1881
    612 GGUAGAUC A AAGAAGGA 1383 UCCUUCUU CUGAUGAGGCCGUUAGGCCGAA IAUCUACC 1882
    624 AAGGAAGC A AAAAAUGC 1384 GCAUUUUU CUGAUGAGGCCGUUAGGCCGAA ICUUCCUU 1883
    633 AAAAAUGC C GCAGCCAA 1385 UUGGCUGC CUGAUGAGGCCGUUAGGCCGAA ICAUUUUU 1884
    636 AAUGCCGC A GCCAAAUU 1386 AAUUUGGC CUGAUGAGGCCGUUAGGCCGAA ICGGCAUU 1885
    639 GCCGCAGC C AAAUUAGC 1387 GCUAAUUU CUGAUGAGGCCGUUAGGCCGAA ICUGCGGC 1886
    640 CCGCAGCC A AAUUAGCU 1388 AGCUAAUU CUGAUGAGGCCGUUAGGCCGAA IGCUGCGG 1887
    648 AAAUUAGC U GUUGAGAU 1389 AUCUCAAC CUGAUGAGGCCGUUAGGCCGAA ICUAAUUU 1888
    659 UGAGAUAC U UAAUAAGG 1390 CCUUAUUA CUGAUGAGGCCGUUAGGCCGAA IUAUCUCA 1889
    678 AAGAAGGC A GUUAGUCC 1391 GGACUAAC CUGAUGAGGCCGUUAGGCCGAA ICCUUCUU 1890
    686 AGUUAGUC C UUUAUUAU 1392 AUAAUAAA CUGAUGAGGCCGUUAGGCCGAA IACUAACU 1891
    687 GUUAGUCC U UUAUUAUU 1393 AAUAAUAA CUGAUGAGGCCGUUAGGCCGAA IGACUAAC 1892
    699 UUAUUGAC A ACAACGAA 1394 UUCGUUGU CUGAUGAGGCCGUUAGGCCGAA IUCAAUAA 1893
    702 UUGACAAC A ACGAAUUC 1395 GAAUUCGU CUGAUGAGGCCGUUAGGCCGAA IUUGUCAA 1894
    711 ACGAAUUC U UCAGAAGG 1396 CCUUCUGA CUGAUGAGGCCGUUAGGCCGAA IAAUUCGU 1895
    714 AAUUCUUC A GAAGGAUU 1397 AAUCCUUC CUGAUGAGGCCGUUAGGCCGAA IAAGAAUU 1896
    726 GGAUUAUC C AUGGGGAA 1398 UUCCCCAU CUGAUGAGGCCGUUAGGCCGAA IAUAAUCC 1897
    727 GAUUAUCC A UGGGGAAU 1399 AUUCCCCA CUGAUGAGGCCGUUAGGCCGAA IGAUAAUC 1898
    739 GGAAUUAC A UAGGCCUU 1400 AAGGCCUA CUGAUGAGGCCGUUAGGCCGAA IUAAUUCC 1899
    745 ACAUAGGC C UUAUCAAU 1401 AUUGAUAA CUGAUGAGGCCGUUAGGCCGAA ICCUAUGU 1900
    746 CAUAGGCC U UAUCAAUA 1402 UAUUGAUA CUGAUGAGGCCGUUAGGCCGAA IGCCUAUG 1901
    751 GCCUUAUC A AUAGAAUU 1403 AAUUCUAU CUGAUGAGGCCGUUAGGCCGAA IAUAAGGC 1902
    762 AGAAUUGC C CAGAAGAA 1404 UUCUUCUG CUGAUGAGGCCGUUAGGCCGAA ICAAUUCU 1903
    763 GAAUUGCC C AGAAGAAA 1405 UUUCUUCU CUGAUGAGGCCGUUAGGCCGAA IGCAAUUC 1904
    764 AAUUGCCC A GAAGAAAA 1406 UUUUCUUC CUGAUGAGGCCGUUAGGCCGAA IGGCAAUU 1905
    776 GAAAAGAC U AACUGUAA 1407 UUACAGUU CUGAUGAGGCCGUUAGGCCGAA IUCUUUUC 1906
    780 AGACUAAC U GUAAAUUA 1408 UAAUUUAC CUGAUGAGGCCGUUAGGCCGAA IUUAGUCU 1907
    794 UUAUGAAC A GUGUGCAU 1409 AUGCACAC CUGAUGAGGCCGUUAGGCCGAA IUUCAUAA 1908
    801 CAGUGUGC A UCGGGGGU 1410 ACCCCCGA CUGAUGAGGCCGUUAGGCCGAA ICACACUG 1909
    812 GGGGGUGC A UGGGCCAG 1411 CUGGCCCA CUGAUGAGGCCGUUAGGCCGAA ICACCCCC 1910
    818 GCAUGGGC C AGAAGGAU 1412 AUCCUUCU CUGAUGAGGCCGUUAGGCCGAA ICCCAUGC 1911
    819 CAUGGGCC A GAAGGAUU 1413 AAUCCUUC CUGAUGAGGCCGUUAGGCCGAA IGCCCAUG 1912
    830 AGGAUUUC A UUAUAAAU 1414 AUUUAUAA CUGAUGAGGCCGUUAGGCCGAA IAAAUCCU 1913
    841 AUAAAUGC A AAAUGGGA 1415 UCCCAUUU CUGAUGAGGCCGUUAGGCCGAA ICAUUUAU 1914
    851 AAUGGGAC A GAAAGAAU 1416 AUUCUUUC CUGAUGAGGCCGUUAGGCCGAA IUCCCAUU 1915
    873 AUUGGUAC A GGUUCUAC 1417 GUAGAACC CUGAUGAGGCCGUUAGGCCGAA IUACCAAU 1916
    879 ACAGGUUC U ACUAAACA 1418 UGUUUAGU CUGAUGAGGCCGUUAGGCCGAA IAACCUGU 1917
    882 GGUUCUAC U AAACAGGA 1419 UCCUGUUU CUGAUGAGGCCGUUAGGCCGAA IUAGAACC 1918
    887 UACUAAAC A GGAAGCAA 1420 UUGCUUCC CUGAUGAGGCCGUUAGGCCGAA IUUUAGUA 1919
    894 CAGGAAGC A AAACAAUU 1421 AAUUGUUU CUGAUGAGGCCGUUAGGCCGAA ICUUCCUG 1920
    899 AGCAAAAC A AUUGGCCG 1422 CGGCCAAU CUGAUGAGGCCGUUAGGCCGAA IUUUUGCU 1921
    906 CAAUUGGC C GCUAAACU 1423 AGUUUAGC CUGAUGAGGCCGUUAGGCCGAA ICCAAUUG 1922
    909 UUGGCCGC U AAACUUGC 1424 GCAAGUUU CUGAUGAGGCCGUUAGGCCGAA ICGGCCAA 1923
    914 CGCUAAAC U UGCAUAUC 1425 GAUAUGCA CUGAUGAGGCCGUUAGGCCGAA IUUUAGCG 1924
    918 AAACUUGC A UAUCUUCA 1426 UGAAGAUA CUGAUGAGGCCGUUAGGCCGAA ICAAGUUU 1925
    923 UGCAUAUC U UCAGAUAU 1427 AUAUCUGA CUGAUGAGGCCGUUAGGCCGAA IAUAUGCA 1926
    926 AUAUCUUC A GAUAUUAU 1428 AUAAUAUC CUGAUGAGGCCGUUAGGCCGAA IAAGAUAU 1927
    936 AUAUUAUC A GAAGAAAC 1429 GUUUCUUC CUGAUGAGGCCGUUAGGCCGAA IAUAAUAU 1928
    945 GAAGAAAC C UCAGUGAA 1430 UUCACUGA CUGAUGAGGCCGUUAGGCCGAA IUUUCUUC 1929
    946 AAGAAACC U CAGUGAAA 1431 UUUCACUG CUGAUGAGGCCGUUAGGCCGAA IGUUUCUU 1930
    948 GAAACCUC A GUGAAAUC 1432 GAUUUCAC CUGAUGAGGCCGUUAGGCCGAA IAGGUUUC 1931
    957 GUGAAAUC U GACUACCU 1433 AGGUAGUC CUGAUGAGGCCGUUAGGCCGAA IAUUUCAC 1932
    961 AAUCUGAC U ACCUGUCC 1434 GGACAGGU CUGAUGAGGCCGUUAGGCCGAA IUCAGAUU 1933
    964 CUGACUAC C UGUCCUCU 1435 AGAGGACA CUGAUGAGGCCGUUAGGCCGAA IUAGUCAG 1934
    965 UGACUACC U GUCCUCUG 1436 CAGAGGAC CUGAUGAGGCCGUUAGGCCGAA IGUAGUCA 1935
    969 UACCUGUC C UCUGGUUC 1437 GAACCAGA CUGAUGAGGCCGUUAGGCCGAA IACAGGUA 1936
    970 ACCUGUCC U CUGGUUCU 1438 AGAACCAG CUGAUGAGGCCGUUAGGCCGAA IGACAGGU 1937
    972 CUGUCCUC U GGUUCUUU 1439 AAAGAACC CUGAUGAGGCCGUUAGGCCGAA IAGGACAG 1938
    978 UCUGGUUC U UUUGCUAC 1440 GUAGCAAA CUGAUGAGGCCGUUAGGCCGAA IAACCAGA 1939
    984 UCUUUUGC U ACUACGUG 1441 CACGUAGU CUGAUGAGGCCGUUAGGCCGAA ICAAAAGA 1940
    987 UUUGCUAC U ACGUGUGA 1442 UCACACGU CUGAUGAGGCCGUUAGGCCGAA IUAGCAAA 1941
    999 UGUGAGUC C CAAAGCAA 1443 UUGCUUUG CUGAUGAGGCCGUUAGGCCGAA IACUCACA 1942
    1000 GUGAGUCC C AAAGCAAC 1444 GUUGCUUU CUGAUGAGGCCGUUAGGCCGAA IGACUCAC 1943
    1001 UGAGUCCC A AAGCAACU 1445 AGUUGCUU CUGAUGAGGCCGUUAGGCCGAA IGGACUCA 1944
    1006 CCCAAAGC A ACUCUUUA 1446 UAAAGAGU CUGAUGAGGCCGUUAGGCCGAA ICUUUGGG 1945
    1009 AAAGCAAC U CUUUAGUG 1447 CACUAAAG CUGAUGAGGCCGUUAGGCCGAA IUUGCUUU 1946
    1011 AGCAACUC U UUAGUGAC 1448 GUCACUAA CUGAUGAGGCCGUUAGGCCGAA IAGUUGCU 1947
    1020 UUAGUGAC C AGCACACU 1449 AGUGUGCU CUGAUGAGGCCGUUAGGCCGAA IUCACUAA 1948
    1021 UAGUGACC A GCACACUC 1450 GAGUGUGC CUGAUGAGGCCGUUAGGCCGAA IGUCACUA 1949
    1024 UGACCAGC A CACUCGCU 1451 AGCGAGUG CUGAUGAGGCCGUUAGGCCGAA ICUGGUCA 1950
    1026 ACCAGCAC A CUCGCUUC 1452 GAAGCGAG CUGAUGAGGCCGUUAGGCCGAA IUGCUGGU 1951
    1028 CAGCACAC U CGCUUCUG 1453 CAGAAGCG CUGAUGAGGCCGUUAGGCCGAA IUGUGCUG 1952
    1032 ACACUCGC U UCUGAAUC 1454 GAUUCAGA CUGAUGAGGCCGUUAGGCCGAA ICGAGUGU 1953
    1035 CUCGCUUC U GAAUCAUC 1455 GAUGAUUC CUGAUGAGGCCGUUAGGCCGAA IAAGCGAG 1954
    1041 UCUGAAUC A UCAUCUGA 1456 UCAGAUGA CUGAUGAGGCCGUUAGGCCGAA IAUUCAGA 1955
    1044 GAAUCAUC A UCUGAAGG 1457 CCUUCAGA CUGAUGAGGCCGUUAGGCCGAA IAUGAUUC 1956
    1047 UCAUCAUC U GAAGGUGA 1458 UCACCUUC CUGAUGAGGCCGUUAGGCCGAA IAUGAUGA 1957
    1057 AAGGUGAC U UCUCAGCA 1459 UGCUGAGA CUGAUGAGGCCGUUAGGCCGAA IUCACCUU 1958
    1060 GUGACUUC U CAGCAGAU 1460 AUCUGCUG CUGAUGAGGCCGUUAGGCCGAA IAAGUCAC 1959
    1062 GACUUCUC A GCAGAUAC 1461 GUAUCUGC CUGAUGAGGCCGUUAGGCCGAA IAGAAGUC 1960
    1065 UUCUCAGC A GAUACAUC 1462 GAUGUAUC CUGAUGAGGCCGUUAGGCCGAA ICUGAGAA 1961
    1071 GCAGAUAC A UCAGAGAU 1463 AUCUCUGA CUGAUGAGGCCGUUAGGCCGAA IUAUCUGC 1962
    1074 GAUACAUC A GAGAUAAA 1464 UUUAUCUC CUGAUGAGGCCGUUAGGCCGAA IAUGUAUC 1963
    1086 AUAAAUUC U AACAGUGA 1465 UCACUGUU CUGAUGAGGCCGUUAGGCCGAA IAAUUUAU 1964
    1090 AUUCUAAC A GUGACAGU 1466 ACUGUCAC CUGAUGAGGCCGUUAGGCCGAA IUUAGAAU 1965
    1096 ACAGUGAC A GUUUAAAC 1467 GUUUAAAC CUGAUGAGGCCGUUAGGCCGAA IUCACUGU 1966
    1105 GUUUAAAC A GUUCUUCG 1468 CGAAGAAC CUGAUGAGGCCGUUAGGCCGAA IUUUAAAC 1967
    1110 AACAGUUC U UCGUUGCU 1469 AGCAACGA CUGAUGAGGCCGUUAGGCCGAA IAACUGUU 1968
    1118 UUCGUUGC U UAUGAAUG 1470 CAUUCAUA CUGAUGAGGCCGUUAGGCCGAA ICAACGAA 1969
    1130 GAAUGGUC U CAGAAAUA 1471 UAUUUCUG CUGAUGAGGCCGUUAGGCCGAA IACCAUUC 1970
    1132 AUGGUCUC A GAAAUAAU 1472 AUUAUUUC CUGAUGAGGCCGUUAGGCCGAA IAGACCAU 1971
    1142 AAAUAAUC A AAGGAAGG 1473 CCUUCCUU CUGAUGAGGCCGUUAGGCCGAA IAUUAUUU 1972
    1152 AGGAAGGC A AAAAGAUC 1474 GAUCUUUU CUGAUGAGGCCGUUAGGCCGAA ICCUUCCU 1973
    1161 AAAAGAUC U UUGGCACC 1475 GGUGCCAA CUGAUGAGGCCGUUAGGCCGAA IAUCUUUU 1974
    1167 UCUUUGGC A CCCAGAUU 1476 AAUCUGGG CUGAUGAGGCCGUUAGGCCGAA ICCAAAGA 1975
    1169 UUUGGCAC C CAGAUUUG 1477 CAAAUCUG CUGAUGAGGCCGUUAGGCCGAA IUGCCAAA 1976
    1170 UUGGCACC C AGAUUUGA 1478 UCAAAUCU CUGAUGAGGCCGUUAGGCCGAA IGUGCCAA 1977
    1171 UGGCACCC A GAUUUGAC 1479 GUCAAAUC CUGAUGAGGCCGUUAGGCCGAA IGGUGCCA 1978
    1180 GAUUUGAC C UUCCUGAC 1480 GUCAGGAA CUGAUGAGGCCGUUAGGCCGAA IUCAAAUC 1979
    1181 AUUUGACC U UCCUGACA 1481 UGUCAGGA CUGAUGAGGCCGUUAGGCCGAA IGUCAAAU 1980
    1184 UGACCUUC C UGACAUGA 1482 UCAUGUCA CUGAUGAGGCCGUUAGGCCGAA IAAGGUCA 1981
    1185 GACCUUCC U GACAUGAA 1483 UUCAUGUC CUGAUGAGGCCGUUAGGCCGAA IGAAGGUC 1982
    1189 UUCCUGAC A UGAAAGAA 1484 UUCUUUCA CUGAUGAGGCCGUUAGGCCGAA IUCAGGAA 1983
    1200 AAAGAAAC A AAGUAUAC 1485 GUAUACUU CUGAUGAGGCCGUUAGGCCGAA IUUUCUUU 1984
    1209 AAGUAUAC U GUGGACAA 1486 UUGUCCAC CUGAUGAGGCCGUUAGGCCGAA IUAUACUU 1985
    1216 CUGUGGAC A AGAGGUUU 1487 AAACCUCU CUGAUGAGGCCGUUAGGCCGAA IUCCACAG 1986
    1228 GGUUUGGC A UGGAUUUU 1488 AAAAUCCA CUGAUGAGGCCGUUAGGCCGAA ICCAAACC 1987
    1258 UAAUUGGC U CAGGUGGA 1489 UCCACCUG CUGAUGAGGCCGUUAGGCCGAA ICCAAUUA 1988
    1260 AUUGGCUC A GGUGGAUU 1490 AAUCCACC CUGAUGAGGCCGUUAGGCCGAA IAGCCAAU 1989
    1273 GAUUUGGC C AAGUUUUC 1491 GAAAACUU CUGAUGAGGCCGUUAGGCCGAA ICCAAAUC 1990
    1274 AUUUGGCC A AGUUUUCA 1492 UGAAAACU CUGAUGAGGCCGUUAGGCCGAA IGCCAAAU 1991
    1282 AAGUUUUC A AAGCAAAA 1493 UUUUGCUU CUGAUGAGGCCGUUAGGCCGAA IAAAACUU 1992
    1287 UUCAAAGC A AAACACAG 1494 CUGUGUUU CUGAUGAGGCCGUUAGGCCGAA ICUUUGAA 1993
    1292 AGCAAAAC A CAGAAUUG 1495 CAAUUCUG CUGAUGAGGCCGUUAGGCCGAA IUUUUGCU 1994
    1294 CAAAACAC A GAAUUGAC 1496 GUCAAUUC CUGAUGAGGCCGUUAGGCCGAA IUGUUUUG 1995
    1311 GGAAAGAC U UACGUUAU 1497 AUAACGUA CUGAUGAGGCCGUUAGGCCGAA IUCUUUCC 1996
    1368 GUAAAAGC A UUGGCAAA 1498 UUUGCCAA CUGAUGAGGCCGUUAGGCCGAA ICUUUUAC 1997
    1374 GCAUUGGC A AAACUUGA 1499 UCAAGUUU CUGAUGAGGCCGUUAGGCCGAA ICCAAUGC 1998
    1379 GGCAAAAC U UGAUCAUG 1500 CAUGAUCA CUGAUGAGGCCGUUAGGCCGAA IUUUUGCC 1999
    1385 ACUUGAUC A UGUAAAUA 1501 UAUUUACA CUGAUGAGGCCGUUAGGCCGAA IAUCAAGU 2000
    1400 UAUUGUUC A CUACAAUG 1502 CAUUGUAG CUGAUGAGGCCGUUAGGCCGAA IAACAAUA 2001
    1402 UUGUUCAC U ACAAUGGC 1503 GCCAUUGU CUGAUGAGGCCGUUAGGCCGAA IUGAACAA 2002
    1405 UUCACUAC A AUGGCUGU 1504 ACAGCCAU CUGAUGAGGCCGUUAGGCCGAA IUAGUGAA 2003
    1411 ACAAUGGC U GUUGGGAU 1505 AUCCCAAC CUGAUGAGGCCGUUAGGCCGAA ICCAUUGU 2004
    1436 UUAUGAUC C UGAGACCA 1506 UGGUCUCA CUGAUGAGGCCGUUAGGCCGAA IAUCAUAA 2005
    1437 UAUGAUCC U GAGACCAG 1507 CUGGUCUC CUGAUGAGGCCGUUAGGCCGAA IGAUCAUA 2006
    1443 CCUGAGAC C AGUGAUGA 1508 UCAUCACU CUGAUGAGGCCGUUAGGCCGAA IUCUCAGG 2007
    1444 CUGAGACC A GUGAUGAU 1509 AUCAUCAC CUGAUGAGGCCGUUAGGCCGAA IGUCUCAG 2008
    1455 GAUGAUUC U CUUGAGAG 1510 CUCUCAAG CUGAUGAGGCCGUUAGGCCGAA IAAUCAUC 2009
    1457 UGAUUCUC U UGAGAGCA 1511 UGCUCUCA CUGAUGAGGCCGUUAGGCCGAA IAGAAUCA 2010
    1465 UUGAGAGC A GUGAUUAU 1512 AUAAUCAC CUGAUGAGGCCGUUAGGCCGAA ICUCUCAA 2011
    1478 UUAUGAUC C UGAGAACA 1513 UGUUCUCA CUGAUGAGGCCGUUAGGCCGAA IAUCAUAA 2012
    1479 UAUGAUCC U GAGAACAG 1514 CUGUUCUC CUGAUGAGGCCGUUAGGCCGAA IGAUCAUA 2013
    1486 CUGAGAAC A GCAAAAAU 1515 AUUUUUGC CUGAUGAGGCCGUUAGGCCGAA IUUCUCAG 2014
    1489 AGAACAGC A AAAAUAGU 1516 ACUAUUUU CUGAUGAGGCCGUUAGGCCGAA ICUGUUCU 2015
    1500 AAUAGUUC A AGGUCAAA 1517 UUUGACCU CUGAUGAGGCCGUUAGGCCGAA IAACUAUU 2016
    1506 UCAAGGUC A AAGACUAA 1518 UUAGUCUU CUGAUGAGGCCGUUAGGCCGAA IACCUUGA 2017
    1512 UCAAAGAC U AAGUGCCU 1519 AGGCACUU CUGAUGAGGCCGUUAGGCCGAA IUCUUUGA 2018
    1519 CUAAGUGC C UUUUCAUC 1520 GAUGAAAA CUGAUGAGGCCGUUAGGCCGAA ICACUUAG 2019
    1520 UAAGUGCC U UUUCAUCC 1521 GGAUGAAA CUGAUGAGGCCGUUAGGCCGAA IGCACUUA 2020
    1525 GCCUUUUC A UCCAAAUG 1522 CAUUUGGA CUGAUGAGGCCGUUAGGCCGAA IAAAAGGC 2021
    1528 UUUUCAUC C AAAUGGAA 1523 UUCCAUUU CUGAUGAGGCCGUUAGGCCGAA IAUGAAAA 2022
    1529 UUUCAUCC A AAUGGAAU 1524 AUUCCAUU CUGAUGAGGCCGUUAGGCCGAA IGAUGAAA 2023
    1540 UGGAAUUC U GUGAUAAA 1525 UUUAUCAC CUGAUGAGGCCGUUAGGCCGAA IAAUUCCA 2024
    1554 AAAGGGAC C UUGGAACA 1526 UGUUCCAA CUGAUGAGGCCGUUAGGCCGAA IUCCCUUU 2025
    1555 AAGGGACC U UGGAACAA 1527 UUGUUCCA CUGAUGAGGCCGUUAGGCCGAA IGUCCCUU 2026
    1562 CUUGGAAC A AUGGAUUG 1528 CAAUCCAU CUGAUGAGGCCGUUAGGCCGAA IUUCCAAG 2027
    1592 CGAGAAAC U AGACAAAG 1529 CUUUGUCU CUGAUGAGGCCGUUAGGCCGAA IUUUCUCG 2028
    1597 AACUAGAC A AAGUUUUG 1530 CAAAACUU CUGAUGAGGCCGUUAGGCCGAA IUCUAGUU 2029
    1608 GUUUUGGC U UUGGAACU 1531 AGUUCCAA CUGAUGAGGCCGUUAGGCCGAA ICCAAAAC 2030
    1616 UUUGGAAC U CUUUGAAC 1532 GUUCAAAG CUGAUGAGGCCGUUAGGCCGAA IUUCCAAA 2031
    1618 UGGAACUC U UUGAACAA 1533 UUGUUCAA CUGAUGAGGCCGUUAGGCCGAA IAGUUCCA 2032
    1625 CUUUGAAC A AAUAACAA 1534 UUGUUAUU CUGAUGAGGCCGUUAGGCCGAA IUUCAAAG 2033
    1632 CAAAUAAC A AAAGGGGU 1535 ACCCCUUU CUGAUGAGGCCGUUAGGCCGAA IUUAUUUG 2034
    1652 UUAUAUAC A UUCAAAAA 1536 UUUUUGAA CUGAUGAGGCCGUUAGGCCGAA IUAUAUAA 2035
    1656 AUACAUUC A AAAAAAUU 1537 AAUUUUUU CUGAUGAGGCCGUUAGGCCGAA IAAUGUAU 2036
    1670 AUUAAUUC A UAGAGAUC 1538 GAUCUCUA CUGAUGAGGCCGUUAGGCCGAA IAAUUAAU 2037
    1679 UAGAGAUC U UAAGCCAA 1539 UUGGCUUA CUGAUGAGGCCGUUAGGCCGAA IAUCUCUA 2038
    1685 UCUUAAGC C AAGUAAUA 1540 UAUUACUU CUGAUGAGGCCGUUAGGCCGAA ICUUAAGA 2039
    1686 CUUAAGCC A AGUAAUAU 1541 AUAUUACU CUGAUGAGGCCGUUAGGCCGAA IGCUUAAG 2040
    1699 AUAUAUUC U UAGUAGAU 1542 AUCUACUA CUGAUGAGGCCGUUAGGCCGAA IAAUAUAU 2041
    1710 GUAGAUAC A AAACAAGU 1543 ACUUGUUU CUGAUGAGGCCGUUAGGCCGAA IUAUCUAC 2042
    1715 UACAAAAC A AGUAAAGA 1544 UCUUUACU CUGAUGAGGCCGUUAGGCCGAA IUUUUGUA 2043
    1732 UUGGAGAC U UUGGACUU 1545 AAGUCCAA CUGAUGAGGCCGUUAGGCCGAA IUCUCCAA 2044
    1739 CUUUGGAC U UGUAACAU 1546 AUGUUACA CUGAUGAGGCCGUUAGGCCGAA IUCCAAAG 2045
    1746 CUUGUAAC A UCUCUGAA 1547 UUCAGAGA CUGAUGAGGCCGUUAGGCCGAA IUUACAAG 2046
    1749 GUAACAUC U CUGAAAAA 1548 UUUUUCAG CUGAUGAGGCCGUUAGGCCGAA IAUGUUAC 2047
    1751 AACAUCUC U GAAAAAUG 1549 CAUUUUUC CUGAUGAGGCCGUUAGGCCGAA IAGAUGUU 2048
    1773 AAGCGAAC A AGGAGUAA 1550 UUACUCCU CUGAUGAGGCCGUUAGGCCGAA IUUCGCUU 2049
    1788 AAGGGAAC U UUGCGAUA 1551 UAUCGCAA CUGAUGAGGCCGUUAGGCCGAA IUUCCCUU 2050
    1798 UGCGAUAC A UGAGCCCA 1552 UGGGCUCA CUGAUGAGGCCGUUAGGCCGAA IUAUCGCA 2051
    1804 ACAUGAGC C CAGAACAG 1553 CUGUUCUG CUGAUGAGGCCGUUAGGCCGAA ICUCAUGU 2052
    1805 CAUGAGCC C AGAACAGA 1554 UCUGUUCU CUGAUGAGGCCGUUAGGCCGAA IGCUCAUG 2053
    1806 AUGAGCCC A GAACAGAU 1555 AUCUGUUC CUGAUGAGGCCGUUAGGCCGAA IGGCUCAU 2054
    1811 CCCAGAAC A GAUUUCUU 1556 AAGAAAUC CUGAUGAGGCCGUUAGGCCGAA IUUCUGGG 2055
    1818 CAGAUUUC U UCGCAAGA 1557 UCUUGCGA CUGAUGAGGCCGUUAGGCCGAA IAAAUCUG 2056
    1823 UUCUUCGC A AGACUAUG 1558 CAUAGUCU CUGAUGAGGCCGUUAGGCCGAA ICGAAGAA 2057
    1828 CGCAAGAC U AUGGAAAG 1559 CUUUCCAU CUGAUGAGGCCGUUAGGCCGAA IUCUUGCG 2058
    1846 AAGUGGAC C UCUACGCU 1560 AGCGUAGA CUGAUGAGGCCGUUAGGCCGAA IUCCACUU 2059
    1847 AGUGGACC U CUACGCUU 1561 AAGCGUAG CUGAUGAGGCCGUUAGGCCGAA IGUCCACU 2060
    1849 UGGACCUC U ACGCUUUG 1562 CAAAGCGU CUGAUGAGGCCGUUAGGCCGAA IAGGUCCA 2061
    1854 CUCUACGC U UUGGGGCU 1563 AGCCCCAA CUGAUGAGGCCGUUAGGCCGAA ICGUAGAG 2062
    1862 UUUGGGGC U AAUUCUUG 1564 CAAGAAUU CUGAUGAGGCCGUUAGGCCGAA ICCCCAAA 2063
    1868 GCUAAUUC U UGCUGAAC 1565 GUUCAGCA CUGAUGAGGCCGUUAGGCCGAA IAAUUAGC 2064
    1872 AUUCUUGC U GAACUUCU 1566 AGAAGUUC CUGAUGAGGCCGUUAGGCCGAA ICAAGAAU 2065
    1877 UGCUGAAC U UCUUCAUG 1567 CAUGAAGA CUGAUGAGGCCGUUAGGCCGAA IUUCAGCA 2066
    1880 UGAACUUC U UCAUGUAU 1568 AUACAUGA CUGAUGAGGCCGUUAGGCCGAA IAAGUUCA 2067
    1883 ACUUCUUC A UGUAUGUG 1569 CACAUACA CUGAUGAGGCCGUUAGGCCGAA IAAGAAGU 2068
    1894 UAUGUGAC A CUGCUUUU 1570 AAAAGCAG CUGAUGAGGCCGUUAGGCCGAA IUCACAUA 2069
    1896 UGUGACAC U GCUUUUGA 1571 UCAAAAGC CUGAUGAGGCCGUUAGGCCGAA IUGUCACA 2070
    1899 GACACUGC U UUUGAAAC 1572 GUUUCAAA CUGAUGAGGCCGUUAGGCCGAA ICAGUGUC 2071
    1908 UUUGAAAC A UCAAAGUU 1573 AACUUUGA CUGAUGAGGCCGUUAGGCCGAA IUUUCAAA 2072
    1911 GAAACAUC A AAGUUUUU 1574 AAAAACUU CUGAUGAGGCCGUUAGGCCGAA IAUGUUUC 2073
    1921 AGUUUUUC A CAGACCUA 1575 UAGGUCUG CUGAUGAGGCCGUUAGGCCGAA IAAAAACU 2074
    1923 UUUUUCAC A GACCUACG 1576 CGUAGGUC CUGAUGAGGCCGUUAGGCCGAA IUGAAAAA 2075
    1927 UCACAGAC C UACGGGAU 1577 AUCCCGUA CUGAUGAGGCCGUUAGGCCGAA IUCUGUGA 2076
    1928 CACAGACC U ACGGGAUG 1578 CAUCCCGU CUGAUGAGGCCGUUAGGCCGAA IGUCUGUG 2077
    1939 GGGAUGGC A UCAUCUCA 1579 UGAGAUGA CUGAUGAGGCCGUUAGGCCGAA ICCAUCCC 2078
    1942 AUGGCAUC A UCUCAGAU 1580 AUCUGAGA CUGAUGAGGCCGUUAGGCCGAA IAUGCCAU 2079
    1945 GCAUCAUC U CAGAUAUA 1581 UAUAUCUG CUGAUGAGGCCGUUAGGCCGAA IAUGAUGC 2080
    1947 AUCAUCUC A GAUAUAUU 1582 AAUAUAUC CUGAUGAGGCCGUUAGGCCGAA IAGAUGAU 2081
    1974 GAAAAAAC U CUUCUACA 1583 UGUAGAAG CUGAUGAGGCCGUUAGGCCGAA IUUUUUUC 2082
    1976 AAAAACUC U UCUACAGA 1584 UCUGUAGA CUGAUGAGGCCGUUAGGCCGAA IAGUUUUU 2083
    1979 AACUCUUC U ACAGAAAU 1585 AUUUCUGU CUGAUGAGGCCGUUAGGCCGAA IAAGAGUU 2084
    1982 UCUUCUAC A GAAAUUAC 1586 GUAAUUUC CUGAUGAGGCCGUUAGGCCGAA IUAGAAGA 2085
    1991 GAAAUUAC U CUCAAAGA 1587 UCUUUGAG CUGAUGAGGCCGUUAGGCCGAA IUAAUUUC 2086
    1993 AAUUACUC U CAAAGAAA 1588 UUUCUUUG CUGAUGAGGCCGUUAGGCCGAA IAGUAAUU 2087
    1995 UUACUCUC A AAGAAACC 1589 GGUUUCUU CUGAUGAGGCCGUUAGGCCGAA IAGAGUAA 2088
    2003 AAAGAAAC C UGAGGAUC 1590 GAUCCUCA CUGAUGAGGCCGUUAGGCCGAA IUUUCUUU 2089
    2004 AAGAAACC U GAGGAUCG 1591 CGAUCCUC CUGAUGAGGCCGUUAGGCCGAA IGUUUCUU 2090
    2015 GGAUCGAC C UAACACAU 1592 AUGUGUUA CUGAUGAGGCCGUUAGGCCGAA IUCGAUCC 2091
    2016 GAUCGACC U AACACAUC 1593 GAUGUGUU CUGAUGAGGCCGUUAGGCCGAA IGUCGAUC 2092
    2020 GACCUAAC A CAUCUGAA 1594 UUCAGAUG CUGAUGAGGCCGUUAGGCCGAA IUUAGGUC 2093
    2022 CCUAACAC A UCUGAAAU 1595 AUUUCAGA CUGAUGAGGCCGUUAGGCCGAA IUGUUAGG 2094
    2025 AACACAUC U GAAAUACU 1596 AGUAUUUC CUGAUGAGGCCGUUAGGCCGAA IAUGUGUU 2095
    2033 UGAAAUAC U AAGGACCU 1597 AGGUCCUU CUGAUGAGGCCGUUAGGCCGAA IUAUUUCA 2096
    2040 CUAAGGAC C UUGACUGU 1598 ACAGUCAA CUGAUGAGGCCGUUAGGCCGAA IUCCUUAG 2097
    2041 UAAGGACC U UGACUGUG 1599 CACAGUCA CUGAUGAGGCCGUUAGGCCGAA IGUCCUUA 2098
    2046 ACCUUGAC U GUGUGGAA 1600 UUCCACAC CUGAUGAGGCCGUUAGGCCGAA IUCAAGGU 2099
    2062 AGAAAAGC C CAGAGAAA 1601 UUUCUCUG CUGAUGAGGCCGUUAGGCCGAA ICUUUUCU 2100
    2063 GAAAAGCC C AGAGAAAA 1602 UUUUCUCU CUGAUGAGGCCGUUAGGCCGAA IGCUUUUC 2101
    2064 AAAAGCCC A GAGAAAAA 1603 UUUUUCUC CUGAUGAGGCCGUUAGGCCGAA IGGCUUUU 2102
    2081 UGAACGAC A CACAUGUU 1604 AACAUGUG CUGAUGAGGCCGUUAGGCCGAA IUCGUUCA 2103
    2083 AACGACAC A CAUGUUAG 1605 CUAACAUG CUGAUGAGGCCGUUAGGCCGAA IUGUCGUU 2104
    2085 CGACACAC A UGUUAGAG 1606 CUCUAACA CUGAUGAGGCCGUUAGGCCGAA IUGUGUCG 2105
    2095 GUUAGAGC C CUUCUGAA 1607 UUCAGAAG CUGAUGAGGCCGUUAGGCCGAA ICUCUAAC 2106
    2096 UUAGAGCC C UUCUGAAA 1608 UUUCAGAA CUGAUGAGGCCGUUAGGCCGAA IGCUCUAA 2107
    2097 UAGAGCCC U UCUGAAAA 1609 UUUUCAGA CUGAUGAGGCCGUUAGGCCGAA IGGCUCUA 2108
    2100 AGCCCUUC U GAAAAAGU 1610 ACUUUUUC CUGAUGAGGCCGUUAGGCCGAA IAAGGGCU 2109
    2112 AAAGUAUC C UGCUUCUG 1611 CAGAAGCA CUGAUGAGGCCGUUAGGCCGAA IAUACUUU 2110
    2113 AAGUAUCC U GCUUCUGA 1612 UCAGAAGC CUGAUGAGGCCGUUAGGCCGAA IGAUACUU 2111
    2116 UAUCCUGC U UCUGAUAU 1613 AUAUCAGA CUGAUGAGGCCGUUAGGCCGAA ICAGGAUA 2112
    2119 CCUGCUUC U GAUAUGCA 1614 UGCAUAUC CUGAUGAGGCCGUUAGGCCGAA IAAGCAGG 2113
    2127 UGAUAUGC A GUUUUCCU 1615 AGGAAAAC CUGAUGAGGCCGUUAGGCCGAA ICAUAUCA 2114
    2134 CAGUUUUC C UUAAAUUA 1616 UAAUUUAA CUGAUGAGGCCGUUAGGCCGAA IAAAACUG 2115
    2135 AGUUUUCC U UAAAUUAU 1617 AUAAUUUA CUGAUGAGGCCGUUAGGCCGAA IGAAAACU 2116
    2145 AAAUUAUC U AAAAUCUG 1618 CAGAUUUU CUGAUGAGGCCGUUAGGCCGAA IAUAAUUU 2117
    2152 CUAAAAUC U GCUAGGGA 1619 UCCCUAGC CUGAUGAGGCCGUUAGGCCGAA IAUUUUAG 2118
    2155 AAAUCUGC U AGGGAAUA 1620 UAUUCCCU CUGAUGAGGCCGUUAGGCCGAA ICAGAUUU 2119
    2166 GGAAUAUC A AUAGAUAU 1621 AUAUCUAU CUGAUGAGGCCGUUAGGCCGAA IAUAUUCC 2120
    2179 AUAUUUAC C UUUUAUUU 1622 AAAUAAAA CUGAUGAGGCCGUUAGGCCGAA IUAAAUAU 2121
    2180 UAUUUACC U UUUAUUUU 1623 AAAAUAAA CUGAUGAGGCCGUUAGGCCGAA IGUAAAUA 2122
    2197 AAUGUUUC C UUUAAUUU 1624 AAAUUAAA CUGAUGAGGCCGUUAGGCCGAA IAAACAUU 2123
    2198 AUGUUUCC U UUAAUUUU 1625 AAAAUUAA CUGAUGAGGCCGUUAGGCCGAA IGAAACAU 2124
    2211 UUUUUUAC U AUUUUUAC 1626 GUAAAAAU CUGAUGAGGCCGUUAGGCCGAA IUAAAAAA 2125
    2220 AUUUUUAC U AAUCUUUC 1627 GAAAGAUU CUGAUGAGGCCGUUAGGCCGAA IUAAAAAU 2126
    2225 UACUAAUC U UUCUGCAG 1628 CUGCAGAA CUGAUGAGGCCGUUAGGCCGAA IAUUAGUA 2127
    2229 AAUCUUUC U GCAGAAAC 1629 GUUUCUGC CUGAUGAGGCCGUUAGGCCGAA IAAAGAUU 2128
    2232 CUUUCUGC A GAAACAGA 1630 UCUGUUUC CUGAUGAGGCCGUUAGGCCGAA ICAGAAAG 2129
    2238 GCAGAAAC A GAAAGGUU 1631 AACCUUUC CUGAUGAGGCCGUUAGGCCGAA IUUUCUGC 2130
    2250 AGGUUUUC U UCUUUUUG 1632 CAAAAAGA CUGAUGAGGCCGUUAGGCCGAA IAAAACCU 2131
    2253 UUUUCUUC U UUUUGCUU 1633 AAGCAAAA CUGAUGAGGCCGUUAGGCCGAA IAAGAAAA 2132
    2260 CUUUUUGC U UCAAAAAC 1634 GUUUUUGA CUGAUGAGGCCGUUAGGCCGAA ICAAAAAG 2133
    2263 UUUGCUUC A AAAACAUU 1635 AAUGUUUU CUGAUGAGGCCGUUAGGCCGAA IAAGCAAA 2134
    2269 UCAAAAAC A UUCUUACA 1636 UGUAAGAA CUGAUGAGGCCGUUAGGCCGAA IUUUUUGA 2135
    2273 AAACAUUC U UACAUUUU 1637 AAAAUGUA CUGAUGAGGCCGUUAGGCCGAA IAAUGUUU 2136
    2277 AUUCUUAC A UUUUACUU 1638 AAGUAAAA CUGAUGAGGCCGUUAGGCCGAA IUAAGAAU 2137
    2284 CAUUUUAC U UUUUCCUG 1639 CAGGAAAA CUGAUGAGGCCGUUAGGCCGAA IUAAAAUG 2138
    2290 ACUUUUUC C UGGCUCAU 1640 AUGAGCCA CUGAUGAGGCCGUUAGGCCGAA IAAAAAGU 2139
    2291 CUUUUUCC U GGCUCAUC 1641 GAUGAGCC CUGAUGAGGCCGUUAGGCCGAA IGAAAAAG 2140
    2295 UUCCUGGC U CAUCUCUU 1642 AAGAGAUG CUGAUGAGGCCGUUAGGCCGAA ICCAGGAA 2141
    2297 CCUGGCUC A UCUCUUUA 1643 UAAAGAGA CUGAUGAGGCCGUUAGGCCGAA IAGCCAGG 2142
    2300 GGCUCAUC U CUUUAUUC 1644 GAAUAAAG CUGAUGAGGCCGUUAGGCCGAA IAUGAGCC 2143
    2302 CUCAUCUC U UUAUUCUU 1645 AAGAAUAA CUGAUGAGGCCGUUAGGCCGAA IAGAUGAG 2144
    2309 CUUUAUUC U UUUUUUUU 1646 AAAAAAAA CUGAUGAGGCCGUUAGGCCGAA IAAUAAAG 2145
    2329 UUAAAGAC A GAGUCUCG 1647 CGAGACUC CUGAUGAGGCCGUUAGGCCGAA IUCUUUAA 2146
    2335 ACAGAGUC U CGCUCUGU 1648 ACAGAGCG CUGAUGAGGCCGUUAGGCCGAA IACUCUGU 2147
    2339 AGUCUCGC U CUGUUGCC 1649 GGCAACAG CUGAUGAGGCCGUUAGGCCGAA ICGAGACU 2148
    2341 UCUCGCUC U GUUGCCCA 1650 UGGGCAAC CUGAUGAGGCCGUUAGGCCGAA IAGCGAGA 2149
    2347 UCUGUUGC C CAGGCUGG 1651 CCAGCCUG CUGAUGAGGCCGUUAGGCCGAA ICAACAGA 2150
    2348 CUGUUGCC C AGGCUGGA 1652 UCCAGCCU CUGAUGAGGCCGUUAGGCCGAA IGCAACAG 2151
    2349 UGUUGCCC A GGCUGGAG 1653 CUCCAGCC CUGAUGAGGCCGUUAGGCCGAA IGGCAACA 2152
    2353 GCCCAGGC U GGAGUGCA 1654 UGCACUCC CUGAUGAGGCCGUUAGGCCGAA ICCUGGGC 2153
    2361 UGGAGUGC A AUGACACA 1655 UGUGUCAU CUGAUGAGGCCGUUAGGCCGAA ICACUCCA 2154
    2367 GCAAUGAC A CAGUCUUG 1656 CAAGACUG CUGAUGAGGCCGUUAGGCCGAA IUCAUUGC 2155
    2369 AAUGACAC A GUCUUGGC 1657 GCCAAGAC CUGAUGAGGCCGUUAGGCCGAA IUGUCAUU 2156
    2373 ACACAGUC U UGGCUCAC 1658 GUGAGCCA CUGAUGAGGCCGUUAGGCCGAA IACUGUGU 2157
    2378 GUCUUGGC U CACUGCAA 1659 UUGCAGUG CUGAUGAGGCCGUUAGGCCGAA ICCAAGAC 2158
    2380 CUUGGCUC A CUGCAACU 1660 AGUUGCAG CUGAUGAGGCCGUUAGGCCGAA IAGCCAAG 2159
    2382 UGGCUCAC U GCAACUUC 1661 GAAGUUGC CUGAUGAGGCCGUUAGGCCGAA IUGAGCCA 2160
    2385 CUCACUGC A ACUUCUGC 1662 GCAGAAGU CUGAUGAGGCCGUUAGGCCGAA ICAGUGAG 2161
    2388 ACUGCAAC U UCUGCCUC 1663 GAGGCAGA CUGAUGAGGCCGUUAGGCCGAA IUUGCAGU 2162
    2391 GCAACUUC U GCCUCUUG 1664 CAAGAGGC CUGAUGAGGCCGUUAGGCCGAA IAAGUUGC 2163
    2394 ACUUCUGC C UCUUGGGU 1665 ACCCAAGA CUGAUGAGGCCGUUAGGCCGAA ICAGAAGU 2164
    2395 CUUCUGCC U CUUGGGUU 1666 AACCCAAG CUGAUGAGGCCGUUAGGCCGAA IGCAGAAG 2165
    2397 UCUGCCUC U UGGGUUCA 1667 UGAACCCA CUGAUGAGGCCGUUAGGCCGAA IAGGCAGA 2166
    2405 UUGGGUUC A AGUGAUUC 1668 GAAUCACU CUGAUGAGGCCGUUAGGCCGAA IAACCCAA 2167
    2414 AGUGAUUC U CCUGCCUC 1669 GAGGCAGG CUGAUGAGGCCGUUAGGCCGAA IAAUCACU 2168
    2416 UGAUUCUC C UGCCUCAG 1670 CUGAGGCA CUGAUGAGGCCGUUAGGCCGAA IAGAAUCA 2169
    2417 GAUUCUCC U GCCUCAGC 1671 GCUGAGGC CUGAUGAGGCCGUUAGGCCGAA IGAGAAUC 2170
    2420 UCUCCUGC C UCAGCCUC 1672 GAGGCUGA CUGAUGAGGCCGUUAGGCCGAA ICAGGAGA 2171
    2421 CUCCUGCC U CAGCCUCC 1673 GGAGGCUG CUGAUGAGGCCGUUAGGCCGAA IGCAGGAG 2172
    2423 CCUGCCUC A GCCUCCUG 1674 CAGGAGGC CUGAUGAGGCCGUUAGGCCGAA IAGGCAGG 2173
    2426 GCCUCAGC C UCCUGAGU 1675 ACUCAGGA CUGAUGAGGCCGUUAGGCCGAA ICUGAGGC 2174
    2427 CCUCAGCC U CCUGAGUA 1676 UACUCAGG CUGAUGAGGCCGUUAGGCCGAA IGCUGAGG 2175
    2429 UCAGCCUC C UGAGUAGC 1677 GCUACUCA CUGAUGAGGCCGUUAGGCCGAA IAGGCUGA 2176
    2430 CAGCCUCC U GAGUAGCU 1678 AGCUACUC CUGAUGAGGCCGUUAGGCCGAA IGAGGCUG 2177
    2438 UGAGUAGC U GGAUUACA 1679 UGUAAUCC CUGAUGAGGCCGUUAGGCCGAA ICUACUCA 2178
    2446 UGGAUUAC A GGCAUGUG 1680 CACAUGCC CUGAUGAGGCCGUUAGGCCGAA IUAAUCCA 2179
    2450 UUACAGGC A UGUGCCAC 1681 GUGGCACA CUGAUGAGGCCGUUAGGCCGAA ICCUGUAA 2180
    2456 GCAUGUGC C ACCCACCC 1682 GGGUGGGU CUGAUGAGGCCGUUAGGCCGAA ICACAUGC 2181
    2457 CAUGUGCC A CCCACCCA 1683 UGGGUGGG CUGAUGAGGCCGUUAGGCCGAA IGCACAUG 2182
    2459 UGUGCCAC C CACCCAAC 1684 GUUGGGUG CUGAUGAGGCCGUUAGGCCGAA IUGGCACA 2183
    2460 GUGCCACC C ACCCAACU 1685 AGUUGGGU CUGAUGAGGCCGUUAGGCCGAA IGUGGCAC 2184
    2461 UGCCACCC A CCCAACUA 1686 UAGUUGGG CUGAUGAGGCCGUUAGGCCGAA IGGUGGCA 2185
    2463 CCACCCAC C CAACUAAU 1687 AUUAGUUG CUGAUGAGGCCGUUAGGCCGAA IUGGGUGG 2186
    2464 CACCCACC C AACUAAUU 1688 AAUUAGUU CUGAUGAGGCCGUUAGGCCGAA IGUGGGUG 2187
    2465 ACCCACCC A ACUAAUUU 1689 AAAUUAGU CUGAUGAGGCCGUUAGGCCGAA IGGUGGGU 2188
    2468 CACCCAAC U AAUUUUUG 1690 CAAAAAUU CUGAUGAGGCCGUUAGGCCGAA IUUGGGUG 2189
    2493 AUAAAGAC A GGGUUUCA 1691 UGAAACCC CUGAUGAGGCCGUUAGGCCGAA IUCUUUAU 2190
    2501 AGGGUUUC A CCAUGUUG 1692 CAACAUGG CUGAUGAGGCCGUUAGGCCGAA IAAACCCU 2191
    2503 GGUUUCAC C AUGUUGGC 1693 GCCAACAU CUGAUGAGGCCGUUAGGCCGAA IUGAAACC 2192
    2504 GUUUCACC A UGUUGGCC 1694 GGCCAACA CUGAUGAGGCCGUUAGGCCGAA IGUGAAAC 2193
    2512 AUGUUGGC C AGGCUGGU 1695 ACCAGCCU CUGAUGAGGCCGUUAGGCCGAA ICCAACAU 2194
    2513 UGUUGGCC A GGCUGGUC 1696 GACCAGCC CUGAUGAGGCCGUUAGGCCGAA IGCCAACA 2195
    2517 GGCCAGGC U GGUCUCAA 1697 UUGAGACC CUGAUGAGGCCGUUAGGCCGAA ICCUGGCC 2196
    2522 GGCUGGUC U CAAACUCC 1698 GGAGUUUG CUGAUGAGGCCGUUAGGCCGAA IACCAGCC 2197
    2524 CUGGUCUC A AACUCCUG 1699 CAGGAGUU CUGAUGAGGCCGUUAGGCCGAA IAGACCAG 2198
    2528 UCUCAAAC U CCUGACCU 1700 AGGUCAGG CUGAUGAGGCCGUUAGGCCGAA IUUUGAGA 2199
    2530 UCAAACUC C UGACCUCA 1701 UGAGGUCA CUGAUGAGGCCGUUAGGCCGAA IAGUUUGA 2200
    2531 CAAACUCC U GACCUCAA 1702 UUGAGGUC CUGAUGAGGCCGUUAGGCCGAA IGAGUUUG 2201
    2535 CUCCUGAC C UCAAGUAA 1703 UUACUUGA CUGAUGAGGCCGUUAGGCCGAA IUCAGGAG 2202
    2536 UCCUGACC U CAAGUAAU 1704 AUUACUUG CUGAUGAGGCCGUUAGGCCGAA IGUCAGGA 2203
    2538 CUGACCUC A AGUAAUCC 1705 GGAUUACU CUGAUGAGGCCGUUAGGCCGAA IAGGUCAG 2204
    2546 AAGUAAUC C ACCUGCCU 1706 AGGCAGGU CUGAUGAGGCCGUUAGGCCGAA IAUUACUU 2205
    2547 AGUAAUCC A CCUGCCUC 1707 GAGGCAGG CUGAUGAGGCCGUUAGGCCGAA IGAUUACU 2206
    2549 UAAUCCAC C UGCCUCGG 1708 CCGAGGCA CUGAUGAGGCCGUUAGGCCGAA IUGGAUUA 2207
    2550 AAUCCACC U GCCUCGGC 1709 GCCGAGGC CUGAUGAGGCCGUUAGGCCGAA IGUGGAUU 2208
    2553 CCACCUGC C UCGGCCUC 1710 GAGGCCGA CUGAUGAGGCCGUUAGGCCGAA ICAGGUGG 2209
    2554 CACCUGCC U CGGCCUCC 1711 GGAGGCCG CUGAUGAGGCCGUUAGGCCGAA IGCAGGUG 2210
    2559 GCCUCGGC C UCCCAAAG 1712 CUUUGGGA CUGAUGAGGCCGUUAGGCCGAA ICCGAGGC 2211
    2560 CCUCGGCC U CCCAAAGU 1713 ACUUUGGG CUGAUGAGGCCGUUAGGCCGAA IGCCGAGG 2212
    2562 UCGGCCUC C CAAAGUGC 1714 GCACUUUG CUGAUGAGGCCGUUAGGCCGAA IAGGCCGA 2213
    2563 CGGCCUCC C AAAGUGCU 1715 AGCACUUU CUGAUGAGGCCGUUAGGCCGAA IGAGGCCG 2214
    2564 GGCCUCCC A AAGUGCUG 1716 CAGCACUU CUGAUGAGGCCGUUAGGCCGAA IGGAGGCC 2215
    2571 CAAAGUGC U GGGAUUAC 1717 GUAAUCCC CUGAUGAGGCCGUUAGGCCGAA ICACUUUG 2216
    2580 GGGAUUAC A GGGAUGAG 1718 CUCAUCCC CUGAUGAGGCCGUUAGGCCGAA IUAAUCCC 2217
    2590 GGAUGAGC C ACCGCGCC 1719 GGCGCGGU CUGAUGAGGCCGUUAGGCCGAA ICUCAUCC 2218
    2591 GAUGAGCC A CCGCGCCC 1720 GGGCGCGG CUGAUGAGGCCGUUAGGCCGAA IGCUCAUC 2219
    2593 UGAGCCAC C GCGCCCAG 1721 CUGGGCGC CUGAUGAGGCCGUUAGGCCGAA IUGGCUCA 2220
    2598 CACCGCGC C CAGCCUCA 1722 UGAGGCUG CUGAUGAGGCCGUUAGGCCGAA ICGCGGUG 2221
    2599 ACCGCGCC C AGCCUCAU 1723 AUGAGGCU CUGAUGAGGCCGUUAGGCCGAA IGCGCGGU 2222
    2600 CCGCGCCC A GCCUCAUC 1724 GAUGAGGC CUGAUGAGGCCGUUAGGCCGAA IGGCGCGG 2223
    2603 CGCCCAGC C UCAUCUCU 1725 AGAGAUGA CUGAUGAGGCCGUUAGGCCGAA ICUGGGCG 2224
    2604 GCCCAGCC U CAUCUCUU 1726 AAGAGAUG CUGAUGAGGCCGUUAGGCCGAA IGCUGGGC 2225
    2606 CCAGCCUC A UCUCUUUG 1727 CAAAGAGA CUGAUGAGGCCGUUAGGCCGAA IAGGCUGG 2226
    2609 GCCUCAUC U CUUUGUUC 1728 GAACAAAG CUGAUGAGGCCGUUAGGCCGAA IAUGAGGC 2227
    2611 CUCAUCUC U UUGUUCUA 1729 UAGAACAA CUGAUGAGGCCGUUAGGCCGAA IAGAUGAG 2228
    2618 CUUUGUUC U AAAGAUGG 1730 CCAUCUUU CUGAUGAGGCCGUUAGGCCGAA IAACAAAG 2229
    2633 GGAAAAAC C ACCCCCAA 1731 UUGGGGGU CUGAUGAGGCCGUUAGGCCGAA IUUUUUCC 2230
    2634 GAAAAACC A CCCCCAAA 1732 UUUGGGGG CUGAUGAGGCCGUUAGGCCGAA IGUUUUUC 2231
    2636 AAAACCAC C CCCAAAUU 1733 AAUUUGGG CUGAUGAGGCCGUUAGGCCGAA IUGGUUUU 2232
    2637 AAACCACC C CCAAAUUU 1734 AAAUUUGG CUGAUGAGGCCGUUAGGCCGAA IGUGGUUU 2233
    2638 AACCACCC C CAAAUUUU 1735 AAAAUUUG CUGAUGAGGCCGUUAGGCCGAA IGGUGGUU 2234
    2639 ACCACCCC C AAAUUUUC 1736 GAAAAUUU CUGAUGAGGCCGUUAGGCCGAA IGGGUGGU 2235
    2640 CCACCCCC A AAUUUUCU 1737 AGAAAAUU CUGAUGAGGCCGUUAGGCCGAA IGGGGUGG 2236
    2648 AAAUUUUC U UUUUAUAC 1738 GUAUAAAA CUGAUGAGGCCGUUAGGCCGAA IAAAAUUU 2237
    2657 UUUUAUAC U AUUAAUGA 1739 UCAUUAAU CUGAUGAGGCCGUUAGGCCGAA IUAUAAAA 2238
    2669 AAUGAAUC A AUCAAUUC 1740 GAAUUGAU CUGAUGAGGCCGUUAGGCCGAA IAUUCAUU 2239
    2673 AAUCAAUC A AUUCAUAU 1741 AUAUGAAU CUGAUGAGGCCGUUAGGCCGAA IAUUGAUU 2240
    2678 AUCAAUUC A UAUCUAUU 1742 AAUAGAUA CUGAUGAGGCCGUUAGGCCGAA IAAUUGAU 2241
    2683 UUCAUAUC U AUUUAUUA 1743 UAAUAAAU CUGAUGAGGCCGUUAGGCCGAA IAUAUGAA 2242
    2698 UAAAUUUC U ACCGCUUU 1744 AAAGCGGU CUGAUGAGGCCGUUAGGCCGAA IAAAUUUA 2243
    2701 AUUUCUAC C GCUUUUAG 1745 CUAAAAGC CUGAUGAGGCCGUUAGGCCGAA IUAGAAAU 2244
    2704 UCUACCGC U UUUAGGCC 1746 GGCCUAAA CUGAUGAGGCCGUUAGGCCGAA ICGGUAGA 2245
    2712 UUUUAGGC C AAAAAAAU 1747 AUUUUUUU CUGAUGAGGCCGUUAGGCCGAA ICCUAAAA 2246
    2713 UUUAGGCC A AAAAAAUG 1748 CAUUUUUU CUGAUGAGGCCGUUAGGCCGAA IGCCUAAA 2247
    2733 GAUCGUUC U CUGCCUCA 1749 UGAGGCAG CUGAUGAGGCCGUUAGGCCGAA IAACGAUC 2248
    2735 UCGUUCUC U GCCUCACA 1750 UGUGAGGC CUGAUGAGGCCGUUAGGCCGAA IAGAACGA 2249
    2738 UUCUCUGC C UCACAUAG 1751 CUAUGUGA CUGAUGAGGCCGUUAGGCCGAA ICAGAGAA 2250
    2739 UCUCUGCC U CACAUAGC 1752 GCUAUGUG CUGAUGAGGCCGUUAGGCCGAA IGCAGAGA 2251
    2741 UCUGCCUC A CAUAGCUU 1753 AAGCUAUG CUGAUGAGGCCGUUAGGCCGAA IAGGCAGA 2252
    2743 UGCCUCAC A UAGCUUAC 1754 GUAAGCUA CUGAUGAGGCCGUUAGGCCGAA IUGAGGCA 2253
    2748 CACAUAGC U UACAAGCC 1755 GGCUUGUA CUGAUGAGGCCGUUAGGCCGAA ICUAUGUG 2254
    2752 UAGCUUAC A AGCCAGCU 1756 AGCUGGCU CUGAUGAGGCCGUUAGGCCGAA IUAAGCUA 2255
    2756 UUACAAGC C AGCUGGAG 1757 CUCCAGCU CUGAUGAGGCCGUUAGGCCGAA ICUUGUAA 2256
    2757 UACAAGCC A GCUGGAGA 1758 UCUCCAGC CUGAUGAGGCCGUUAGGCCGAA IGCUUGUA 2257
    2760 AAGCCAGC U GGAGAAAU 1759 AUUUCUCC CUGAUGAGGCCGUUAGGCCGAA ICUGGCUU 2258
    2776 UAUGGUAC U CAUUAAAA 1760 UUUUAAUG CUGAUGAGGCCGUUAGGCCGAA IUACCAUA 2259
    2778 UGGUACUC A UUAAAAAA 1761 UUUUUUAA CUGAUGAGGCCGUUAGGCCGAA IAGUACCA 2260

    Input Sequence = NM_002759. Cut Site = CH/.

    Arm Length = 8. Core Sequence = CUGAUGAG X CGAA (X = GCCGUUAGGC or other stem II)

    NM_002759 (Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)

    Underlined region can be any X sequence or linker, as described herein.

    “I” stands for Inosine.
  • TABLE X
    Human PKR Zinzyme and Substrate Sequence
    Seq
    Pos Substrate Seq ID Zinzyme ID
    10 CGGCGGCG G CGGCGCAG 2261 CUGCGCCG GCCGAAAGGCGAGUGAGGUCU CGCCGCCG 2480
    13 CGGCGGCG G CGCAGUUU 2433 AAACUGCG GCCGAAAGGCGAGUGAGGUCU CGCCGCCG 2652
    15 GCGGCGGC G CAGUUUGC 2434 GCAAACUG GCCGAAAGGCGAGUGAGGUCU GCCGCCGC 2653
    18 GCGGCGCA G UUUGCUCA 2435 UGAGCAAA GCCGAAAGGCGAGUGAGGUCU UGCGCCGC 2654
    22 CGCAGUUU G CUCAUACU 2436 AGUAUGAG GCCGAAAGGCGAGUGAGGUCU AAACUGCG 2655
    33 CAUACUUU G UGACUUGC 2437 GCAAGUCA GCCGAAAGGCGAGUGAGGUCU AAAGUAUG 2656
    40 UGUGACUU G CGGUCACA 2438 UGUGACCG GCCGAAAGGCGAGUGAGGUCU AAGUCACA 2657
    43 GACUUGCG G UCACAGUG 2439 CACUGUGA GCCGAAAGGCGAGUGAGGUCU CGCAAGUC 2658
    49 CGGUCACA G UGGCAUUC 2440 GAAUGCCA GCCGAAAGGCGAGUGAGGUCU UGUGACCG 2659
    52 UCACAGUG G CAUUCAGC 2441 GCUGAAUG GCCGAAAGGCGAGUGAGGUCU CACUGUGA 2660
    59 GGCAUUCA G CUCCACAC 2442 GUGUGGAG GCCGAAAGGCGAGUGAGGUCU UGAAUGCC 2661
    71 CACACUUG G UAGAACCA 2443 UGGUUCUA GCCGAAAGGCGAGUGAGGUCU CAAGUGUG 2662
    83 AACCACAG G CACGACAA 2444 UUGUCGUG GCCGAAAGGCGAGUGAGGUCU CUGUGGUU 2663
    92 CACGACAA G CAUAGAAA 2445 UUUCUAUG GCCGAAAGGCGAGUGAGGUCU UUGUCGUG 2664
    124 UCAUCGAG G CAUCGAGG 2446 CCUCGAUG GCCGAAAGGCGAGUGAGGUCU CUCGAUGA 2665
    132 GCAUCGAG G UCCAUCCC 2447 GGGAUGGA GCCGAAAGGCGAGUGAGGUCU CUCGAUGC 2666
    162 AGACCCUG G CUAUCAUA 2448 UAUGAUAG GCCGAAAGGCGAGUGAGGUCU CAGGGUCU 2667
    178 AGACCUUA G UCUUCGCU 2449 AGCGAAGA GCCGAAAGGCGAGUGAGGUCU UAAGGUCU 2668
    184 UAGUCUUC G CUGGUAUA 2450 UAUACCAG GCCGAAAGGCGAGUGAGGUCU GAAGACUA 2669
    188 CUUCGCUG G UAUACUCG 2451 CGAGUAUA GCCGAAAGGCGAGUGAGGUCU CAGCGAAG 2670
    196 GUAUACUC G CUGUCUGU 2452 ACAGACAG GCCGAAAGGCGAGUGAGGUCU GAGUAUAC 2671
    199 UACUCGCU G UCUGUCAA 2453 UUGACAGA GCCGAAAGGCGAGUGAGGUCU AGCGAGUA 2672
    203 CGCUGUCU G UCAACCAG 2454 CUGGUUGA GCCGAAAGGCGAGUGAGGUCU AGACAGCG 2673
    211 GUCAACCA G CGGUUGAC 2455 GUCAACCG GCCGAAAGGCGAGUGAGGUCU UGGUUGAC 2674
    214 AACCAGCG G UUGACUUU 2456 AAAGUCAA GCCGAAAGGCGAGUGAGGUCU CGCUGGUU 2675
    229 UUUUUUAA G CCUUCUUU 2457 AAAGAAGG GCCGAAAGGCGAGUGAGGUCU UUAAAAAA 2676
    252 UUUUACCA G UUUCUGGA 2458 UCCAGAAA GCCGAAAGGCGAGUGAGGUCU UGGUAAAA 2677
    261 UUUCUGGA G CAAAUUCA 2459 UGAAUUUG GCCGAAAGGCGAGUGAGGUCU UCCAGAAA 2678
    270 CAAAUUCA G UUUGCCUU 2460 AAGGCAAA GCCGAAAGGCGAGUGAGGUCU UGAAUUUG 2679
    274 UUCAGUUU G CCUUCCUG 2461 CAGGAAGG GCCGAAAGGCGAGUGAGGUCU AAACUGAA 2680
    288 CUGGAUUU G UAAAUUGU 2462 ACAAUUUA GCCGAAAGGCGAGUGAGGUCU AAAUCCAG 2681
    295 UGUAAAUU G UAAUGACC 2463 GGUCAUUA GCCGAAAGGCGAGUGAGGUCU AAUUUACA 2682
    315 AAACUUUA G CAGUUCUU 2464 AAGAACUG GCCGAAAGGCGAGUGAGGUCU UAAAGUUU 2683
    318 CUUUAGCA G UUCUUCCA 2465 UGGAAGAA GCCGAAAGGCGAGUGAGGUCU UGCUAAAG 2684
    337 UGACUCAG G UUUGCUUC 2466 GAAGCAAA GCCGAAAGGCGAGUGAGGUCU CUGAGUCA 2685
    341 UCAGGUUU G CUUCUCUG 2467 CAGAGAAG GCCGAAAGGCGAGUGAGGUCU AAACCUGA 2686
    350 CUUCUCUG G CGGUCUUC 2468 GAAGACCG GCCGAAAGGCGAGUGAGGUCU CAGAGAAG 2687
    353 CUCUGGCG G UCUUCAGA 2469 UCUGAAGA GCCGAAAGGCGAGUGAGGUCU CGCCAGAG 2688
    380 ACACUUCC G UGAUUAUC 2470 GAUAAUCA GCCGAAAGGCGAGUGAGGUCU GGAAGUGU 2689
    390 GAUUAUCU G CGUGCAUU 2471 AAUGCACG GCCGAAAGGCGAGUGAGGUCU AGAUAAUC 2690
    392 UUAUCUGC G UGCAUUUU 2472 AAAAUGCA GCCGAAAGGCGAGUGAGGUCU GCAGAUAA 2691
    394 AUCUGCGU G CAUUUUGG 2473 CCAAAAUG GCCGAAAGGCGAGUGAGGUCU ACGCAGAU 2692
    408 UGGACAAA G CUUCCAAC 2474 GUUGGAAG GCCGAAAGGCGAGUGAGGUCU UUUGUCCA 2693
    439 AAGAAAUG G CUGGUGAU 2475 AUCACCAG GCCGAAAGGCGAGUGAGGUCU CAUUUCUU 2694
    443 AAUGGCUG G UGAUCUUU 2476 AAAGAUCA GCCGAAAGGCGAGUGAGGUCU CAGCCAUU 2695
    454 AUCUUUCA G CAGGUUUC 2477 GAAACCUG GCCGAAAGGCGAGUGAGGUCU UGAAAGAU 2696
    458 UUCAGCAG G UUUCUUCA 2478 UGAAGAAA GCCGAAAGGCGAGUGAGGUCU CUGCUGAA 2697
    488 UACAUACC G UCAGAAGC 2479 GCUUCUGA GCCGAAAGGCGAGUGAGGUCU GGUAUGUA 2698
    495 CGUCAGAA G CAGGGAGU 2262 ACUCCCUG GCCGAAAGGCGAGUGAGGUCU UUCUGACG 2481
    502 AGCAGGGA G UAGUACUU 2263 AAGUACUA GCCGAAAGGCGAGUGAGGUCU UCCCUGCU 2482
    505 AGGGAGUA G UACUUAAA 2264 UUUAAGUA GCCGAAAGGCGAGUGAGGUCU UACUCCCU 2483
    525 CAAGAACU G CCUAAUUC 2265 GAAUUAGG GCCGAAAGGCGAGUGAGGUCU AGUUCUUG 2484
    555 GAUAGGAG G UUUACAUU 2266 AAUGUAAA GCCGAAAGGCGAGUGAGGUCU CUCCUAUC 2485
    568 CAUUUCAA G UUAUAAUA 2267 UAUUAUAA GCCGAAAGGCGAGUGAGGUCU UUGAAAUG 2486
    599 UCCAGAAG G UGAAGGUA 2268 UACCUUCA GCCGAAAGGCGAGUGAGGUCU CUUCUGGA 2487
    605 AGGUGAAG G UAGAUCAA 2269 UUGAUCUA GCCGAAAGGCGAGUGAGGUCU CUUCACCU 2488
    622 AGAAGGAA G CAAAAAAU 2270 AUUUUUUG GCCGAAAGGCGAGUGAGGUCU UUCCUUCU 2489
    631 CAAAAAAU G CCGCAGCC 2271 GGCUGCGG GCCGAAAGGCGAGUGAGGUCU AUUUUUUG 2490
    634 AAAAUGCC G CAGCCAAA 2272 UUUGGCUG GCCGAAAGGCGAGUGAGGUCU GGCAUUUU 2491
    637 AUGCCGCA G CCAAAUUA 2273 UAAUUUGG GCCGAAAGGCGAGUGAGGUCU UGCGGCAU 2492
    646 CCAAAUUA G CUGUUGAG 2274 CUCAACAG GCCGAAAGGCGAGUGAGGUCU UAAUUUGG 2493
    649 AAUUAGCU G UUGAGAUA 2275 UAUCUCAA GCCGAAAGGCGAGUGAGGUCU AGCUAAUU 2494
    676 AAAAGAAG G CAGUUAGU 2276 ACUAACUG GCCGAAAGGCGAGUGAGGUCU CUUCUUUU 2495
    679 AGAAGGCA G UUAGUCCU 2277 AGGACUAA GCCGAAAGGCGAGUGAGGUCU UGCCUUCU 2496
    683 GGCAGUUA G UCCUUUAU 2278 AUAAAGGA GCCGAAAGGCGAGUGAGGUCU UAACUGCC 2497
    743 UUACAUAG G CCUUAUCA 2279 UGAUAAGG GCCGAAAGGCGAGUGAGGUCU CUAUGUAA 2498
    760 AUAGAAUU G CCCAGAAG 2280 CUUCUGGG GCCGAAAGGCGAGUGAGGUCU AAUUCUAU 2499
    781 GACUAACU G UAAAUUAU 2281 AUAAUUUA GCCGAAAGGCGAGUGAGGUCU AGUUAGUC 2500
    795 UAUCAACA G UGUGCAUC 2282 GAUGCACA GCCGAAAGGCGAGUGAGGUCU UGUUCAUA 2501
    797 UGAACAGU G UGCAUCGG 2283 CCGAUGCA GCCGAAAGGCGAGUGAGGUCU ACUGUUCA 2502
    799 AACAGUGU G CAUCGGGG 2284 CCCCGAUG GCCGAAAGGCGAGUGAGGUCU ACACUGUU 2503
    808 CAUCGGGG G UGCAUGGG 2285 CCCAUGCA GCCGAAAGGCGAGUGAGGUCU CCCCGAUG 2504
    810 UCGGGGGU G CAUGGGCC 2286 GGCCCAUG GCCGAAAGGCGAGUGAGGUCU ACCCCCGA 2505
    816 GUGCAUGG G CCAGAAGG 2287 CCUUCUGG GCCGAAAGGCGAGUGAGGUCU CCAUGCAC 2506
    839 UUAUAAAU G CAAAAUGG 2288 CCAUUUUG GCCGAAAGGCGAGUGAGGUCU AUUUAUAA 2507
    863 AGAAUAUA G UAUUGGUA 2289 UACCAAUA GCCGAAAGGCGAGUGAGGUCU UAUAUUCU 2508
    869 UAGUAUUG G UACAGGUU 2290 AACCUGUA GCCGAAAGGCGAGUGAGGUCU CAAUACUA 2509
    875 UGGUACAG G UUCUACUA 2291 UAGUAGAA GCCGAAAGGCGAGUGAGGUCU CUGUACCA 2510
    892 AACAGGAA G CAAAACAA 2292 UUGUUUUG GCCGAAAGGCGAGUGAGGUCU UUCCUGUU 2511
    904 AACAAUUG G CCGCUAAA 2293 UUUAGCGG GCCGAAAGGCGAGUGAGGUCU CAAUUGUU 2512
    907 AAUUGGCC G CUAAACUU 2294 AAGUUUAG GCCGAAAGGCGAGUGAGGUCU GGCCAAUU 2513
    916 CUAAACUU G CAUAUCUU 2295 AAGAUAUG GCCGAAAGGCGAGUGAGGUCU AAGUUUAG 2514
    949 AAACCUCA G UGAAAUCU 2296 AGAUUUCA GCCGAAAGGCGAGUGAGGUCU UGAGGUUU 2515
    966 GACUACCU G UCCUCUGG 2297 CCACAGGA GCCGAAAGGCGAGUGAGGUCU AGGUAGUC 2516
    974 GUCCUCUG G UUCUUUUG 2298 CAAAAGAA GCCGAAAGGCGAGUGAGGUCU CAGAGGAC 2517
    982 GUUCUUUU G CUACUACG 2299 CGUAGUAG GCCGAAAGGCGAGUGAGGUCU AAAAGAAC 2518
    990 GCUACUAC G UGUGAGUC 2300 GACUCACA GCCGAAAGGCGAGUGAGGUCU GUAGUAGC 2519
    992 UACUACCU G UGAGUCCC 2301 GGGACUCA GCCGAAAGGCGAGUGAGGUCU ACGUAGUA 2520
    996 ACGUCUGA G UCCCAAAG 2302 CUUUGGGA GCCGAAAGGCGAGUGAGGUCU UCACACGU 2521
    1004 GUCCCAAA G CAACUCUU 2303 AAGAGUUG GCCGAAAGGCGAGUGAGGUCU UUUGGGAC 2522
    1015 ACUCUUUA G UGACCAGC 2304 GCUGGUCA GCCGAAAGGCGAGUGAGGUCU UAAAGAGU 2523
    1022 AGUGACCA G CACACUCG 2305 CGAGUGUG GCCGAAAGGCGAGUGAGGUCU UGGUCACU 2524
    1030 GCACACUC G CUUCUGAA 2306 UUCAGAAG GCCGAAAGGCGAGUGAGGUCU GAGUGUGC 2525
    1052 AUCUGAAG G UGACUUCU 2307 AGAAGUCA GCCGAAAGGCGAGUGAGGUCU CUUCAGAU 2526
    1063 ACUUCUGA G CAGAUACA 2308 UGUAUCUG GCCGAAAGGCGAGUGAGGUCU UGAGAAGU 2527
    1091 UUCUAACA G UGACAGUU 2309 AACUGUCA GCCGAAAGGCGAGUGAGGUCU UGUUAGAA 2528
    1097 CAGUGACA G UUUAAACA 2310 UGUUUAAA GCCGAAAGGCGAGUGAGGUCU UGUCACUG 2529
    1106 UUUAAACA G UUCUUCGU 2311 ACGAAGAA GCCGAAAGGCGAGUGAGGUCU UGUUUAAA 2530
    1113 AGUUCUUC G UUGCUUAU 2312 AUAAGCAA GCCGAAAGGCGAGUGAGGUCU GAAGAACU 2531
    1116 UCUUCGUU G CUUAUGAA 2313 UUCAUAAG GCCGAAAGGCGAGUGAGGUCU AACGAAGA 2532
    1127 UAUGAAUG G UCUCAGAA 2314 UUCUGAGA GCCGAAAGGCGAGUGAGGUCU CAUUCAUA 2533
    1150 AAAGGAAG G CAAAAAGA 2315 UCUUUUUG GCCGAAAGGCGAGUGAGGUCU CUUCCUUU 2534
    1165 GAUCUUUG G CACCCAGA 2316 UCUGGGUG GCCGAAAGGCGAGUGAGGUCU CAAAGAUC 2535
    1203 GAAACAAA G UAUACUGU 2317 ACAGUAUA GCCGAAAGGCGAGUGAGGUCU UUUGUUUC 2536
    1210 AGUAUACU G UGGACAAG 2318 CUUGUCCA GCCGAAAGGCGAGUGAGGUCU AGUAUACU 2537
    1221 GACAAGAG G UUUGGCAU 2319 AUGCCAAA GCCGAAAGGCGAGUGAGGUCU CUCUUGUC 2538
    1226 GAGGUUUG G CAUGGAUU 2320 AAUCCAUG GCCGAAAGGCGAGUGAGGUCU CAAACCUC 2539
    1256 AUUAAUUG G CUCAGGUG 2321 CACCUGAG GCCGAAAGGCGAGUGAGGUCU CAAUUAAU 2540
    1262 UGGCUCAG G UGGAUUUG 2322 CAAAUCCA GCCGAAAGGCGAGUGAGGUCU CUGAGCCA 2541
    1271 UGGAUUUG G CCAAGUUU 2323 AAACUUGG GCCGAAAGGCGAGUGAGGUCU CAAAUCCA 2542
    1276 UUGGCCAA G UUUUCAAA 2324 UUUGAAAA GCCGAAAGGCGAGUGAGGUCU UUGGCCAA 2543
    1285 UUUUCAAA G CAAAACAC 2325 GUGUUUUG GCCGAAAGGCGAGUGAGGUCU UUUGAAAA 2544
    1315 AGACUUAC G UUAUUAAA 2326 UUUAAUAA GCCGAAAGGCGAGUGAGGUCU GUAAGUCU 2545
    1325 UAUUAAAC G UGUUAAAU 2327 AUUUAACA GCCGAAAGGCGAGUGAGGUCU GUUUAAUA 2546
    1327 UUAAACGU G UUAAAUAU 2328 AUAUUUAA GCCGAAAGGCGAGUGAGGUCU ACGUUUAA 2547
    1348 ACGAGAAG G CGGAGCGU 2329 ACGCUCCG GCCGAAAGGCGAGUGAGGUCU CUUCUCGU 2548
    1353 AAGGCGGA G CGUGAAGU 2330 ACUUCACG GCCGAAAGGCGAGUGAGGUCU UCCGCCUU 2549
    1355 GGCGGAGC G UGAAGUAA 2331 UUACUUCA GCCGAAAGGCGAGUGAGGUCU GCUCCGCC 2550
    1360 AGCGUGAA G UAAAAGCA 2332 UGCUUUUA GCCGAAAGGCGAGUGAGGUCU UUCACGCU 2551
    1366 AAGUAAAA G CAUUGGCA 2333 UGCCAAUG GCCGAAAGGCGAGUGAGGUCU UUUUACUU 2552
    1372 AAGCAUUG G CAAAACUU 2334 AAGUUUUG GCCGAAAGGCGAGUGAGGUCU CAAUGCUU 2553
    1387 UUGAUCAU G UAAAUAUU 2335 AAUAUUUA GCCGAAAGGCGAGUGAGGUCU AUGAUCAA 2554
    1396 UAAAUAUU G UUCACUAC 2336 GUAGUGAA GCCGAAAGGCGAGUGAGGUCU AAUAUUUA 2555
    1409 CUACAAUG G CUGUUGGG 2337 CCCAACAG GCCGAAAGGCGAGUGAGGUCU CAUUGUAG 2556
    1412 CAAUGGCU G UUGGGAUG 2338 CAUCCCAA GCCGAAAGGCGAGUGAGGUCU AGCCAUUG 2557
    1445 UGAGACCA G UGAUGAUU 2339 AAUCAUCA GCCGAAAGGCGAGUGAGGUCU UGGUCUCA 2558
    1463 UCUUGAGA G CAGUGAUU 2340 AAUCACUG GCCGAAAGGCGAGUGAGGUCU UCUCAAGA 2559
    1466 UGAGAGCA G UGAUUAUG 2341 CAUAAUCA GCCGAAAGGCGAGUGAGGUCU UGCUCUCA 2560
    1487 UGAGAACA G CAAAAAUA 2342 UAUUUUUG GCCGAAAGGCGAGUGAGGUCU UGUUCUCA 2561
    1496 CAAAAAUA G UUCAAGGU 2343 ACCUUGAA GCCGAAAGGCGAGUGAGGUCU UAUUUUUG 2562
    1503 AGUUCAAG G UCAAAGAC 2344 GUCUUUGA GCCGAAAGGCGAGUGAGGUCU CUUGAACU 2563
    1515 AAGACUAA G UGCCUUUU 2345 AAAAGGCA GCCGAAAGGCGAGUGAGGUCU UUAGUCUU 2564
    1517 GACUAAGU G CCUUUUCA 2346 UGAAAAGG GCCGAAAGGCGAGUGAGGUCU ACUUAGUC 2565
    1541 GGAAUUCU G UGAUAAAG 2347 CUUUAUCA GCCGAAAGGCGAGUGAGGUCU AGAAUUCC 2566
    1583 AAGAAGAG G CGAGAAAC 2348 GUUUCUCG GCCGAAAGGCGAGUGAGGUCU CUCUUCUU 2567
    1600 UAGACAAA G UUUUGGCU 2349 AGCCAAAA GCCGAAAGGCGAGUGAGGUCU UUUGUCUA 2568
    1606 AAGUUUUG G CUUUGGAA 2350 UUCCAAAG GCCGAAAGGCGAGUGAGGUCU CAAAACUU 2569
    1639 CAAAAGGG G UGGAUUAU 2351 AUAAUCCA GCCGAAAGGCGAGUGAGGUCU CCCUUUUG 2570
    1683 GAUCUUAA G CCAAGUAA 2352 UUACUUGG GCCGAAAGGCGAGUGAGGUCU UUAAGAUC 2571
    1688 UAAGCCAA G UAAUAUAU 2353 AUAUAUUA GCCGAAAGGCGAGUGAGGUCU UUGGCUUA 2572
    1702 UAUUCUUA G UAGAUACA 2354 UGUAUCUA GCCGAAAGGCGAGUGAGGUCU UAAGAAUA 2573
    1717 CAAAACAA G UAAAGAUU 2355 AAUCUUUA GCCGAAAGGCGAGUGAGGUCU UUGUUUUG 2574
    1741 UUGGACUU G UAACAUCU 2356 AGAUGUUA GCCGAAAGGCGAGUGAGGUCU AAGUCCAA 2575
    1767 GAUGGAAA G CGAACAAG 2357 CUUGUUCG GCCGAAAGGCGAGUGAGGUCU UUUCCAUC 2576
    1778 AACAAGGA G UAAGGGAA 2358 UUCCCUUA GCCGAAAGGCGAGUGAGGUCU UCCUUGUU 2577
    1791 GGAACUUU G CGAUACAU 2359 AUGUAUCG GCCGAAAGGCGAGUGAGGUCU AAAGUUCC 2578
    1802 AUACAUGA G CCCAGAAC 2360 GUUCUGGG GCCGAAAGGCGAGUGAGGUCU UCAUGUAU 2579
    1821 AUUUCUUC G CAAGACUA 2361 UAGUCUUG GCCGAAAGGCGAGUGAGGUCU GAAGAAAU 2580
    1840 GAAAGGAA G UGGACCUC 2362 GAGGUCCA GCCGAAAGGCGAGUGAGGUCU UUCCUUUC 2581
    1852 ACCUCUAC G CUUUGGGG 2363 CCCCAAAG GCCGAAAGGCGAGUGAGGUCU GUAGAGGU 2582
    1860 GCUUUGGG G CUAAUUCU 2364 AGAAUUAG GCCGAAAGGCGAGUGAGGUCU CCCAAAGC 2583
    1870 UAAUUCUU G CUGAACUU 2365 AAGUUCAG GCCGAAAGGCGAGUGAGGUCU AAGAAUUA 2584
    1885 UUCUUCAU G UAUGUGAC 2366 GUCACAUA GCCGAAAGGCGAGUGAGGUCU AUGAAGAA 2585
    1889 UCAUGUAU G UGACACUG 2367 CAGUGUCA GCCGAAAGGCGAGUGAGGUCU AUACAUGA 2586
    1897 GUGACACU G CUUUUGAA 2368 UUCAAAAG GCCGAAAGGCGAGUGAGGUCU AGUGUCAC 2587
    1914 ACAUCAAA G UUUUUCAC 2369 GUGAAAAA GCCGAAAGGCGAGUGAGGUCU UUUGAUGU 2588
    1937 ACGGGAUG G CAUCAUCU 2370 AGAUGAUG GCCGAAAGGCGAGUGAGGUCU CAUCCCGU 2589
    2047 CCUUGACU G UGUGGAAG 2371 CUUCCACA GCCGAAAGGCGAGUGAGGUCU AGUCAAGG 2590
    2049 UUGACUGU G UGGAAGAA 2372 UUCUUCCA GCCGAAAGGCGAGUGAGGUCU ACAGUCAA 2591
    2060 GAAGAAAA G CCCAGAGA 2373 UCUCUGGG GCCGAAAGGCGAGUGAGGUCU UUUUCUUC 2592
    2087 ACACACAU G UUAGAGCC 2374 GGCUCUAA GCCGAAAGGCGAGUGAGGUCU AUGUGUGU 2593
    2093 AUGUUAGA G CCCUUCUG 2375 CAGAAGGG GCCGAAAGGCGAGUGAGGUCU UCUAACAU 2594
    2107 CUGAAAAA G UAUCCUGC 2376 GCAGGAUA GCCGAAAGGCGAGUGAGGUCU UUUUUCAG 2595
    2114 AGUAUCCU G CUUCUGAU 2377 AUCAGAAG GCCGAAAGGCGAGUGAGGUCU AGGAUACU 2596
    2125 UCUGAUAU G CAGUUUUC 2378 GAAAACUG GCCGAAAGGCGAGUGAGGUCU AUAUCAGA 2597
    2128 GAUAUGCA G UUUUCCUU 2379 AAGGAAAA GCCGAAAGGCGAGUGAGGUCU UGCAUAUC 2598
    2153 UAAAAUCU G CUAGGGAA 2380 UUCCCUAG GCCGAAAGGCGAGUGAGGUCU AGAUUUUA 2599
    2192 AUUUUAAU G UUUCCUUU 2381 AAAGGAAA GCCGAAAGGCGAGUGAGGUCU AUUAAAAU 2600
    2230 AUCUUUCU G CAGAAACA 2382 UGUUUCUG GCCGAAAGGCGAGUGAGGUCU AGAAAGAU 2601
    2244 ACAGAAAG G UUUUCUUC 2383 GAAGAAAA GCCGAAAGGCGAGUGAGGUCU CUUUCUGU 2602
    2258 UUCUUUUU G CUUCAAAA 2384 UUUUGAAG GCCGAAAGGCGAGUGAGGUCU AAAAAGAA 2603
    2293 UUUUCCUG G CUCAUCUC 2385 GAGAUGAG GCCGAAAGGCGAGUGAGGUCU CAGGAAAA 2604
    2332 AAGACAGA G UCUCGCUC 2386 GAGCGAGA GCCGAAAGGCGAGUGAGGUCU UCUGUCUU 2605
    2337 AGAGUCUC G CUCUGUUG 2387 CAACAGAG GCCGAAAGGCGAGUGAGGUCU GAGACUCU 2606
    2342 CUCGCUCU G UUGCCCAG 2388 CUGGGCAA GCCGAAAGGCGAGUGAGGUCU AGAGCGAG 2607
    2345 GCUCUGUU G CCCAGGCU 2389 AGCCUGGG GCCGAAAGGCGAGUGAGGUCU AACAGAGC 2608
    2351 UUGCCCAG G CUGGAGUG 2390 CACUCCAG GCCGAAAGGCGAGUGAGGUCU CUGGGCAA 2609
    2357 AGGCUGGA G UGCAAUGA 2391 UCAUUGCA GCCGAAAGGCGAGUGAGGUCU UCCAGCCU 2610
    2359 GCUGGAGU G CAAUGACA 2392 UGUCAUUG GCCGAAAGGCGAGUGAGGUCU ACUCCAGC 2611
    2370 AUGACACA G UCUUGGCU 2393 AGCCAAGA GCCGAAAGGCGAGUGAGGUCU UGUGUCAU 2612
    2376 CAGUCUUG G CUCACUGC 2394 GCAGUGAG GCCGAAAGGCGAGUGAGGUCU CAAGACUG 2613
    2383 GGCUCACU G CAACUUCU 2395 AGAAGUUG GCCGAAAGGCGAGUGAGGUCU AGUGAGCC 2614
    2392 CAACUUCU G CCUCUUGG 2396 CCAAGAGG GCCGAAAGGCGAGUGAGGUCU AGAAGUUG 2615
    2401 CCUCUUGG G UUCAAGUG 2397 CACUUGAA GCCGAAAGGCGAGUGAGGUCU CCAAGAGG 2616
    2407 GGGUUCAA G UGAUUCUC 2398 GAGAAUCA GCCGAAAGGCGAGUGAGGUCU UUGAACCC 2617
    2418 AUUCUCCU G CCUCAGCC 2399 GGCUGAGG GCCGAAAGGCGAGUGAGGUCU AGGAGAAU 2618
    2424 CUGCCUCA G CCUCCUGA 2400 UCAGGAGG GCCGAAAGGCGAGUGAGGUCU UGAGGCAG 2619
    2433 CCUCCUGA G UAGCUGGA 2401 UCCAGCUA GCCGAAAGGCGAGUGAGGUCU UCAGGAGG 2620
    2436 CCUGAGUA G CUGGAUUA 2402 UAAUCCAG GCCGAAAGGCGAGUGAGGUCU UACUCAGG 2621
    2448 GAUUACAG G CAUGUGCC 2403 GGCACAUG GCCGAAAGGCGAGUGAGGUCU CUGUAAUC 2622
    2452 ACAGGCAU G UGCCACCC 2404 GGGUGGCA GCCGAAAGGCGAGUGAGGUCU AUGCCUGU 2623
    2454 AGGCAUGU G CCACCCAC 2405 GUGGGUGG GCCGAAAGGCGAGUGAGGUCU ACAUGCCU 2624
    2476 UAAUUUUU G UGUUUUUA 2406 UAAAAACA GCCGAAAGGCGAGUGAGGUCU AAAAAUUA 2625
    2478 AUUUUUGU G UUUUUAAU 2407 AUUAAAAA GCCGAAAGGCGAGUGAGGUCU ACAAAAAU 2626
    2496 AAGACAGG G UUUCACCA 2408 UGGUGAAA GCCGAAAGGCGAGUGAGGUCU CCUGUCUU 2627
    2506 UUCACCAU G UUGGCCAG 2409 CUGGCCAA GCCGAAAGGCGAGUGAGGUCU AUGGUGAA 2628
    2510 CCAUGUUG G CCAGGCUG 2410 CAGCCUGG GCCGAAAGGCGAGUGAGGUCU CAACAUGG 2629
    2515 UUGGCCAG G CUGGUCUC 2411 GAGACCAG GCCGAAAGGCGAGUGAGGUCU CUGGCCAA 2630
    2519 CCAGGCUG G UCUCAAAC 2412 GUUUGAGA GCCGAAAGGCGAGUGAGGUCU CAGCCUGG 2631
    2540 GACCUCAA G UAAUCCAC 2413 GUGGAUUA GCCGAAAGGCGAGUGAGGUCU UUGAGGUC 2632
    2551 AUCCACCU G CCUCGGCC 2414 GGCCGAGG GCCGAAAGGCGAGUGAGGUCU AGGUGGAU 2633
    2557 CUGCCUCG G CCUCCCAA 2415 UUGGGAGG GCCGAAAGGCGAGUGAGGUCU CGAGGCAG 2634
    2567 CUCCCAAA G UGCUGGGA 2416 UCCCAGCA GCCGAAAGGCGAGUGAGGUCU UUUGGGAG 2635
    2569 CCCAAAGU G CUGGGAUU 2417 AAUCCCAG GCCGAAAGGCGAGUGAGGUCU ACUUUGGG 2636
    2588 AGGGAUGA G CCACCGCG 2418 CGCGGUGG GCCGAAAGGCGAGUGAGGUCU UCAUCCCU 2637
    2594 GAGCCACC G CGCCCAGC 2419 GCUGGGCG GCCGAAAGGCGAGUGAGGUCU GGUGGCUC 2638
    2596 GCCACCGC G CCCAGCCU 2420 AGGCUGGG GCCGAAAGGCGAGUGAGGUCU GCGGUGGC 2639
    2601 CGCGCCCA G CCUCAUCU 2421 AGAUGAGG GCCGAAAGGCGAGUGAGGUCU UGGGCGCG 2640
    2614 AUCUCUUU G UUCUAAAG 2422 CUUUAGAA GCCGAAAGGCGAGUGAGGUCU AAAGAGAU 2641
    2702 UUUCUACC G CUUUUAGG 2423 CCUAAAAG GCCGAAAGGCGAGUGAGGUCU GGUAGAAA 2642
    2710 GCUUUUAG G CCAAAAAA 2424 UUUUUUGG GCCGAAAGGCGAGUGAGGUCU CUAAAAGC 2643
    2721 AAAAAAAU G UAAGAUCG 2425 CGAUCUUA GCCGAAAGGCGAGUGAGGUCU AUUUUUUU 2644
    2729 GUAAGAUC G UUCUCUGC 2426 GCAGAGAA GCCGAAAGGCGAGUGAGGUCU GAUCUUAC 2645
    2736 CGUUCUCU G CCUCACAU 2427 AUGUGAGG GCCGAAAGGCGAGUGAGGUCU AGAGAACG 2646
    2746 CUCACAUA G CUUACAAG 2428 CUUGUAAG GCCGAAAGGCGAGUGAGGUCU UAUGUGAG 2647
    2754 GCUUACAA G CCAGCUGG 2429 CCAGCUGG GCCGAAAGCCCAGUGAGGUCU UUGUAAGC 2648
    2758 ACAAGCCA G CUGGAGAA 2430 UUCUCCAG GCCGAAACGCGAGUGAGCUCU UCGCUUGU 2649
    2772 GAAAUAUG G UACUCAUU 2431 AAUGAGUA GCCGAAAGGCGAGUGAGGUCU CAUAUUUC 2650
    2796 AAAAAAAA G UGAUGUAC 2432 GUACAUCA GCCGAAAGGCGAGUGAGGUCU UUUUUUUU 2651

    Input Sequence = NM_002759. Cut Site = G/Y

    Arm Length = 8. Core Sequence = GCcgaaagGCGaGuCaaGGuCu

    NM_002759 (Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)
  • TABLE XI
    Human PKR DNAzyme and Substrate Sequence
    Seq
    Pos Substrate Seq ID DNAzyme ID
    10 CGGCGGCG G CGGCGCAG 2261 CTGCGCCG GGCTAGCTACAACGA CGCCGCCG 2904
    13 CGGCGGCG G CGCAGUUU 2433 AAACTGCG GGCTAGCTACAACGA CGCCGCCG 2905
    15 GCGGCGGC G CAGUUUGC 2434 GCAAACTG GGCTAGCTACAACGA GCCGCCGC 2906
    18 GCGGCGCA G UUUGCUCA 2435 TGAGCAAA GGCTAGCTACAACGA TGCGCCGC 2907
    22 CGCAGUUU G CUCAUACU 2436 AGTATGAG GGCTAGCTACAACGA AAACTGCG 2908
    26 GUUUGCUC A UACUUUGU 1265 ACAAAGTA GGCTAGCTACAACGA GAGCAAAC 2909
    28 UUGCUCAU A CUUUGUGA 4 TCACAAAG GGCTAGCTACAACGA ATGAGCAA 2910
    33 CAUACUUU G UGACUUGC 2437 GCAAGTCA GGCTAGCTACAACGA AAAGTATG 2911
    36 ACUUUGUG A CUUGCGGU 2699 ACCGCAAG GGCTAGCTACAACGA CACAAAGT 2912
    40 UGUGACUU G CGGUCACA 2438 TGTGACCG GGCTAGCTACAACGA AAGTCACA 2913
    43 GACUUGCG G UCACAGUG 2439 CACTGTGA GGCTAGCTACAACGA CGCAAGTC 2914
    46 UUGCGGUC A CAGUGGCA 1268 TGCCACTG GGCTAGCTACAACGA GACCGCAA 2915
    49 CGGUCACA G UGGCAUUC 2440 GAATGCCA GGCTAGCTACAACGA TGTGACCG 2916
    52 UCACAGUG G CAUUCAGC 2441 GCTGAATG GGCTAGCTACAACGA CACTGTGA 2917
    54 ACAGUGGC A UUCAGCUC 1270 GAGCTGAA GGCTAGCTACAACGA GCCACTGT 2918
    59 GGCAUUCA G CUCCACAC 2442 GTGTGGAG GGCTAGCTACAACGA TGAATGCC 2919
    64 UCAGCUCC A CACUUGGU 1274 ACCAAGTG GGCTAGCTACAACGA GGAGCTGA 2920
    66 AGCUCCAC A CUUGGUAG 1275 CTACCAAG GGCTAGCTACAACGA GTGGAGCT 2921
    71 CACACUUG G UAGAACCA 2443 TGGTTCTA GGCTAGCTACAACGA CAAGTGTG 2922
    76 UUGGUAGA A CCACAGGC 2700 GCCTGTGG GGCTAGCTACAACGA TCTACCAA 2923
    79 GUAGAACC A CAGGCACG 1278 CGTGCCTG GGCTAGCTACAACGA GGTTCTAC 2924
    83 AACCACAG G CACGACAA 2444 TTGTCGTG GGCTAGCTACAACGA CTGTGGTT 2925
    85 CCACAGGC A CGACAAGC 1280 GCTTGTCG GGCTAGCTACAACGA GCCTGTGG 2926
    88 CAGGCACG A CAAGCAUA 2701 TATGCTTG GGCTAGCTACAACGA CGTGCCTG 2927
    92 CACGACAA G CAUAGAAA 2445 TTTCTATG GGCTAGCTACAACGA TTGTCGTG 2928
    94 CGACAAGC A UAGAAACA 1282 TGTTTCTA GGCTAGCTACAACGA GCTTGTCG 2929
    100 GCAUAGAA A CAUCCUAA 2702 TTAGGATG GGCTAGCTACAACGA TTCTATGC 2930
    102 AUAGAAAC A UCCUAAAC 1283 GTTTAGGA GGCTAGCTACAACGA GTTTCTAT 2931
    109 CAUCCUAA A CAAUCUUC 2703 GAAGATTG GGCTAGCTACAACGA TTAGGATG 2932
    112 CCUAAACA A UCUUCAUC 2704 GATGAAGA GGCTAGCTACAACGA TGTTTAGG 2933
    118 CAAUCUUC A UCGAGGCA 1288 TGCCTCGA GGCTAGCTACAACGA GAAGATTG 2934
    124 UCAUCGAG C CAUCGAGG 2446 CCTCGATG GGCTAGCTACAACGA CTCGATGA 2935
    126 AUCGAGGC A UCCAGGUC 1289 GACCTCGA GGCTAGCTACAACGA GCCTCGAT 2936
    132 GCAUCGAG G UCCAUCCC 2447 GGGATGGA GGCTAGCTACAACGA CTCGATGC 2937
    136 CGAGGUCC A UCCCAAUA 1291 TATTGGGA GGCTAGCTACAACGA GGACCTCG 2938
    142 CCAUCCCA A UAAAAAUC 2705 GATTTTTA GGCTAGCTACAACGA TGGGATGG 2939
    148 CAAUAAAA A UCAGGAGA 2706 TCTCCTGA GGCTAGCTACAACGA TTTTATTG 2940
    156 AUCAGGAG A CCCUGGCU 2707 AGCCAGGG GGCTAGCTACAACGA CTCCTGAT 2941
    162 AGACCCUG G CUAUCAUA 2448 TATGATAG GGCTAGCTACAACGA CAGGGTCT 2942
    165 CCCUGGCU A UCAUAGAC 26 GTCTATGA GGCTAGCTACAACGA AGCCAGGG 2943
    168 UGGCUAUC A UAGACCUU 1300 AAGGTCTA GGCTAGCTACAACGA GATAGCCA 2944
    172 UAUCAUAG A CCUUAGUC 2708 GACTAAGG GGCTAGCTACAACGA CTATGATA 2945
    178 AGACCUUA G UCUUCGCU 2449 AGCGAAGA GGCTAGCTACAACGA TAAGGTCT 2946
    184 UAGUCUUC G CUGGUAUA 2450 TATACCAG GGCTAGCTACAACGA GAAGACTA 2947
    188 CUUCGCUG G UAUACUCG 2451 CGAGTATA GGCTAGCTACAACGA CAGCGAAG 2948
    190 UCGCUGGU A UACUCGCU 34 AGCGAGTA GGCTAGCTACAACGA ACCAGCGA 2949
    192 GCUGGUAU A CUCGCUGU 35 ACAGCGAG GGCTAGCTACAACGA ATACCAGC 2950
    196 GUAUACUC G CUGUCUGU 2452 ACAGACAG GGCTAGCTACAACGA GAGTATAC 2951
    199 UACUCGCU G UCUGUCAA 2453 TTGACAGA GGCTAGCTACAACGA AGCGAGTA 2952
    203 CGCUGUCU G UCAACCAG 2454 CTGGTTGA GGCTAGCTACAACGA AGACAGCG 2953
    207 GUCUGUCA A CCAGCGGU 2709 ACCGCTGG GGCTAGCTACAACGA TGACAGAC 2954
    211 GUCAACCA G CGGUUGAC 2455 GTCAACCG GGCTAGCTACAACGA TGGTTGAC 2955
    214 AACCAGCG G UUGACUUU 2456 AAAGTCAA GGCTAGCTACAACGA CGCTGGTT 2956
    218 AGCGGUUG A CUUUUUUU 2710 AAAAAAAG GGCTAGCTACAACGA CAACCGCT 2957
    229 UUUUUUAA G CCUUCUUU 2457 AAAGAAGG GGCTAGCTACAACGA TTAAAAAA 2958
    248 UCUCUUUU A CCAGUUUC 59 GAAACTGG GGCTAGCTACAACGA AAAAGAGA 2959
    252 UUUUACCA G UUUCUGGA 2458 TCCAGAAA GGCTAGCTACAACGA TGGTAAAA 2960
    261 UUUCUGGA G CAAAUUCA 2459 TGAATTTG GGCTAGCTACAACGA TCCAGAAA 2961
    265 UGGAGCAA A UUCAGUUU 2711 AAACTGAA GGCTAGCTACAACGA TTGCTCCA 2962
    270 CAAAUUCA G UUUGCCUU 2460 AAGGCAAA GGCTAGCTACAACGA TGAATTTG 2963
    274 UUCAGUUU G CCUUCCUG 2461 CAGGAAGG GGCTAGCTACAACGA AAACTGAA 2964
    284 CUUCCUGG A UUUGUAAA 2712 TTTACAAA GGCTAGCTACAACGA CCAGGAAG 2965
    288 CUGGAUUU G UAAAUUGU 2462 ACAATTTA GGCTAGCTACAACGA AAATCCAG 2966
    292 AUUUGUAA A UUGUAAUG 2713 CATTACAA GGCTAGCTACAACGA TTACAAAT 2967
    295 UGUAAAUU G UAAUGACC 2463 GGTCATTA GGCTAGCTACAACGA AATTTACA 2968
    298 AAAUUGUA A UGACCUCA 2714 TGAGGTCA GGCTAGCTACAACGA TACAATTT 2969
    301 UUGUAAUG A CCUCAAAA 2715 TTTTGAGG GGCTAGCTACAACGA CATTACAA 2970
    309 ACCUCAAA A CUUUAGCA 2716 TGCTAAAG GGCTAGCTACAACGA TTTGAGGT 2971
    315 AAACUUUA G CAGUUCUU 2464 AAGAACTG GGCTAGCTACAACGA TAAAGTTT 2972
    318 CUUUAGCA G UUCUUCCA 2465 TGGAAGAA GGCTAGCTACAACGA TGCTAAAG 2973
    326 GUUCUUCC A UCUGACUC 1333 GAGTCAGA GGCTAGCTACAACGA GGAAGAAC 2974
    331 UCCAUCUG A CUCAGGUU 2717 AACCTGAG GGCTAGCTACAACGA CAGATGGA 2975
    337 UGACUCAG G UUUGCUUC 2466 GAAGCAAA GGCTAGCTACAACGA CTGAGTCA 2976
    341 UCAGGUUU G CUUCUCUG 2467 CAGAGAAG GGCTAGCTACAACGA AAACCTGA 2977
    350 CUUCUCUG G CGGUCUUC 2468 GAAGACCG GGCTAGCTACAACGA CAGAGAAG 2978
    353 CUCUGGCG G UCUUCAGA 2469 TCTGAAGA GGCTAGCTACAACGA CGCCAGAG 2979
    362 UCUUCAGA A UCAACAUC 2718 GATGTTGA GGCTAGCTACAACGA TCTGAAGA 2980
    366 CAGAAUCA A CAUCCACA 2719 TGTGGATG GGCTAGCTACAACGA TGATTCTG 2981
    368 GAAUCAAC A UCCACACU 1343 AGTGTGGA GGCTAGCTACAACGA GTTGATTC 2982
    372 CAACAUCC A CACUUCCG 1345 CGGAAGTG GGCTAGCTACAACGA GGATGTTG 2983
    374 ACAUCCAC A CUUCCGUG 1346 CACGGAAG GGCTAGCTACAACGA GTGGATGT 2984
    380 ACACUUCC G UGAUUAUC 2470 GATAATCA GGCTAGCTACAACGA GGAAGTGT 2985
    383 CUUCCGUG A UUAUCUGC 2720 GCAGATAA GGCTAGCTACAACGA CACGGAAG 2986
    386 CCGUGAUU A UCUGCGUG 97 CACGCAGA GGCTAGCTACAACGA AATCACGG 2987
    390 GAUUAUCU G CGUGCAUU 2471 AATGCACG GGCTAGCTACAACGA AGATAATC 2988
    392 UUAUCUGC G UGCAUUUU 2472 AAAATGCA GGCTAGCTACAACGA GCAGATAA 2989
    394 AUCUGCGU G CAUUUUGG 2473 CCAAAATG GGCTAGCTACAACGA ACGCAGAT 2990
    396 CUGCGUGC A UUUUGGAC 1350 GTCCAAAA GGCTAGCTACAACGA GCACGCAG 2991
    403 CAUUUUGG A CAAAGCUU 2721 AAGCTTTG GGCTAGCTACAACGA CCAAAATG 2992
    408 UGGACAAA G CUUCCAAC 2474 GTTGGAAG GGCTAGCTACAACGA TTTGTCCA 2993
    415 AGCUUCCA A CCAGGAUA 2722 TATCCTGG GGCTAGCTACAACGA TGGAAGCT 2994
    421 CAACCAGG A UACGGGAA 2723 TTCCCGTA GGCTAGCTACAACGA CCTGGTTG 2995
    423 ACCAGGAU A CGGGAAGA 104 TCTTCCCG GGCTAGCTACAACGA ATCCTGGT 2996
    436 AAGAAGAA A UGGCUGGU 2724 ACCAGCCA GGCTAGCTACAACGA TTCTTCTT 2997
    439 AAGAAAUG G CUGGUGAU 2475 ATCACCAG GGCTAGCTACAACGA CATTTCTT 2998
    443 AAUGGCUG G UGAUCUUU 2476 AAAGATCA GGCTAGCTACAACGA CAGCCATT 2999
    446 GGCUGGUG A UCUUUCAG 2725 CTGAAAGA GGCTAGCTACAACGA CACCAGCC 3000
    454 AUCUUUCA G CAGGUUUC 2477 GAAACCTG GGCTAGCTACAACGA TGAAAGAT 3001
    458 UUCAGCAG G UUUCUUCA 2478 TGAAGAAA GGCTAGCTACAACGA CTGCTGAA 3002
    466 GUUUCUUC A UGGAGGAA 1362 TTCCTCCA GGCTAGCTACAACGA GAAGAAAC 3003
    474 AUGGAGGA A CUUAAUAC 2726 GTATTAAG GGCTAGCTACAACGA TCCTCCAT 3004
    479 GGAACUUA A UACAUACC 2727 GGTATGTA GGCTAGCTACAACGA TAAGTTCC 3005
    481 AACUUAAU A CAUACCGU 116 ACGGTATG GGCTAGCTACAACGA ATTAAGTT 3006
    483 CUUAAUAC A UACCGUCA 1364 TGACGGTA GGCTAGCTACAACGA GTATTAAG 3007
    485 UAAUACAU A CCGUCAGA 117 TCTGACGG GGCTAGCTACAACGA ATGTATTA 3008
    488 UACAUACC G UCAGAAGC 2479 GCTTCTGA GGCTAGCTACAACGA GGTATGTA 3009
    495 CGUCAGAA G CAGGGAGU 2262 ACTCCCTG GGCTAGCTACAACGA TTCTGACG 3010
    502 AGCAGGGA G UAGUACUU 2263 AAGTACTA GGCTAGCTACAACGA TCCCTGCT 3011
    505 AGGGAGUA G UACUUAAA 2264 TTTAAGTA GGCTAGCTACAACGA TACTCCCT 3012
    507 GGAGUAGU A CUUAAAUA 120 TATTTAAG GGCTAGCTACAACGA ACTACTCC 3013
    513 GUACUUAA A UAUCAAGA 2728 TCTTGATA GGCTAGCTACAACGA TTAAGTAC 3014
    515 ACUUAAAU A UCAAGAAC 123 GTTCTTGA GGCTAGCTACAACGA ATTTAAGT 3015
    522 UAUCAAGA A CUGCCUAA 2729 TTAGGCAG GGCTAGCTACAACGA TCTTGATA 3016
    525 CAAGAACU G CCUAAUUC 2265 GAATTAGG GGCTAGCTACAACGA AGTTCTTG 3017
    530 ACUGCCUA A UUCAGGAC 2730 GTCCTGAA GGCTAGCTACAACGA TAGGCAGT 3018
    537 AAUUCAGG A CCUCCACA 2731 TGTGGAGG GGCTAGCTACAACGA CCTGAATT 3019
    543 GGACCUCC A CAUGAUAG 1377 CTATCATG GGCTAGCTACAACGA GGAGGTCC 3020
    545 ACCUCCAC A UGAUAGGA 1378 TCCTATCA GGCTAGCTACAACGA GTGGAGGT 3021
    548 UCCACAUG A UAGGAGGU 2732 ACCTCCTA GGCTAGCTACAACGA CATGTGGA 3022
    555 GAUAGGAG G UUUACAUU 2266 AATGTAAA GGCTAGCTACAACGA CTCCTATC 3023
    559 GGAGGUUU A CAUUUCAA 132 TTGAAATG GGCTAGCTACAACGA AAACCTCC 3024
    561 AGGUUUAC A UUUCAAGU 1379 ACTTGAAA GGCTAGCTACAACGA GTAAACCT 3025
    568 CAUUUCAA G UUAUAAUA 2267 TATTATAA GGCTAGCTACAACGA TTGAAATG 3026
    571 UUCAAGUU A UAAUAGAU 137 ATCTATTA GGCTAGCTACAACGA AACTTGAA 3027
    574 AAGUUAUA A UAGAUGGA 2733 TCCATCTA GGCTAGCTACAACGA TATAACTT 3028
    578 UAUAAUAG A UGGAAGAG 2734 CTCTTCCA GGCTAGCTACAACGA CTATTATA 3029
    588 GGAAGAGA A UUUCCAGA 2735 TCTGGAAA GGCTAGCTACAACGA TCTCTTCC 3030
    599 UCCAGAAG G UGAAGGUA 2268 TACCTTCA GGCTAGCTACAACGA CTTCTGGA 3031
    605 AGGUGAAG G UAGAUCAA 2269 TTGATCTA GGCTAGCTACAACGA CTTCACCT 3032
    609 GAAGGUAG A UCAAAGAA 2736 TTCTTTGA GGCTAGCTACAACGA CTACCTTC 3033
    622 AGAAGGAA G CAAAAAAU 2270 ATTTTTTG GGCTAGCTACAACGA TTCCTTCT 3034
    629 AGCAAAAA A UGCCGCAG 2737 CTGCGGCA GGCTAGCTACAACGA TTTTTGCT 3035
    631 CAAAAAAU G CCGCAGCC 2271 GGCTGCGG GGCTAGCTACAACGA ATTTTTTG 3036
    634 AAAAUGCC G CAGCCAAA 2272 TTTGGCTG GGCTAGCTACAACGA GGCATTTT 3037
    637 AUGCCGCA G CCAAAUUA 2273 TAATTTGG GGCTAGCTACAACGA TGCGGCAT 3038
    642 GCAGCCAA A UUAGCUGU 2738 ACAGCTAA GGCTAGCTACAACGA TTGGCTGC 3039
    646 CCAAAUUA G CUGUUGAG 2274 CTCAACAG GGCTAGCTACAACGA TAATTTGG 3040
    649 AAUUAGCU G UUGAGAUA 2275 TATCTCAA GGCTAGCTACAACGA AGCTAATT 3041
    655 CUGUUGAG A UACUUAAU 2739 ATTAAGTA GGCTAGCTACAACGA CTCAACAG 3042
    657 GUUGAGAU A CUUAAUAA 148 TTATTAAG GGCTAGCTACAACGA ATCTCAAC 3043
    662 GAUACUUA A UAAGGAAA 2740 TTTCCTTA GGCTAGCTACAACGA TAAGTATC 3044
    676 AAAAGAAG G CAGUUAGU 2276 ACTAACTG GGCTAGCTACAACGA CTTCTTTT 3045
    679 AGAAGGCA G UUAGUCCU 2277 AGGACTAA GGCTAGCTACAACGA TGCCTTCT 3046
    683 GGCAGUUA G UCCUUUAU 2278 ATAAAGGA GGCTAGCTACAACGA TAACTGCC 3047
    690 AGUCCUUU A UUAUUGAC 157 GTCAATAA GGCTAGCTACAACGA AAAGGACT 3048
    693 CCUUUAUU A UUGACAAC 159 GTTGTCAA GGCTAGCTACAACGA AATAAAGG 3049
    697 UAUUAUUG A CAACAACG 2741 CGTTGTTG GGCTAGCTACAACGA CAATAATA 3050
    700 UAUUGACA A CAACGAAU 2742 ATTCGTTG GGCTAGCTACAACGA TGTCAATA 3051
    703 UGACAACA A CGAAUUCU 2743 AGAATTCG GGCTAGCTACAACGA TGTTGTCA 3052
    707 AACAACGA A UUCUUCAG 2744 CTGAAGAA GGCTAGCTACAACGA TCGTTGTT 3053
    720 UCAGAAGG A UUAUCCAU 2745 ATGGATAA GGCTAGCTACAACGA CCTTCTGA 3054
    723 GAAGGAUU A UCCAUGGG 166 CCCATGGA GGCTAGCTACAACGA AATCCTTC 3055
    727 GAUUAUCC A UGGGGAAU 1399 ATTCCCCA GGCTAGCTACAACGA GGATAATC 3056
    734 CAUGGGGA A UUACAUAG 2746 CTATGTAA GGCTAGCTACAACGA TCCCCATG 3057
    737 GGGGAAUU A CAUAGGCC 169 GGCCTATG GGCTAGCTACAACGA AATTCCCC 3058
    739 GGAAUUAC A UAGGCCUU 1400 AAGGCCTA GGCTAGCTACAACGA GTAATTCC 3059
    743 UUACAUAG G CCUUAUCA 2279 TGATAAGG GGCTAGCTACAACGA CTATGTAA 3060
    748 UAGGCCUU A UCAAUAGA 172 TCTATTGA GGCTAGCTACAACGA AAGGCCTA 3061
    752 CCUUAUCA A UAGAAUUG 2747 CAATTCTA GGCTAGCTACAACGA TGATAAGG 3062
    757 UCAAUAGA A UUGCCCAG 2748 CTGGGCAA GGCTAGCTACAACGA TCTATTGA 3063
    760 AUAGAAUU G CCCAGAAG 2280 CTTCTGGG GGCTAGCTACAACGA AATTCTAT 3064
    774 AAGAAAAG A CUAACUGU 2749 ACAGTTAG GGCTAGCTACAACGA CTTTTCTT 3065
    778 AAAGACUA A CUGUAAAU 2750 ATTTACAG GGCTAGCTACAACGA TAGTCTTT 3066
    781 GACUAACU G UAAAUUAU 2281 ATAATTTA GGCTAGCTACAACGA AGTTAGTC 3067
    785 AACUGUAA A UUAUGAAC 2751 GTTCATAA GGCTAGCTACAACGA TTACAGTT 3068
    788 UGUAAAUU A UGAACAGU 179 ACTGTTCA GGCTAGCTACAACGA AATTTACA 3069
    792 AAUUAUGA A CAGUGUGC 2752 GCACACTG GGCTAGCTACAACGA TCATAATT 3070
    795 UAUGAACA G UGUGCAUC 2282 GATGCACA GGCTAGCTACAACGA TGTTCATA 3071
    797 UGAACAGU G UGCAUCGG 2283 CCGATGCA GGCTAGCTACAACGA ACTGTTCA 3072
    799 AACAGUGU G CAUCGGGG 2284 CCCCGATG GGCTAGCTACAACGA ACACTGTT 3073
    801 CAGUGUGC A UCGGGGGU 1410 ACCCCCGA GGCTAGCTACAACGA GCACACTG 3074
    808 CAUCGGGG G UGCAUGGG 2285 CCCATGCA GGCTAGCTACAACGA CCCCGATG 3075
    810 UCGGGGGU G CAUGGGCC 2286 GGCCCATG GGCTAGCTACAACGA ACCCCCGA 3076
    812 GGGGGUGC A UGGGCCAG 1411 CTGGCCCA GGCTAGCTACAACGA GCACCCCC 3077
    816 GUGCAUGG G CCAGAAGG 2287 CCTTCTGG GGCTAGCTACAACGA CCATGCAC 3078
    825 CCAGAAGG A UUUCAUUA 2753 TAATGAAA GGCTAGCTACAACGA CCTTCTGG 3079
    830 AGGAUUUC A UUAUAAAU 1414 ATTTATAA GGCTAGCTACAACGA GAAATCCT 3080
    833 AUUUCAUU A UAAAUGCA 185 TGCATTTA GGCTAGCTACAACGA AATGAAAT 3081
    837 CAUUAUAA A UGCAAAAU 2754 ATTTTGCA GGCTAGCTACAACGA TTATAATG 3082
    839 UUAUAAAU G CAAAAUGG 2288 CCATTTTG GGCTAGCTACAACGA ATTTATAA 3083
    844 AAUGCAAA A UGGGACAG 2755 CTGTCCCA GGCTAGCTACAACGA TTTGCATT 3084
    849 AAAAUGGG A CAGAAAGA 2756 TCTTTCTG GGCTAGCTACAACGA CCCATTTT 3085
    858 CAGAAAGA A UAUAGUAU 2757 ATACTATA GGCTAGCTACAACGA TCTTTCTG 3086
    860 GAAAGAAU A UAGUAUUG 187 CAATACTA GGCTAGCTACAACGA ATTCTTTC 3087
    863 AGAAUAUA G UAUUGGUA 2289 TACCAATA GGCTAGCTACAACGA TATATTCT 3088
    865 AAUAUAGU A UUGGUACA 189 TGTACCAA GGCTAGCTACAACGA ACTATATT 3089
    869 UAGUAUUG G UACAGGUU 2290 AACCTGTA GGCTAGCTACAACGA CAATACTA 3090
    871 GUAUUGGU A CAGGUUCU 191 AGAACCTG GGCTAGCTACAACGA ACCAATAC 3091
    875 UGGUACAG G UUCUACUA 2291 TAGTAGAA GGCTAGCTACAACGA CTGTACCA 3092
    880 CAGGUUCU A CUAAACAG 194 CTGTTTAG GGCTAGCTACAACGA AGAACCTG 3093
    885 UCUACUAA A CAGGAAGC 2758 GCTTCCTG GGCTAGCTACAACGA TTAGTAGA 3094
    892 AACAGGAA G CAAAACAA 2292 TTGTTTTG GGCTAGCTACAACGA TTCCTGTT 3095
    897 GAAGCAAA A CAAUUGGC 2759 GCCAATTG GGCTAGCTACAACGA TTTGCTTC 3096
    900 GCAAAACA A UUGGCCGC 2760 GCGGCCAA GGCTAGCTACAACGA TGTTTTGC 3097
    904 AACAAUUG G CCGCUAAA 2293 TTTAGCGG GGCTAGCTACAACGA CAATTGTT 3098
    907 AAUUGGCC G CUAAACUU 2294 AAGTTTAG GGCTAGCTACAACGA GGCCAATT 3099
    912 GCCGCUAA A CUUGCAUA 2761 TATGCAAG GGCTAGCTACAACGA TTAGCGGC 3100
    916 CUAAACUU G CAUAUCUU 2295 AAGATATG GGCTAGCTACAACGA AAGTTTAG 3101
    918 AAACUUGC A UAUCUUCA 1426 TGAAGATA GGCTAGCTACAACGA GCAAGTTT 3102
    920 ACUUGCAU A UCUUCAGA 199 TCTGAAGA GGCTAGCTACAACGA ATGCAAGT 3103
    928 AUCUUCAG A UAUUAUCA 2762 TGATAATA GGCTAGCTACAACGA CTGAAGAT 3104
    930 CUUCAGAU A UUAUCAGA 203 TCTGATAA GGCTAGCTACAACGA ATCTGAAG 3105
    933 CAGAUAUU A UCAGAAGA 205 TCTTCTGA GGCTAGCTACAACGA AATATCTG 3106
    943 CAGAAGAA A CCUCAGUG 2763 CACTGAGG GGCTAGCTACAACGA TTCTTCTG 3107
    949 AAACCUCA G UGAAAUCU 2296 AGATTTCA GGCTAGCTACAACGA TGAGGTTT 3108
    954 UCAGUGAA A UCUGACUA 2764 TAGTCAGA GGCTAGCTACAACGA TTCACTGA 3109
    959 GAAAUCUG A CUACCUGU 2765 ACAGGTAG GGCTAGCTACAACGA CAGATTTC 3110
    962 AUCUGACU A CCUGUCCU 209 AGGACAGG GGCTAGCTACAACGA AGTCAGAT 3111
    966 GACUACCU G UCCUCUGG 2297 CCAGAGGA GGCTAGCTACAACGA AGGTAGTC 3112
    974 GUCCUCUG G UUCUUUUG 2298 CAAAAGAA GGCTAGCTACAACGA CAGAGGAC 3113
    982 GUUCUUUU G CUACUACG 2299 CGTAGTAG GGCTAGCTACAACGA AAAAGAAC 3114
    985 CUUUUGCU A CUACGUGU 217 ACACGTAG GGCTAGCTACAACGA AGCAAAAG 3115
    988 UUGCUACU A CGUGUGAG 218 CTCACACG GGCTAGCTACAACGA AGTAGCAA 3116
    990 GCUACUAC G UGUGAGUC 2300 GACTCACA GGCTAGCTACAACGA GTAGTAGC 3117
    992 UACUACGU G UGAGUCCC 2301 GGGACTCA GGCTAGCTACAACGA ACGTAGTA 3118
    996 ACGUGUGA G UCCCAAAG 2302 CTTTGGGA GGCTAGCTACAACGA TCACACGT 3119
    1004 GUCCCAAA G CAACUCUU 2303 AAGAGTTG GGCTAGCTACAACGA TTTGGGAC 3120
    1007 CCAAAGCA A CUCUUUAG 2766 CTAAAGAG GGCTAGCTACAACGA TGCTTTGG 3121
    1015 ACUCUUUA G UGACCAGC 2304 GCTGGTCA GGCTAGCTACAACGA TAAAGAGT 3122
    1018 CUUUAGUG A CCAGCACA 2767 TGTGCTGG GGCTAGCTACAACGA CACTAAAG 3123
    1022 AGUGACCA G CACACUCG 2305 CGAGTGTG GGCTAGCTACAACGA TGGTCACT 3124
    1024 UGACCAGC A CACUCGCU 1451 AGCGAGTG GGCTAGCTACAACGA GCTGGTCA 3125
    1026 ACCAGCAC A CUCGCUUC 1452 GAAGCGAG GGCTAGCTACAACGA GTGCTGGT 3126
    1030 GCACACUC G CUUCUGAA 2306 TTCAGAAG GGCTAGCTACAACGA GAGTGTGC 3127
    1038 GCUUCUGA A UCAUCAUC 2768 GATGATGA GGCTAGCTACAACGA TCAGAAGC 3128
    1041 UCUGAAUC A UCAUCUGA 1456 TCAGATGA GGCTAGCTACAACGA GATTCAGA 3129
    1044 GAAUCAUC A UCUGAAGG 1457 CCTTCAGA GGCTAGCTACAACGA GATGATTC 3130
    1052 AUCUGAAG G UGACUUCU 2307 AGAAGTCA GGCTAGCTACAACGA CTTCAGAT 3131
    1055 UGAAGGUG A CUUCUCAG 2769 CTGAGAAG GGCTAGCTACAACGA CACCTTCA 3132
    1063 ACUUCUCA G CAGAUACA 2308 TGTATCTG GGCTAGCTACAACGA TGAGAAGT 3133
    1067 CUCAGCAG A UACAUCAG 2770 CTGATGTA GGCTAGCTACAACGA CTGCTGAG 3134
    1069 CAGCAGAU A CAUCAGAG 233 CTCTGATG GGCTAGCTACAACGA ATCTGCTG 3135
    1071 GCAGAUAC A UCAGAGAU 1463 ATCTCTGA GGCTAGCTACAACGA GTATCTGC 3136
    1078 CAUCAGAG A UAAAUUCU 2771 AGAATTTA GGCTAGCTACAACGA CTCTGATG 3137
    1082 AGAGAUAA A UUCUAACA 2772 TGTTAGAA GGCTAGCTACAACGA TTATCTCT 3138
    1088 AAAUUCUA A CAGUGACA 2773 TGTCACTG GGCTAGCTACAACGA TAGAATTT 3139
    1091 UUCUAACA G UGACAGUU 2309 AACTGTCA GGCTAGCTACAACGA TGTTAGAA 3140
    1094 UAACAGUG A CAGUUUAA 2774 TTAAACTG GGCTAGCTACAACGA CACTGTTA 3141
    1097 CAGUGACA G UUUAAACA 2310 TGTTTAAA GGCTAGCTACAACGA TGTCACTG 3142
    1103 CAGUUUAA A CAGUUCUU 2775 AAGAACTG GGCTAGCTACAACGA TTAAACTG 3143
    1106 UUUAAACA G UUCUUCGU 2311 ACGAAGAA GGCTAGCTACAACGA TGTTTAAA 3144
    1113 AGUUCUUC G UUGCUUAU 2312 ATAAGCAA GGCTAGCTACAACGA GAAGAACT 3145
    1116 UCUUCGUU G CUUAUGAA 2313 TTCATAAG GGCTAGCTACAACGA AACGAAGA 3146
    1120 CGUUGCUU A UGAAUGGU 248 ACCATTCA GGCTAGCTACAACGA AAGCAACG 3147
    1124 GCUUAUGA A UGGUCUCA 2776 TGAGACCA GGCTAGCTACAACGA TCATAAGC 3148
    1127 UAUGAAUG G UCUCAGAA 2314 TTCTGAGA GGCTAGCTACAACGA CATTCATA 3149
    1136 UCUCAGAA A UAAUCAAA 2777 TTTGATTA GGCTAGCTACAACGA TTCTGAGA 3150
    1139 CAGAAAUA A UCAAAGGA 2778 TCCTTTGA GGCTAGCTACAACGA TATTTCTG 3151
    1150 AAAGGAAG G CAAAAAGA 2315 TCTTTTTG GGCTAGCTACAACGA CTTCCTTT 3152
    1158 GCAAAAAG A UCUUUGGC 2779 GCCAAAGA GGCTAGCTACAACGA CTTTTTGC 3153
    1165 GAUCUUUG G CACCCAGA 2316 TCTGGGTG GGCTAGCTACAACGA CAAAGATC 3154
    1167 UCUUUGGC A CCCAGAUU 1476 AATCTGGG GGCTAGCTACAACGA GCCAAAGA 3155
    1173 GCACCCAG A UUUGACCU 2780 AGGTCAAA GGCTAGCTACAACGA CTGGGTGC 3156
    1178 CAGAUUUG A CCUUCCUG 2781 CAGGAAGG GGCTAGCTACAACGA CAAATCTG 3157
    1187 CCUUCCUG A CAUGAAAG 2782 CTTTCATG GGCTAGCTACAACGA CAGGAAGG 3158
    1189 UUCCUGAC A UGAAAGAA 1484 TTCTTTCA GGCTAGCTACAACGA GTCAGGAA 3159
    1198 UGAAAGAA A CAAAGUAU 2783 ATACTTTG GGCTAGCTACAACGA TTCTTTCA 3160
    1203 GAAACAAA G UAUACUGU 2317 ACAGTATA GGCTAGCTACAACGA TTTGTTTC 3161
    1205 AACAAAGU A UACUGUGG 260 CCACAGTA GGCTAGCTACAACGA ACTTTGTT 3162
    1207 CAAAGUAU A CUGUGGAC 261 GTCCACAG GGCTAGCTACAACGA ATACTTTG 3163
    1210 AGUAUACU G UGGACAAG 2318 CTTGTCCA GGCTAGCTACAACGA AGTATACT 3164
    1214 UACUGUGG A CAAGAGGU 2784 ACCTCTTG GGCTAGCTACAACGA CCACAGTA 3165
    1221 GACAAGAG G UUUGGCAU 2319 ATGCCAAA GGCTAGCTACAACGA CTCTTGTC 3166
    1226 GAGGUUUG G CAUGGAUU 2320 AATCCATG GGCTAGCTACAACGA CAAACCTC 3167
    1228 GGUUUGGC A UGGAUUUU 1488 AAAATCCA GGCTAGCTACAACGA GCCAAACC 3168
    1232 UGGCAUGG A UUUUAAAG 2785 CTTTAAAA GGCTAGCTACAACGA CCATGCCA 3169
    1243 UUAAAGAA A UAGAAUUA 2786 TAATTCTA GGCTAGCTACAACGA TTCTTTAA 3170
    1248 GAAAUAGA A UUAAUUGG 2787 CCAATTAA GGCTAGCTACAACGA TCTATTTC 3171
    1252 UAGAAUUA A UUGGCUCA 2788 TGAGCCAA GGCTAGCTACAACGA TAATTCTA 3172
    1256 AUUAAUUG G CUCAGGUG 2321 CACCTGAG GGCTAGCTACAACGA CAATTAAT 3173
    1262 UGGCUCAG G UGGAUUUG 2322 CAAATCCA GGCTAGCTACAACGA CTGAGCCA 3174
    1266 UCAGGUGG A UUUGGCCA 2789 TGGCCAAA GGCTAGCTACAACGA CCACCTGA 3175
    1271 UGGAUUUG G CCAAGUUU 2323 AAACTTGG GGCTAGCTACAACGA CAAATCCA 3176
    1276 UUGGCCAA G UUUUCAAA 2324 TTTGAAAA GGCTAGCTACAACGA TTGGCCAA 3177
    1285 UUUUCAAA G CAAAACAC 2325 GTGTTTTG GGCTAGCTACAACGA TTTGAAAA 3178
    1290 AAAGCAAA A CACAGAAU 2790 ATTCTGTG GGCTAGCTACAACGA TTTGCTTT 3179
    1292 AGCAAAAC A CAGAAUUG 1495 CAATTCTG GGCTAGCTACAACGA GTTTTGCT 3180
    1297 AACACAGA A UUGACGGA 2791 TCCGTCAA GGCTAGCTACAACGA TCTGTGTT 3181
    1301 CAGAAUUG A CGGAAAGA 2792 TCTTTCCG GGCTAGCTACAACGA CAATTCTG 3182
    1309 ACGGAAAG A CUUACGUU 2793 AACGTAAG GGCTAGCTACAACGA CTTTCCGT 3183
    1313 AAAGACUU A CGUUAUUA 281 TAATAACG GGCTAGCTACAACGA AAGTCTTT 3184
    1315 AGACUUAC G UUAUUAAA 2326 TTTAATAA GGCTAGCTACAACGA GTAAGTCT 3185
    1318 CUUACGUU A UUAAACGU 283 ACGTTTAA GGCTAGCTACAACGA AACGTAAG 3186
    1323 GUUAUUAA A CGUGUUAA 2794 TTAACACG GGCTAGCTACAACGA TTAATAAC 3187
    1325 UAUUAAAC G UGUUAAAU 2327 ATTTAACA GGCTAGCTACAACGA GTTTAATA 3188
    1327 UUAAACGU G UUAAAUAU 2328 ATATTTAA GGCTAGCTACAACGA ACGTTTAA 3189
    1332 CGUGUUAA A UAUAAUAA 2795 TTATTATA GGCTAGCTACAACGA TTAACACG 3190
    1334 UGUUAAAU A UAAUAACG 288 CGTTATTA GGCTAGCTACAACGA ATTTAACA 3191
    1337 UAAAUAUA A UAACGAGA 2796 TCTCGTTA GGCTAGCTACAACGA TATATTTA 3192
    1340 AUAUAAUA A CGAGAAGG 2797 CCTTCTCG GGCTAGCTACAACGA TATTATAT 3193
    1348 ACGAGAAG G CGGAGCGU 2329 ACGCTCCG GGCTAGCTACAACGA CTTCTCGT 3194
    1353 AAGGCGGA G CGUGAAGU 2330 ACTTCACG GGCTAGCTACAACGA TCCGCCTT 3195
    1355 GGCGGAGC G UGAAGUAA 2331 TTACTTCA GGCTAGCTACAACGA GCTCCGCC 3196
    1360 AGCGUGAA G UAAAAGCA 2332 TGCTTTTA GGCTAGCTACAACGA TTCACGCT 3197
    1366 AAGUAAAA G CAUUGGCA 2333 TGCCAATG GGCTAGCTACAACGA TTTTACTT 3198
    1368 GUAAAAGC A UUGGCAAA 1498 TTTGCCAA GGCTAGCTACAACGA GCTTTTAC 3199
    1372 AAGCAUUG G CAAAACUU 2334 AAGTTTTG GGCTAGCTACAACGA CAATGCTT 3200
    1377 UUGGCAAA A CUUGAUCA 2798 TGATCAAG GGCTAGCTACAACGA TTTGCCAA 3201
    1382 AAAACUUG A UCAUGUAA 2799 TTACATGA GGCTAGCTACAACGA CAAGTTTT 3202
    1385 ACUUGAUC A UGUAAAUA 1501 TATTTACA GGCTAGCTACAACGA GATCAAGT 3203
    1387 UUGAUCAU G UAAAUAUU 2335 AATATTTA GGCTAGCTACAACGA ATGATCAA 3204
    1391 UCAUGUAA A UAUUGUUC 2800 GAACAATA GGCTAGCTACAACGA TTACATGA 3205
    1393 AUGUAAAU A UUGUUCAC 296 GTGAACAA GGCTAGCTACAACGA ATTTACAT 3206
    1396 UAAAUAUU G UUCACUAC 2336 GTAGTGAA GGCTAGCTACAACGA AATATTTA 3207
    1400 UAUUGUUC A CUACAAUG 1502 CATTGTAG GGCTAGCTACAACGA GAACAATA 3208
    1403 UGUUCACU A CAAUGGCU 300 AGCCATTG GGCTAGCTACAACGA AGTGAACA 3209
    1406 UCACUACA A UGGCUGUU 2801 AACAGCCA GGCTAGCTACAACGA TGTAGTGA 3210
    1409 CUACAAUG G CUGUUGGG 2337 CCCAACAG GGCTAGCTACAACGA CATTGTAG 3211
    1412 CAAUGGCU G UUGGGAUG 2338 CATCCCAA GGCTAGCTACAACGA AGCCATTG 3212
    1418 CUGUUGGG A UGGAUUUG 2802 CAAATCCA GGCTAGCTACAACGA CCCAACAG 3213
    1422 UGGGAUGG A UUUGAUUA 2803 TAATCAAA GGCTAGCTACAACGA CCATCCCA 3214
    1427 UGGAUUUG A UUAUGAUC 2804 GATCATAA GGCTAGCTACAACGA CAAATCCA 3215
    1430 AUUUGAUU A UGAUCCUG 305 CAGGATCA GGCTAGCTACAACGA AATCAAAT 3216
    1433 UGAUUAUG A UCCUGAGA 2805 TCTCAGGA GGCTAGCTACAACGA CATAATCA 3217
    1441 AUCCUGAG A CCAGUGAU 2806 ATCACTGG GGCTAGCTACAACGA CTCAGGAT 3218
    1445 UGAGACCA G UGAUGAUU 2339 AATCATCA GGCTAGCTACAACGA TGGTCTCA 3219
    1448 GACCAGUG A UGAUUCUC 2807 GAGAATCA GGCTAGCTACAACGA CACTGGTC 3220
    1451 CAGUGAUG A UUCUCUUG 2808 CAAGAGAA GGCTAGCTACAACGA CATCACTG 3221
    1463 UCUUGAGA G CAGUGAUU 2340 AATCACTG GGCTAGCTACAACGA TCTCAAGA 3222
    1466 UGAGAGCA G UGAUUAUG 2341 CATAATCA GGCTAGCTACAACGA TGCTCTCA 3223
    1469 GAGCAGUG A UUAUGAUC 2809 GATCATAA GGCTAGCTACAACGA CACTGCTC 3224
    1472 CAGUGAUU A UGAUCCUG 312 CAGGATCA GGCTAGCTACAACGA AATCACTG 3225
    1475 UGAUUAUG A UCCUGAGA 2805 TCTCAGGA GGCTAGCTACAACGA CATAATCA 3217
    1484 UCCUGAGA A CAGCAAAA 2810 TTTTGCTG GGCTAGCTACAACGA TCTCAGGA 3226
    1487 UGAGAACA G CAAAAAUA 2342 TATTTTTG GGCTAGCTACAACGA TGTTCTCA 3227
    1493 CAGCAAAA A UAGUUCAA 2811 TTGAACTA GGCTAGCTACAACGA TTTTGCTG 3228
    1496 CAAAAAUA G UUCAAGGU 2343 ACCTTGAA GGCTAGCTACAACGA TATTTTTG 3229
    1503 AGUUCAAG G UCAAAGAC 2344 GTCTTTGA GGCTAGCTACAACGA CTTGAACT 3230
    1510 GGUCAAAG A CUAAGUGC 2812 GCACTTAG GGCTAGCTACAACGA CTTTGACC 3231
    1515 AAGACUAA G UGCCUUUU 2345 AAAAGGCA GGCTAGCTACAACGA TTAGTCTT 3232
    1517 GACUAAGU G CCUUUUCA 2346 TGAAAAGG GGCTAGCTACAACGA ACTTAGTC 3233
    1525 GCCUUUUC A UCCAAAUG 1522 CATTTGGA GGCTAGCTACAACGA GAAAAGGC 3234
    1531 UCAUCCAA A UGGAAUUC 2813 GAATTCCA GGCTAGCTACAACGA TTGGATGA 3235
    1536 CAAAUGGA A UUCUGUGA 2814 TCACAGAA GGCTAGCTACAACGA TCCATTTG 3236
    1541 GGAAUUCU G UGAUAAAG 2347 CTTTATCA GGCTAGCTACAACGA AGAATTCC 3237
    1544 AUUCUGUG A UAAAGGGA 2815 TCCCTTTA GGCTAGCTACAACGA CACAGAAT 3238
    1552 AUAAAGGG A CCUUGGAA 2816 TTCCAAGG GGCTAGCTACAACGA CCCTTTAT 3239
    1560 ACCUUGGA A CAAUGGAU 2817 ATCCATTG GGCTAGCTACAACGA TCCAAGGT 3240
    1563 UUGGAACA A UGGAUUGA 2818 TCAATCCA GGCTAGCTACAACGA TGTTCCAA 3241
    1567 AACAAUGG A UUGAAAAA 2819 TTTTTCAA GGCTAGCTACAACGA CCATTGTT 3242
    1583 AAGAAGAG G CGAGAAAC 2348 GTTTCTCG GGCTAGCTACAACGA CTCTTCTT 3243
    1590 GGCGAGAA A CUAGACAA 2820 TTGTCTAG GGCTAGCTACAACGA TTCTCGCC 3244
    1595 GAAACUAG A CAAAGUUU 2821 AAACTTTG GGCTAGCTACAACGA CTAGTTTC 3245
    1600 UAGACAAA G UUUUGGCU 2349 AGCCAAAA GGCTAGCTACAACGA TTTGTCTA 3246
    1606 AAGUUUUG G CUUUGGAA 2350 TTCCAAAG GGCTAGCTACAACGA CAAAACTT 3247
    1614 GCUUUGGA A CUCUUUGA 2822 TCAAAGAG GGCTAGCTACAACGA TCCAAAGC 3248
    1623 CUCUUUGA A CAAAUAAC 2823 GTTATTTG GGCTAGCTACAACGA TCAAAGAG 3249
    1627 UUGAACAA A UAACAAAA 2824 TTTTGTTA GGCTAGCTACAACGA TTGTTCAA 3250
    1630 AACAAAUA A CAAAAGGG 2825 CCCTTTTG GGCTAGCTACAACGA TATTTGTT 3251
    1639 CAAAAGGG G UGGAUUAU 2351 ATAATCCA GGCTAGCTACAACGA CCCTTTTG 3252
    1643 AGGGGUGG A UUAUAUAC 2826 GTATATAA GGCTAGCTACAACGA CCACCCCT 3253
    1646 GGUGGAUU A UAUACAUU 340 AATGTATA GGCTAGCTACAACGA AATCCACC 3254
    1648 UGGAUUAU A UACAUUCA 341 TGAATGTA GGCTAGCTACAACGA ATAATCCA 3255
    1650 GAUUAUAU A CAUUCAAA 342 TTTGAATG GGCTAGCTACAACGA ATATAATC 3256
    1652 UUAUAUAC A UUCAAAAA 1536 TTTTTGAA GGCTAGCTACAACGA GTATATAA 3257
    1662 UCAAAAAA A UUAAUUCA 2827 TGAATTAA GGCTAGCTACAACGA TTTTTTGA 3258
    1666 AAAAAUUA A UUCAUAGA 2828 TCTATGAA GGCTAGCTACAACGA TAATTTTT 3259
    1670 AUUAAUUC A UAGAGAUC 1538 GATCTCTA GGCTAGCTACAACGA GAATTAAT 3260
    1676 UCAUAGAG A UCUUAAGC 2829 GCTTAAGA GGCTAGCTACAACGA CTCTATGA 3261
    1683 GAUCUUAA G CCAAGUAA 2352 TTACTTGG GGCTAGCTACAACGA TTAAGATC 3262
    1688 UAAGCCAA G UAAUAUAU 2353 ATATATTA GGCTAGCTACAACGA TTGGCTTA 3263
    1691 GCCAAGUA A UAUAUUCU 2830 AGAATATA GGCTAGCTACAACGA TACTTGGC 3264
    1693 CAAGUAAU A UAUUCUUA 354 TAAGAATA GGCTAGCTACAACGA ATTACTTG 3265
    1695 AGUAAUAU A UUCUUAGU 355 ACTAAGAA GGCTAGCTACAACGA ATATTACT 3266
    1702 UAUUCUUA G UAGAUACA 2354 TGTATCTA GGCTAGCTACAACGA TAAGAATA 3267
    1706 CUUAGUAG A UACAAAAC 2831 GTTTTGTA GGCTAGCTACAACGA CTACTAAG 3268
    1708 UAGUAGAU A CAAAACAA 361 TTGTTTTG GGCTAGCTACAACGA ATCTACTA 3269
    1713 GAUACAAA A CAAGUAAA 2832 TTTACTTG GGCTAGCTACAACGA TTTGTATC 3270
    1717 CAAAACAA G UAAAGAUU 2355 AATCTTTA GGCTAGCTACAACGA TTGTTTTG 3271
    1723 AAGUAAAG A UUGGAGAC 2833 GTCTCCAA GGCTAGCTACAACGA CTTTACTT 3272
    1730 GAUUGGAG A CUUUGGAC 2834 GTCCAAAG GGCTAGCTACAACGA CTCCAATC 3273
    1737 GACUUUGG A CUUGUAAC 2835 GTTACAAG GGCTAGCTACAACGA CCAAAGTC 3274
    1741 UUGGACUU G UAACAUCU 2356 AGATGTTA GGCTAGCTACAACGA AAGTCCAA 3275
    1744 GACUUGUA A CAUCUCUG 2836 CAGAGATG GGCTAGCTACAACGA TACAAGTC 3276
    1746 CUUGUAAC A UCUCUGAA 1547 TTCAGAGA GGCTAGCTACAACGA GTTACAAG 3277
    1757 UCUGAAAA A UGAUGGAA 2837 TTCCATCA GGCTAGCTACAACGA TTTTCAGA 3278
    1760 GAAAAAUG A UGGAAAGC 2838 GCTTTCCA GGCTAGCTACAACGA CATTTTTC 3279
    1767 GAUGGAAA G CGAACAAG 2357 CTTGTTCG GGCTAGCTACAACGA TTTCCATC 3280
    1771 GAAAGCGA A CAAGGAGU 2839 ACTCCTTG GGCTAGCTACAACGA TCGCTTTC 3281
    1778 AACAAGGA G UAAGGGAA 2358 TTCCCTTA GGCTAGCTACAACGA TCCTTGTT 3282
    1786 GUAAGGGA A CUUUGCGA 2840 TCGCAAAG GGCTAGCTACAACGA TCCCTTAC 3283
    1791 GGAACUUU G CGAUACAU 2359 ATGTATCG GGCTAGCTACAACGA AAAGTTCC 3284
    1794 ACUUUGCG A UACAUGAG 2841 CTCATGTA GGCTAGCTACAACGA CGCAAAGT 3285
    1796 UUUGCGAU A CAUGAGCC 373 GGCTCATG GGCTAGCTACAACGA ATCGCAAA 3286
    1798 UGCGAUAC A UGAGCCCA 1552 TGGGCTCA GGCTAGCTACAACGA GTATCGCA 3287
    1802 AUACAUGA G CCCAGAAC 2360 GTTCTGGG GGCTAGCTACAACGA TCATGTAT 3288
    1809 AGCCCAGA A CAGAUUUC 2842 GAAATCTG GGCTAGCTACAACGA TCTGGGCT 3289
    1813 CAGAACAG A UUUCUUCG 2843 CGAAGAAA GGCTAGCTACAACGA CTGTTCTG 3290
    1821 AUUUCUUC G CAAGACUA 2361 TAGTCTTG GGCTAGCTACAACGA GAAGAAAT 3291
    1826 UUCGCAAG A CUAUGGAA 2844 TTCCATAG GGCTAGCTACAACGA CTTGCGAA 3292
    1829 GCAAGACU A UGGAAAGG 379 CCTTTCCA GGCTAGCTACAACGA AGTCTTGC 3293
    1840 GAAAGGAA G UGGACCUC 2362 GAGGTCCA GGCTAGCTACAACGA TTCCTTTC 3294
    1844 GGAAGUGG A CCUCUACG 2845 CGTAGAGG GGCTAGCTACAACGA CCACTTCC 3295
    1850 GGACCUCU A CGCUUUGG 381 CCAAAGCG GGCTAGCTACAACGA AGAGGTCC 3296
    1852 ACCUCUAC G CUUUGGGG 2363 CCCCAAAG GGCTAGCTACAACGA GTAGAGGT 3297
    1860 GCUUUGGG G CUAAUUCU 2364 AGAATTAG GGCTAGCTACAACGA CCCAAAGC 3298
    1864 UGGGGCUA A UUCUUGCU 2846 AGCAAGAA GGCTAGCTACAACGA TAGCCCCA 3299
    1870 UAAUUCUU G CUGAACUU 2365 AAGTTCAG GGCTAGCTACAACGA AAGAATTA 3300
    1875 CUUGCUGA A CUUCUUCA 2847 TGAAGAAG GGCTAGCTACAACGA TCAGCAAG 3301
    1883 ACUUCUUC A UGUAUGUG 1569 CACATACA GGCTAGCTACAACGA GAAGAAGT 3302
    1885 UUCUUCAU G UAUGUGAC 2366 GTCACATA GGCTAGCTACAACGA ATGAAGAA 3303
    1887 CUUCAUGU A UGUGACAC 392 GTGTCACA GGCTAGCTACAACGA ACATGAAG 3304
    1889 UCAUGUAU G UGACACUG 2367 CAGTGTCA GGCTAGCTACAACGA ATACATGA 3305
    1892 UGUAUGUG A CACUGCUU 2848 AAGCAGTG GGCTAGCTACAACGA CACATACA 3306
    1894 UAUGUGAC A CUGCUUUU 1570 AAAAGCAG GGCTAGCTACAACGA GTCACATA 3307
    1897 GUGACACU G CUUUUGAA 2368 TTCAAAAG GGCTAGCTACAACGA AGTGTCAC 3308
    1906 CUUUUGAA A CAUCAAAG 2849 CTTTGATG GGCTAGCTACAACGA TTCAAAAG 3309
    1908 UUUGAAAC A UCAAAGUU 1573 AACTTTGA GGCTAGCTACAACGA GTTTCAAA 3310
    1914 ACAUCAAA G UUUUUCAC 2369 GTGAAAAA GGCTAGCTACAACGA TTTGATGT 3311
    1921 AGUUUUUC A CAGACCUA 1575 TAGGTCTG GGCTAGCTACAACGA GAAAAACT 3312
    1925 UUUCACAG A CCUACGGG 2850 CCCGTAGG GGCTAGCTACAACGA CTGTGAAA 3313
    1929 ACAGACCU A CGGGAUGG 402 CCATCCCG GGCTAGCTACAACGA AGGTCTGT 3314
    1934 CCUACGGG A UGGCAUCA 2851 TGATGCCA GGCTAGCTACAACGA CCCGTAGG 3315
    1937 ACGGGAUG G CAUCAUCU 2370 AGATGATG GGCTAGCTACAACGA CATCCCGT 3316
    1939 GGGAUGGC A UCAUCUCA 1579 TGAGATGA GGCTAGCTACAACGA GCCATCCC 3317
    1942 AUGGCAUC A UCUCAGAU 1580 ATCTGAGA GGCTAGCTACAACGA GATGCCAT 3318
    1949 CAUCUCAG A UAUAUUUG 2852 CAAATATA GGCTAGCTACAACGA CTGAGATG 3319
    1951 UCUCAGAU A UAUUUGAU 406 ATCAAATA GGCTAGCTACAACGA ATCTGAGA 3320
    1953 UCAGAUAU A UUUGAUAA 407 TTATCAAA GGCTAGCTACAACGA ATATCTGA 3321
    1958 UAUAUUUG A UAAAAAAG 2853 CTTTTTTA GGCTAGCTACAACGA CAAATATA 3322
    1972 AAGAAAAA A CUCUUCUA 2854 TAGAAGAG GGCTAGCTACAACGA TTTTTCTT 3323
    1980 ACUCUUCU A CAGAAAUU 414 AATTTCTG GGCTAGCTACAACGA AGAAGAGT 3324
    1986 CUACAGAA A UUACUCUC 2855 GAGAGTAA GGCTAGCTACAACGA TTCTGTAG 3325
    1989 CAGAAAUU A CUCUCAAA 416 TTTGAGAG GGCTAGCTACAACGA AATTTCTG 3326
    2001 UCAAAGAA A CCUGAGGA 2856 TCCTCAGG GGCTAGCTACAACGA TTCTTTGA 3327
    2009 ACCUGAGG A UCGACCUA 2857 TAGGTCGA GGCTAGCTACAACGA CCTCAGGT 3328
    2013 GAGGAUCG A CCUAACAC 2858 GTGTTAGG GGCTAGCTACAACGA CGATCCTC 3329
    2018 UCGACCUA A CACAUCUG 2859 CAGATGTG GGCTAGCTACAACGA TAGGTCGA 3330
    2020 GACCUAAC A CAUCUGAA 1594 TTCAGATG GGCTAGCTACAACGA GTTAGGTC 3331
    2022 CCUAACAC A UCUGAAAU 1595 ATTTCAGA GGCTAGCTACAACGA GTGTTAGG 3332
    2029 CAUCUGAA A UACUAAGG 2860 CCTTAGTA GGCTAGCTACAACGA TTCAGATG 3333
    2031 UCUGAAAU A CUAAGGAC 422 GTCCTTAG GGCTAGCTACAACGA ATTTCAGA 3334
    2038 UACUAAGG A CCUUGACU 2861 AGTCAAGG GGCTAGCTACAACGA CCTTAGTA 3335
    2044 GGACCUUG A CUGUGUGG 2862 CCACACAG GGCTAGCTACAACGA CAAGGTCC 3336
    2047 CCUUGACU G UGUGGAAG 2371 CTTCCACA GGCTAGCTACAACGA AGTCAAGG 3337
    2049 UUGACUGU G UGGAAGAA 2372 TTCTTCCA GGCTAGCTACAACGA ACAGTCAA 3338
    2060 GAAGAAAA G CCCAGAGA 2373 TCTCTGGG GGCTAGCTACAACGA TTTTCTTC 3339
    2072 AGAGAAAA A UGAACGAC 2863 GTCGTTCA GGCTAGCTACAACGA TTTTCTCT 3340
    2076 AAAAAUGA A CGACACAC 2864 GTGTGTCG GGCTAGCTACAACGA TCATTTTT 3341
    2079 AAUGAACG A CACACAUG 2865 CATGTGTG GGCTAGCTACAACGA CGTTCATT 3342
    2081 UGAACGAC A CACAUGUU 1604 AACATGTG GGCTAGCTACAACGA GTCGTTCA 3343
    2083 AACGACAC A CAUGUUAG 1605 CTAACATG GGCTAGCTACAACGA GTGTCGTT 3344
    2085 CGACACAC A UGUUAGAG 1606 CTCTAACA GGCTAGCTACAACGA GTGTGTCG 3345
    2087 ACACACAU G UUAGAGCC 2374 GGCTCTAA GGCTAGCTACAACGA ATGTGTGT 3346
    2093 AUGUUAGA G CCCUUCUG 2375 CAGAAGGG GGCTAGCTACAACGA TCTAACAT 3347
    2107 CUGAAAAA G UAUCCUGC 2376 GCAGGATA GGCTAGCTACAACGA TTTTTCAG 3348
    2109 GAAAAAGU A UCCUGCUU 429 AAGCAGGA GGCTAGCTACAACGA ACTTTTTC 3349
    2114 AGUAUCCU G CUUCUGAU 2377 ATCAGAAG GGCTAGCTACAACGA AGGATACT 3350
    2121 UGCUUCUG A UAUGCAGU 2866 ACTGCATA GGCTAGCTACAACGA CAGAAGCA 3351
    2123 CUUCUGAU A UGCAGUUU 433 AAACTGCA GGCTAGCTACAACGA ATCAGAAG 3352
    2125 UCUGAUAU G CAGUUUUC 2378 GAAAACTG GGCTAGCTACAACGA ATATCAGA 3353
    2128 GAUAUGCA G UUUUCCUU 2379 AAGGAAAA GGCTAGCTACAACGA TGCATATC 3354
    2139 UUCCUUAA A UUAUCUAA 2867 TTAGATAA GGCTAGCTACAACGA TTAAGGAA 3355
    2142 CUUAAAUU A UCUAAAAU 441 ATTTTAGA GGCTAGCTACAACGA AATTTAAG 3356
    2149 UAUCUAAA A UCUGCUAG 2868 CTAGCAGA GGCTAGCTACAACGA TTTAGATA 3357
    2153 UAAAAUCU G CUAGGGAA 2380 TTCCCTAG GGCTAGCTACAACGA AGATTTTA 3358
    2161 GCUAGGGA A UAUCAAUA 2869 TATTGATA GGCTAGCTACAACGA TCCCTAGC 3359
    2163 UAGGGAAU A UCAAUAGA 446 TCTATTGA GGCTAGCTACAACGA ATTCCCTA 3360
    2167 GAAUAUCA A UAGAUAUU 2870 AATATCTA GGCTAGCTACAACGA TGATATTC 3361
    2171 AUCAAUAG A UAUUUACC 2871 GGTAAATA GGCTAGCTACAACGA CTATTGAT 3362
    2173 CAAUAGAU A UUUACCUU 449 AAGGTAAA GGCTAGCTACAACGA ATCTATTG 3363
    2177 AGAUAUUU A CCUUUUAU 452 ATAAAAGG GGCTAGCTACAACGA AAATATCT 3364
    2184 UACCUUUU A UUUUAAUG 456 CATTAAAA GGCTAGCTACAACGA AAAAGGTA 3365
    2190 UUAUUUUA A UGUUUCCU 2872 AGGAAACA GGCTAGCTACAACGA TAAAATAA 3366
    2192 AUUUUAAU G UUUCCUUU 2381 AAAGGAAA GGCTAGCTACAACGA ATTAAAAT 3367
    2202 UUCCUUUA A UUUUUUAC 2873 GTAAAAAA GGCTAGCTACAACGA TAAAGGAA 3368
    2209 AAUUUUUU A CUAUUUUU 472 AAAAATAG GGCTAGCTACAACGA AAAAAATT 3369
    2212 UUUUUACU A UUUUUACU 473 AGTAAAAA GGCTAGCTACAACGA AGTAAAAA 3370
    2218 CUAUUUUU A CUAAUCUU 478 AAGATTAG GGCTAGCTACAACGA AAAAATAG 3371
    2222 UUUUACUA A UCUUUCUG 2874 CAGAAAGA GGCTAGCTACAACGA TAGTAAAA 3372
    2230 AUCUUUCU G CAGAAACA 2382 TGTTTCTG GGCTAGCTACAACGA AGAAAGAT 3373
    2236 CUGCAGAA A CAGAAAGG 2875 CCTTTCTG GGCTAGCTACAACGA TTCTGCAG 3374
    2244 ACAGAAAG G UUUUCUUC 2383 GAAGAAAA GGCTAGCTACAACGA CTTTCTGT 3375
    2258 UUCUUUUU G CUUCAAAA 2384 TTTTGAAG GGCTAGCTACAACGA AAAAAGAA 3376
    2267 CUUCAAAA A CAUUCUUA 2876 TAAGAATG GGCTAGCTACAACGA TTTTGAAG 3377
    2269 UCAAAAAC A UUCUUACA 1636 TGTAAGAA GGCTAGCTACAACGA GTTTTTGA 3378
    2275 ACAUUCUU A CAUUUUAC 499 GTAAAATG GGCTAGCTACAACGA AAGAATGT 3379
    2277 AUUCUUAC A UUUUACUU 1638 AAGTAAAA GGCTAGCTACAACGA GTAAGAAT 3380
    2282 UACAUUUU A CUUUUUCC 503 GGAAAAAG GGCTAGCTACAACGA AAAATGTA 3381
    2293 UUUUCCUG G CUCAUCUC 2385 GAGATGAG GGCTAGCTACAACGA CAGGAAAA 3382
    2297 CCUGGCUC A UCUCUUUA 1643 TAAAGAGA GGCTAGCTACAACGA GAGCCAGG 3383
    2305 AUCUCUUU A UUCUUUUU 514 AAAAAGAA GGCTAGCTACAACGA AAAGAGAT 3384
    2327 UUUUAAAG A CAGAGUCU 2877 AGACTCTG GGCTAGCTACAACGA CTTTAAAA 3385
    2332 AAGACAGA G UCUCGCUC 2386 GAGCGAGA GGCTAGCTACAACGA TCTGTCTT 3386
    2337 AGAGUCUC G CUCUGUUG 2387 CAACAGAG GGCTAGCTACAACGA GAGACTCT 3387
    2342 CUCGCUCU G UUGCCCAG 2388 CTGGGCAA GGCTAGCTACAACGA AGAGCGAG 3388
    2345 GCUCUGUU G CCCAGGCU 2389 AGCCTGGG GGCTAGCTACAACGA AACAGAGC 3389
    2351 UUGCCCAG G CUGGAGUG 2390 CACTCCAG GGCTAGCTACAACGA CTGGGCAA 3390
    2357 AGGCUGGA G UGCAAUGA 2391 TCATTGCA GGCTAGCTACAACGA TCCAGCCT 3391
    2359 GCUGGAGU G CAAUGACA 2392 TGTCATTG GGCTAGCTACAACGA ACTCCAGC 3392
    2362 GGAGUGCA A UGACACAG 2878 CTGTGTCA GGCTAGCTACAACGA TGCACTCC 3393
    2365 GUGCAAUG A CACAGUCU 2879 AGACTGTG GGCTAGCTACAACGA CATTGCAC 3394
    2367 GCAAUGAC A CAGUCUUG 1656 CAAGACTG GGCTAGCTACAACGA GTCATTGC 3395
    2370 AUGACACA G UCUUGGCU 2393 AGCCAAGA GGCTAGCTACAACGA TGTGTCAT 3396
    2376 CAGUCUUG G CUCACUGC 2394 GCAGTGAG GGCTAGCTACAACGA CAAGACTG 3397
    2380 CUUGGCUC A CUGCAACU 1660 AGTTGCAG GGCTAGCTACAACGA GAGCCAAG 3398
    2383 GGCUCACU G CAACUUCU 2395 AGAAGTTG GGCTAGCTACAACGA AGTGAGCC 3399
    2386 UCACUGCA A CUUCUGCC 2880 GGCAGAAG GGCTAGCTACAACGA TGCAGTGA 3400
    2392 CAACUUCU G CCUCUUGG 2396 CCAAGAGG GGCTAGCTACAACGA AGAAGTTG 3401
    2401 CCUCUUGG G UUCAAGUG 2397 CACTTGAA GGCTAGCTACAACGA CCAAGAGG 3402
    2407 GGGUUCAA G UGAUUCUC 2398 GAGAATCA GGCTAGCTACAACGA TTGAACCC 3403
    2410 UUCAAGUG A UUCUCCUG 2881 CAGGAGAA GGCTAGCTACAACGA CACTTGAA 3404
    2418 AUUCUCCU G CCUCAGCC 2399 GGCTGAGG GGCTAGCTACAACGA AGGAGAAT 3405
    2424 CUGCCUCA G CCUCCUGA 2400 TCAGGAGG GGCTAGCTACAACGA TGAGGCAG 3406
    2433 CCUCCUGA G UAGCUGGA 2401 TCCAGCTA GGCTAGCTACAACGA TCAGGAGG 3407
    2436 CCUGAGUA G CUGGAUUA 2402 TAATCCAG GGCTAGCTACAACGA TACTCAGG 3408
    2441 GUAGCUGG A UUACAGGC 2882 GCCTGTAA GGCTAGCTACAACGA CCAGCTAC 3409
    2444 GCUGGAUU A CAGGCAUG 551 CATGCCTG GGCTAGCTACAACGA AATCCAGC 3410
    2448 GAUUACAG G CAUGUGCC 2403 GGCACATG GGCTAGCTACAACGA CTGTAATC 3411
    2450 UUACAGGC A UGUGCCAC 1681 GTGGCACA GGCTAGCTACAACGA GCCTGTAA 3412
    2452 ACAGGCAU G UGCCACCC 2404 GGGTGGCA GGCTAGCTACAACGA ATGCCTGT 3413
    2454 AGGCAUGU G CCACCCAC 2405 GTGGGTGG GGCTAGCTACAACGA ACATGCCT 3414
    2457 CAUGUGCC A CCCACCCA 1683 TGGGTGGG GGCTAGCTACAACGA GGCACATG 3415
    2461 UGCCACCC A CCCAACUA 1686 TAGTTGGG GGCTAGCTACAACGA GGGTGGCA 3416
    2466 CCCACCCA A CUAAUUUU 2883 AAAATTAG GGCTAGCTACAACGA TGGGTGGG 3417
    2470 CCCAACUA A UUUUUGUG 2884 CACAAAAA GGCTAGCTACAACGA TAGTTGGG 3418
    2476 UAAUUUUU G UGUUUUUA 2406 TAAAAACA GGCTAGCTACAACGA AAAAATTA 3419
    2478 AUUUUUGU G UUUUUAAU 2407 ATTAAAAA GGCTAGCTACAACGA ACAAAAAT 3420
    2485 UGUUUUUA A UAAAGACA 2885 TGTCTTTA GGCTAGCTACAACGA TAAAAACA 3421
    2491 UAAUAAAG A CAGGGUUU 2886 AAACCCTG GGCTAGCTACAACGA CTTTATTA 3422
    2496 AAGACAGG G UUUCACCA 2408 TGGTGAAA GGCTAGCTACAACGA CCTGTCTT 3423
    2501 AGGGUUUC A CCAUGUUG 1692 CAACATGG GGCTAGCTACAACGA GAAACCCT 3424
    2504 GUUUCACC A UGUUGGCC 1694 GGCCAACA GGCTAGCTACAACGA GGTGAAAC 3425
    2506 UUCACCAU G UUGGCCAG 2409 CTGGCCAA GGCTAGCTACAACGA ATGGTGAA 3426
    2510 CCAUGUUG G CCAGGCUG 2410 CAGCCTGG GGCTAGCTACAACGA CAACATGG 3427
    2515 UUGGCCAG G CUGGUCUC 2411 GAGACCAG GGCTAGCTACAACGA CTGGCCAA 3428
    2519 CCAGGCUG G UCUCAAAC 2412 GTTTGAGA GGCTAGCTACAACGA CAGCCTGG 3429
    2526 GGUCUCAA A CUCCUGAC 2887 GTCAGGAG GGCTAGCTACAACGA TTGAGACC 3430
    2533 AACUCCUG A CCUCAAGU 2888 ACTTGAGG GGCTAGCTACAACGA CAGGAGTT 3431
    2540 GACCUCAA G UAAUCCAC 2413 GTGGATTA GGCTAGCTACAACGA TTGAGGTC 3432
    2543 CUCAAGUA A UCCACCUG 2889 CAGGTGGA GGCTAGCTACAACGA TACTTGAG 3433
    2547 AGUAAUCC A CCUGCCUC 1707 GAGGCAGG GGCTAGCTACAACGA GGATTACT 3434
    2551 AUCCACCU G CCUCGGCC 2414 GGCCGAGG GGCTAGCTACAACGA AGGTGGAT 3435
    2557 CUGCCUCG G CCUCCCAA 2415 TTGGGAGG GGCTAGCTACAACGA CGAGGCAG 3436
    2567 CUCCCAAA G UGCUGGGA 2416 TCCCAGCA GGCTAGCTACAACGA TTTGGGAG 3437
    2569 CCCAAAGU G CUGGGAUU 2417 AATCCCAG GGCTAGCTACAACGA ACTTTGGG 3438
    2575 GUGCUGGG A UUACAGGG 2890 CCCTGTAA GGCTAGCTACAACGA CCCAGCAC 3439
    2578 CUGGGAUU A CAGGGAUG 576 CATCCCTG GGCTAGCTACAACGA AATCCCAG 3440
    2584 UUACAGGG A UGAGCCAC 2891 GTGGCTCA GGCTAGCTACAACGA CCCTGTAA 3441
    2588 AGGGAUGA G CCACCGCG 2418 CGCGGTGG GGCTAGCTACAACGA TCATCCCT 3442
    2591 GAUGAGCC A CCGCGCCC 1720 GGGCGCGG GGCTAGCTACAACGA GGCTCATC 3443
    2594 GAGCCACC G CGCCCAGC 2419 GCTGGGCG GGCTAGCTACAACGA GGTGGCTC 3444
    2596 GCCACCGC G CCCAGCCU 2420 AGGCTGGG GGCTAGCTACAACGA GCGGTGGC 3445
    2601 CGCGCCCA G CCUCAUCU 2421 AGATGAGG GGCTAGCTACAACGA TGGGCGCG 3446
    2606 CCAGCCUC A UCUCUUUG 1727 CAAAGAGA GGCTAGCTACAACGA GAGGCTGG 3447
    2614 AUCUCUUU G UUCUAAAG 2422 CTTTAGAA GGCTAGCTACAACGA AAAGAGAT 3448
    2623 UUCUAAAG A UGGAAAAA 2892 TTTTTCCA GGCTAGCTACAACGA CTTTAGAA 3449
    2631 AUGGAAAA A CCACCCCC 2893 GGGGGTGG GGCTAGCTACAACGA TTTTCCAT 3450
    2634 GAAAAACC A CCCCCAAA 1732 TTTGGGGG GGCTAGCTACAACGA GGTTTTTC 3451
    2642 ACCCCCAA A UUUUCUUU 2894 AAAGAAAA GGCTAGCTACAACGA TTGGGGGT 3452
    2653 UUCUUUUU A UACUAUUA 593 TAATAGTA GGCTAGCTACAACGA AAAAAGAA 3453
    2655 CUUUUUAU A CUAUUAAU 594 ATTAATAG GGCTAGCTACAACGA ATAAAAAG 3454
    2658 UUUAUACU A UUAAUGAA 595 TTCATTAA GGCTAGCTACAACGA AGTATAAA 3455
    2662 UACUAUUA A UGAAUCAA 2895 TTGATTCA GGCTAGCTACAACGA TAATAGTA 3456
    2666 AUUAAUGA A UCAAUCAA 2896 TTGATTGA GGCTAGCTACAACGA TCATTAAT 3457
    2670 AUGAAUCA A UCAAUUCA 2897 TGAATTGA GGCTAGCTACAACGA TGATTCAT 3458
    2674 AUCAAUCA A UUCAUAUC 2898 GATATGAA GGCTAGCTACAACGA TGATTGAT 3459
    2678 AUCAAUUC A UAUCUAUU 1742 AATAGATA GGCTAGCTACAACGA GAATTGAT 3460
    2680 CAAUUCAU A UCUAUUUA 602 TAAATAGA GGCTAGCTACAACGA ATGAATTG 3461
    2684 UCAUAUCU A UUUAUUAA 604 TTAATAAA GGCTAGCTACAACGA AGATATGA 3462
    2688 AUCUAUUU A UUAAAUUU 607 AAATTTAA GGCTAGCTACAACGA AAATAGAT 3463
    2693 UUUAUUAA A UUUCUACC 2899 GGTAGAAA GGCTAGCTACAACGA TTAATAAA 3464
    2699 AAAUUUCU A CCGCUUUU 613 AAAAGCGG GGCTAGCTACAACGA AGAAATTT 3465
    2702 UUUCUACC G CUUUUAGG 2423 CCTAAAAG GGCTAGCTACAACGA GGTAGAAA 3466
    2710 GCUUUUAG G CCAAAAAA 2424 TTTTTTGG GGCTAGCTACAACGA CTAAAAGC 3467
    2719 CCAAAAAA A UGUAAGAU 2900 ATCTTACA GGCTAGCTACAACGA TTTTTTGG 3468
    2721 AAAAAAAU G UAAGAUCG 2425 CGATCTTA GGCTAGCTACAACGA ATTTTTTT 3469
    2726 AAUGUAAG A UCGUUCUC 2901 GAGAACGA GGCTAGCTACAACGA CTTACATT 3470
    2729 GUAAGAUC G UUCUCUGC 2426 GCAGAGAA GGCTAGCTACAACGA GATCTTAC 3471
    2736 CGUUCUCU G CCUCACAU 2427 ATGTGAGG GGCTAGCTACAACGA AGAGAACG 3472
    2741 UCUGCCUC A CAUAGCUU 1753 AAGCTATG GGCTAGCTACAACGA GAGGCAGA 3473
    2743 UGCCUCAC A UAGCUUAC 1754 GTAAGCTA GGCTAGCTACAACGA GTGAGGCA 3474
    2746 CUCACAUA G CUUACAAG 2428 CTTGTAAG GGCTAGCTACAACGA TATGTGAG 3475
    2750 CAUAGCUU A CAAGCCAG 626 CTGGCTTG GGCTAGCTACAACGA AAGCTATG 3476
    2754 GCUUACAA G CCAGCUGG 2429 CCAGCTGG GGCTAGCTACAACGA TTGTAAGC 3477
    2758 ACAAGCCA G CUGGAGAA 2430 TTCTCCAG GGCTAGCTACAACGA TGGCTTGT 3478
    2767 CUGGAGAA A UAUGGUAC 2902 GTACCATA GGCTAGCTACAACGA TTCTCCAG 3479
    2769 GGAGAAAU A UGGUACUC 627 GAGTACCA GGCTAGCTACAACGA ATTTCTCC 3480
    2772 GAAAUAUG G UACUCAUU 2431 AATGAGTA GGCTAGCTACAACGA CATATTTC 3481
    2774 AAUAUGGU A CUCAUUAA 628 TTAATGAG GGCTAGCTACAACGA ACCATATT 3482
    2778 UGGUACUC A UUAAAAAA 1761 TTTTTTAA GGCTAGCTACAACGA GAGTACCA 3483
    2796 AAAAAAAA G UGAUGUAC 2432 GTACATCA GGCTAGCTACAACGA TTTTTTTT 3484
    2799 AAAAAGUG A UGUACAAC 2903 GTTGTACA GGCTAGCTACAACGA CACTTTTT 3485

    Input Sequence = NM_002759. Cut Site = R/Y

    Arm Length = 8. Core Sequence = GGCTAGCTACAACGA

    NM_002759 (Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)
  • TABLE XII
    Human PKR Amberzyme and Substrate Sequence
    Seq Seq
    Pos Substrate ID Amberzyme ID
    9 GCGGCGGC G GCGGCGCA 3486 UGCGCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCGCCGC 3814
    10 CGGCGGCG G CGGCGCAG 2261 CUGCGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCGCCG 3815
    12 GCGGCGGC G GCGCAGUU 3487 AACUGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCGCCGC 3816
    13 CGGCGGCG G CGCAGUUU 2433 AAACUGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCGCCG 3817
    15 GCGGCGGC G CAGUUUGC 2434 GCAAACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCGCCGC 3818
    18 GCGGCGCA G UUUGCUCA 2435 UGAGCAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGCCGC 3819
    22 CGCAGUUU G CUCAUACU 2436 AGUAUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACUGCG 3820
    33 CAUACUUU G UGACUUGC 2437 GCAAGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGUAUG 3821
    35 UACUUUGU G ACUUGCGG 3488 CCGCAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAAGUA 3822
    40 UGUGACUU G CGGUCACA 2438 UGUGACCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGUCACA 3823
    42 UGACUUGC G GUCACAGU 3489 ACUGUGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAAGUCA 3824
    43 GACUUGCG G UCACAGUG 2439 CACUGUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCAAGUC 3825
    49 CGGUCACA G UGGCAUUC 2440 GAAUGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGACOG 3826
    51 GUCACAGU G GCAUUCAG 3490 CUGAAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGUGAC 3827
    52 UCACAGUG G CAUUCAGC 2441 GCUGAAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACUGUGA 3828
    59 GGCAUUCA G CUCCACAC 2442 GUGUGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAUGCC 3829
    70 CCACACUU G GUAGAACC 3491 GGUUCUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGUGUGG 3830
    71 CACACUUG G UAGAACCA 2443 UGGUUCUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGUGUG 3831
    74 ACUUGGUA G AACCACAG 3492 CUGUGGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACCAAGU 3832
    82 GAACCACA G GCACGACA 3493 UGUCGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGGUUC 3833
    83 AACCACAG G CACGACAA 2444 UUGUCGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUGGUU 3834
    87 ACAGGCAC G ACAAGCAU 3494 AUGCUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGCCUGU 3835
    92 CACGACAA G CAUAGAAA 2445 UUUCUAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUCGUG 3836
    97 CAAGCAUA G AAACAUCC 3495 GGAUGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUGCUUG 3837
    121 UCUUCAUC G AGGCAUCG 3496 CGAUGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUGAAGA 3838
    123 UUCAUCGA G GCAUCGAG 3497 CUCGAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGAUGAA 3839
    124 UCAUCGAG G CAUCGAGG 2446 CCUCGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGAUGA 3840
    129 GAGGCAUC G AGGUCCAU 3498 AUGGACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUGCCUC 3841
    131 GGCAUCGA G GUCCAUCC 3499 GGAUGGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGAUGCC 3842
    132 GCAUCGAG G UCCAUCCC 2447 OGGAUGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCGAUGC 3843
    152 AAAAAUCA G GAGACCCU 3500 AGGGUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUUUUU 3844
    153 AAAAUCAG G AGACCCUG 3501 CAGGGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAUUUU 3845
    155 AAUCAGGA G ACCCUGGC 3502 GCCAGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGAUU 3846
    161 GAGACCCU G GCUAUCAU 3503 AUGAUAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGGUCUC 3847
    162 AGACCCUG G CUAUCAUA 2448 UAUGAUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGGUCU 3848
    171 CUAUCAUA G ACCUUAGU 3504 ACUAAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUGAUAG 3849
    178 AGACCUUA G UCUUCGCU 2449 AGCGAAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAGGUCU 3850
    184 UAGUCUUC G CUGGUAUA 2450 UAUACCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAAGACUA 3851
    187 UCUUCGCU G GUAUACUC 3505 GAGUAUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGAAGA 3852
    188 CUUCGCUG G UAUACUCG 2451 CGAGUAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCGAAG 3853
    196 GUAUACUC G CUGUCUGU 2452 ACAGACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGUAUAC 3854
    199 UACUCGCU G UCUGUCAA 2453 UUGACAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGAGUA 3855
    203 CGCUGUCU G UCAACCAG 2454 CUGGUUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGACAGCG 3856
    211 GUCAACCA G CGGUUGAC 2455 GUCAACCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUUGAC 3857
    213 CAACCAGC G GUUGACUU 3506 AAGUCAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGGUUG 3858
    214 AACCAGCG G UUGACUUU 2456 AAAGUCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCUGGUU 3859
    217 CAGCGGUU G ACUUUUUU 3507 AAAAAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACCGCUG 3860
    229 UUUUUUAA G CCUUCUUU 2457 AAAGAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAAAAAA 3861
    252 UUUUACCA G UUUCUGGA 2458 UCCAGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUAAAA 3862
    258 CAGUUUCU G GAGCAAAU 3508 AUUUGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAACUG 3863
    259 AGUUUCUG G AGCAAAUU 3509 AAUUUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAAACU 3864
    261 UUUCUGGA G CAAAUUCA 2459 UGAAUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGAAA 3865
    270 CAAAUUCA G UUUGCCUU 2460 AAGGCAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAUUUG 3866
    274 UUCAGUUU G CCUUCCUG 2461 CAGGAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACUGAA 3867
    282 GCCUUCCU G GAUUUGUA 3510 UACAAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAAGGC 3868
    283 CCUUCCUG G AUUUGUAA 3511 UUACAAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGAAGG 3869
    288 CUGGAUUU G UAAAUUGU 2462 ACAAUUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAUCCAG 3870
    295 UGUAAAUU G UAAUGACC 2463 GGUCAUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUUUACA 3871
    300 AUUGUAAU G ACCUCAAA 3512 UUUGAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUACAAU 3872
    315 AAACUUUA G CAGUUCUU 2464 AAGAACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAAGUUU 3873
    318 CUUUAGCA G UUCUUCCA 2465 UGGAAGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUAAAG 3874
    330 UUCCAUCU G ACUCAGGU 3513 ACCUGAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUGGAA 3875
    336 CUGACUCA G GUUUGCUU 3514 AAGCAAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGUCAG 3876
    337 UGACUCAG G UUUGCUUC 2466 GAAGCAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAGUCA 3877
    341 UCAGGUUU G CUUCUCUG 2467 CAGAGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACCUGA 3878
    349 GCUUCUCU G GCGGUCUU 3515 AAGACCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGAAGC 3879
    350 CUUCUCUG G CGGUCUUC 2468 GAAGACCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGAAG 3880
    352 UCUCUGGC G GUCUUCAG 3516 CUGAAGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCAGAGA 3881
    353 CUCUGGCG G UCUUCAGA 2469 UCUGAAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCAGAG 3882
    360 GGUCUUCA G AAUCAACA 3517 UGUUGAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAGACC 3883
    380 ACACUUCC G UGAUUAUC 2470 GAUAAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGAAGUGU 3884
    382 ACUUCCGU G AUUAUCUG 3518 CAGAUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGGAAGU 3885
    390 GAUUAUCU G CGUGCAUU 2471 AAUGCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUAAUC 3886
    392 UUAUCUGC G UGCAUUUU 2472 AAAAUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAGAUAA 3887
    394 AUCUGCGU G CAUUUUGG 2473 CCAAAAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCAGAU 3888
    401 UGCAUUUU G GACAAAGC 3519 GCUUUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAUGCA 3889
    402 GCAUUUUG G ACAAAGCU 3520 AGCUUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAAUGC 3890
    408 UGGACAAA G CUUCCAAC 2474 GUUGGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGUCCA 3891
    419 UCCAACCA G GAUACGGG 3521 CCCGUAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUUGGA 3892
    420 CCAACCAG G AUACGGGA 3522 UCCCGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGUUGG 3893
    425 CAGGAUAC G GGAAGAAG 3523 CUUCUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAUCCUG 3894
    426 AGGAUACG G GAAGAAGA 3524 UCUUCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUAUCCU 3895
    427 GGAUACGG G AAGAAGAA 3525 UUCUUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGUAUCC 3896
    430 UACGGGAA G AAGAAAUG 3526 CAUUUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCGUA 3897
    433 GGGAAGAA G AAAUGGCU 3527 AGCCAUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUUCCC 3898
    438 GAAGAAAU G GCUGGUGA 3528 UCACCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUUCUUC 3899
    439 AAGAAAUG G CUGGUGAU 2475 AUCACCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUUCUU 3900
    442 AAAUGGCU G GUGAUCUU 3529 AAGAUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCAUUU 3901
    443 AAUGGCUG G UGAUCUUU 2476 AAAGAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCAUU 3902
    445 UGGCUGGU G AUCUUUCA 3530 UGAAAGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCAGCCA 3903
    454 AUCUUUCA G CAGGUUUC 2477 GAAACCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAAGAU 3904
    457 UUUCAGCA G GUUUCUUC 3531 GAAGAAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGAAA 3905
    458 UUCAGCAG G UUUCUUCA 2478 UGAAGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCUGAA 3906
    468 UUCUUCAU G GAGGAACU 3532 AGUUCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGAAGAA 3907
    469 UCUUCAUG G AGGAACUU 3533 AAGUUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGAAGA 3908
    471 UUCAUGGA G GAACUUAA 3534 UUAAGUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAUGAA 3909
    472 UCAUGGAG G AACUUAAU 3535 AUUAAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCAUGA 3910
    488 UACAUACC G UCAGAAGC 2479 GCUUCUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUAUGUA 3911
    492 UACCGUCA G AAGCAGGG 3536 CCCUGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACGGUA 3912
    495 CGUCAGAA G CAGGGAGU 2262 ACUCCCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGACG 3913
    498 CAGAAGCA G GGAGUAGU 3537 ACUACUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUUCUG 3914
    499 AGAAGCAG G GAGUAGUA 3538 UACUACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGCUUCU 3915
    500 GAAGCAGG G AGUAGUAC 3539 GUACUACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGCUUC 3916
    502 AGCAGGGA G UAGUACUU 2263 AAGUACUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCUGCU 3917
    505 AGGGAGUA G UACUUAAA 2264 UUUAAGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACUCCCU 3918
    520 AAUAUCAA G AACUGCCU 3540 AGGCAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAUAUU 3919
    525 CAAGAACU G CCUAAUUC 2265 GAAUUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUCUUG 3920
    535 CUAAUUCA G GACCUCCA 3541 UGGAGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAUUAG 3921
    536 UAAUUCAG G ACCUCCAC 3542 GUGGAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAAUUA 3922
    547 CUCCACAU G AUAGGAGG 3543 CCUCCUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGUGGAG 3923
    551 ACAUGAUA G GAGGUUUA 3544 UAAACCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUCAUGU 3924
    552 CAUGAUAG G AGGUUUAC 3545 GUAAACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAUCAUG 3925
    554 UGAUAGGA G GUUUACAU 3546 AUGUAAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUAUCA 3926
    555 GAUAGGAG G UUUACAUU 2266 AAUGUAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUAUC 3927
    568 CAUUUCAA G UUAUAAUA 2267 UAUUAUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAAAUG 3928
    577 UUAUAAUA G AUGGAAGA 3547 UCUUCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUAUAA 3929
    580 UAAUAGAU G GAAGAGAA 3548 UUCUCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUAUUA 3930
    581 AAUAGAUG G AAGAGAAU 3549 AUUCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCUAUU 3931
    584 AGAUGGAA G AGAAUUUC 3550 GAAAUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCAUCU 3932
    586 AUGGAAGA G AAUUUCCA 3551 UGGAAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCCAU 3933
    595 AAUUUCCA G AAGGUGAA 3552 UUCACCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAAAUU 3934
    598 UUCCAGAA G GUGAAGGU 3553 ACCUUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGGAA 3935
    599 UCCAGAAG G UGAAGGUA 2268 UACCUUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUGGA 3936
    601 CAGAAGGU G AAGGUAGA 3554 UCUACCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUUCUG 3937
    604 AAGGUGAA G GUAGAUCA 3555 UGAUCUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCACCUU 3938
    605 AGGUGAAG G UAGAUCAA 2269 UUGAUCUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCACCU 3939
    608 UGAAGGUA G AUCAAAGA 3556 UCUUUGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACCUUCA 3940
    615 AGAUCAAA G AAGGAAGC 3557 GCUUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGAUCU 3941
    618 UCAAAGAA G GAAGCAAA 3558 UUUGCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUUUGA 3942
    619 CAAAGAAG G AAGCAAAA 3559 UUUUGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUUUG 3943
    622 AGAAGGAA G CAAAAAAU 2270 AUUUUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCUUCU 3944
    631 CAAAAAAU G CCGCAGCC 2271 GGCUGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUUUUUG 3945
    634 AAAAUGCC G CAGCCAAA 2272 UUUGGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCAUUUU 3946
    637 AUGCCGCA G CCAAAUUA 2273 UAAUUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCGGCAU 3947
    646 CCAAAUUA G CUGUUGAG 2274 CUCAACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAUUUGG 3948
    649 AAUUAGCU G UUGAGAUA 2275 UAUCUCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUAAUU 3949
    652 UAGCUGUU G AGAUACUU 3560 AAGUAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACAGCUA 3950
    654 GCUGUUGA G AUACUUAA 3561 UUAAGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAACAGC 3951
    666 CUUAAUAA G GAAAAGAA 3562 UUCUUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAUUAAG 3952
    667 UUAAUAAG G AAAAGAAG 3563 CUUCUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUAUUAA 3953
    672 AAGGAAAA G AAGGCAGU 3564 ACUGCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUCCUU 3954
    675 GAAAAGAA G GCAGUUAG 3565 CUAACUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUUUUC 3955
    676 AAAAGAAG G CAGUUAGU 2276 ACUAACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUUUU 3956
    679 AGAAGGCA G UUAGUCCU 2277 AGGACUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUUCU 3957
    683 GGCAGUUA G UCCUUUAU 2278 AUAAAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAACUGCC 3958
    696 UUAUUAUU G ACAACAAC 3566 GUUGUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUAAUAA 3959
    705 ACAACAAC G AAUUCUUC 3567 GAAGAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUGUUGU 3960
    715 AUUCUUCA G AAGGAUUA 3568 UAAUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAGAAU 3961
    718 CUUCAGAA G GAUUAUCC 3569 GGAUAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGAAG 3962
    719 UUCAGAAG G AUUAUCCA 3570 UGGAUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUGAA 3963
    729 UUAUCCAU G GGGAAUUA 3571 UAAUUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGAUAA 3964
    730 UAUCCAUG G GGAAUUAC 3572 GUAAUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGGAUA 3965
    731 AUCCAUGG G GAAUUACA 3573 UGUAAUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAUGGAU 3966
    732 UCCAUGGG G AAUUACAU 3574 AUGUAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAUGGA 3967
    742 AUUACAUA G GCCUUAUC 3575 GAUAAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUGUAAU 3968
    743 UUACAUAG G CCUUAUCA 2279 UGAUAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAUGUAA 3969
    755 UAUCAAUA G AAUUGCCC 3576 GGGCAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUGAUA 3970
    760 AUAGAAUU G CCCAGAAG 2280 CUUCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUUCUAU 3971
    765 AUUGCCCA G AAGAAAAG 3577 CUUUUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCAAU 3972
    768 GCCCAGAA G AAAAGACU 3578 AGUCUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGGGC 3973
    773 GAAGAAAA G ACUAACUG 3579 CAGUUAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUCUUC 3974
    781 GACUAACU G UAAAUUAU 2281 AUAAUUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUAGUC 3975
    790 UAAAUUAU G AACAGUGU 3580 ACACUGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAAUUUA 3976
    795 UAUGAACA G UGUGCAUC 2282 GAUGCACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUCAUA 3977
    797 UGAACAGU G UGCAUCGG 2283 CCGAUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGUUCA 3978
    799 AACAGUGU G CAUCGGGG 2284 CCCCGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACUGUU 3979
    804 UGUGCAUC G GGGGUGCA 3581 UGCACCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUGCACA 3980
    805 GUGCAUCG G GGGUGCAU 3582 AUGCACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAUGCAC 3981
    806 UGCAUCGG G GGUGCAUG 3583 CAUGCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGAUGCA 3982
    807 GCAUCGGG G GUGCAUGG 3584 CCAUGCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGAUGC 3983
    808 CAUCGGGG G UGCAUGGG 2285 CCCAUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCGAUG 3984
    810 UCGGGGGU G CAUGGGCC 2286 GGCCCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCCCGA 3985
    814 GGGUGCAU G GGCCAGAA 3585 UUCUGGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCACCC 3986
    815 GGUGCAUG G GCCAGAAG 3586 CUUCUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGCACC 3987
    816 GUGCAUGG G CCAGAAGG 2287 CCUUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAUGCAC 3988
    820 AUGGGCCA G AAGGAUUU 3587 AAAUCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCCAU 3989
    823 GGCCAGAA G GAUUUCAU 3588 AUGAAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGGCC 3990
    824 GCCAGAAG G AUUUCAUU 3589 AAUGAAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUGGC 3991
    839 UUAUAAAU G CAAAAUGG 2288 CCAUUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUUAUAA 3992
    846 UGCAAAAU G GGACAGAA 3590 UUCUGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUUUGCA 3993
    847 GCAAAAUG G GACAGAAA 3591 UUUCUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUUUGC 3994
    848 CAAAAUGG G ACAGAAAG 3592 CUUUCUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAUUUUG 3995
    852 AUGGGACA G AAAGAAUA 3593 UAUUCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCCCAU 3996
    856 GACAGAAA G AAUAUAGU 3594 ACUAUAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCUGUC 3997
    863 AGAAUAUA G UAUUGGUA 2289 UACCAAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUAUUCU 3998
    868 AUAGUAUU G GUACAGGU 3595 ACCUGUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUACUAU 3999
    869 UAGUAUUG G UACAGGUU 2290 AACCUGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAUACUA 4000
    874 UUGGUACA G GUUCUACU 3596 AGUAGAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUACCAA 4001
    875 UGGUACAG G UUCUACUA 2291 UAGUAGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUACCA 4002
    888 ACUAAACA G GAAGCAAA 3597 UUUGCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUUAGU 4003
    889 CUAAACAG G AAGCAAAA 3598 UUUUGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUUUAG 4004
    892 AACAGGAA G CAAAACAA 2292 UUGUUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCUGUU 4005
    903 AAACAAUU G GCCGCUAA 3599 UUAGCGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUUGUUU 4006
    904 AACAAUUG G CCGCUAAA 2293 UUUAGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAUUGUU 4007
    907 AAUUGGCC G CUAAACUU 2294 AAGUUUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCAAUU 4008
    916 CUAAACUU G CAUAUCUU 2295 AAGAUAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGUUUAG 4009
    927 UAUCUUCA G AUAUUAUC 3600 GAUAAUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGOG UGAAGAUA 4010
    937 UAUUAUCA G AAGAAACC 3601 GGUUUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUAAUA 4011
    940 UAUCAGAA G AAACCUCA 3602 UGAGGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUGAUA 4012
    949 AAACCUCA G UGAAAUCU 2296 AGAUUUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGGUUU 4013
    951 ACCUCAGU G AAAUCUGA 3603 UCAGAUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGAGGU 4014
    958 UGAAAUCU G ACUACCUG 3604 CAGGUAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUUUCA 4015
    966 GACUACCU G UCCUCUGG 2297 CCAGAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUAGUC 4016
    973 UGUCCUCU G GUUCUUUU 3605 AAAAGAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGGACA 4017
    974 GUCCUCUG G UUCUUUUG 2298 CAAAAGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAGGAC 4018
    982 GUUCUUUU G CUACUACG 2299 CGUAGUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAGAAC 4019
    990 GCUACUAC G UGUGAGUC 2300 GACUCACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAGUAGC 4020
    992 UACUACGU G UGAGUCCC 2301 GGGACUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGUAGUA 4021
    994 CUACGUGU G AGUCCCAA 3606 UUGGGACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACGUAG 4022
    996 ACGUGUGA G UCCCAAAG 2302 CUUUGGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCACACGU 4023
    1004 GUCCCAAA G CAACUCUU 2303 AAGAGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGGGAC 4024
    1015 ACUCUUUA G UGACCAGC 2304 GCUGGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAAGAGU 4025
    1017 UCUUUAGU G ACCAGCAC 3607 GUGCUGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUAAAGA 4026
    1022 AGUGACCA G CACACUCG 2305 CGAGUGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUCACU 4027
    1030 GCACACUC G CUUCUGAA 2306 UUCAGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGUGUGC 4028
    1036 UCGCUUCU G AAUCAUCA 3608 UGAUGAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGCGA 4029
    1048 CAUCAUCU G AAGGUGAC 3609 GUCACCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUGAUG 4030
    1051 CAUCUGAA G GUGACUUC 3610 GAAGUCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGAUG 4031
    1052 AUCUGAAG G UGACUUCU 2307 AGAAGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCAGAU 4032
    1054 CUGAAGGU G ACUUCUCA 3611 UGAGAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUUCAG 4033
    1063 ACUUCUCA G CAGAUACA 2308 UGUAUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGAAGU 4034
    1066 UCUCAGCA G AUACAUCA 3612 UGAUGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUGAGA 4035
    1075 AUACAUCA G AGAUAAAU 3613 AUUUAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUGUAU 4036
    1077 ACAUCAGA G AUAAAUUC 3614 GAAUUUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGAUGU 4037
    1091 UUCUAACA G UGACAGUU 2309 AACUGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUAGAA 4038
    1093 CUAACAGU G ACAGUUUA 3615 UAAACUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGUUAG 4039
    1097 CAGUGACA G UUUAAACA 2310 UGUUUAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCACUG 4040
    1106 UUUAAACA G UUCUUCGU 2311 ACGAAGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUUAAA 4041
    1113 AGUUCUUC G UUGCUUAU 2312 AUAAGCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAAGAACU 4042
    1116 UCUUCGUU G CUUAUGAA 2313 UUCAUAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACGAAGA 4043
    1122 UUGCUUAU G AAUGGUCU 3616 AGACCAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAAGCAA 4044
    1126 UUAUGAAU G GUCUCAGA 3617 UCUGAGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUCAUAA 4045
    1127 UAUGAAUG G UCUCAGAA 2314 UUCUGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUCAUA 4046
    1133 UGGUCUCA G AAAUAAUC 3618 GAUUAUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGACCA 4047
    1145 UAAUCAAA G GAAGGCAA 3619 UUGCCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGAUUA 4048
    1146 AAUCAAAG G AAGGCAAA 3620 UUUGCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUGAUU 4049
    1149 CAAAGGAA G GCAAAAAG 3621 CUUUUUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCUUUG 4050
    1150 AAAGGAAG G CAAAAAGA 2315 UCUUUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCCUUU 4051
    1157 GGCAAAAA G AUCUUUGG 3622 CCAAAGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUUGCC 4052
    1164 AGAUCUUU G GCACCCAG 3623 CUGGGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGAUCU 4053
    1165 GAUCUUUG G CACCCAGA 2316 UCUGGGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAGAUC 4054
    1172 GGCACCCA G AUUUGACC 3624 GGUCAAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGUGCC 4055
    1177 CCAGAUUU G ACCUUCCU 3625 AGGAAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAUCUGG 4056
    1186 ACCUUCCU G ACAUGAAA 3626 UUUCAUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAAGGU 4057
    1191 CCUGACAU G AAAGAAAC 3627 GUUUCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGUCAGG 4058
    1195 ACAUGAAA G AAACAAAG 3628 CUUUGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCAUGU 4059
    1203 GAAACAAA G UAUACUGU 2317 ACAGUAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGUUUC 4060
    1210 AGUAUACU G UGGACAAG 2318 CUUGUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUAUACU 4061
    1212 UAUACUGU G GACAAGAG 3629 CUCUUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGUAUA 4062
    1213 AUACUGUG G ACAAGAGG 3630 CCUCUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAGUAU 4063
    1218 GUGGACAA G AGGUUUGG 3631 CCAAACCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUCCAC 4064
    1220 GGACAAGA G GUUUGGCA 3632 UGCCAAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUGUCC 4065
    1221 GACAAGAG G UUUGGCAU 2319 AUGCCAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUUGUC 4066
    1225 AGAGGUUU G GCAUGGAU 3633 AUCCAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAACCUCU 4067
    1226 GAGGUUUG G CAUGGAUU 2320 AAUCCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAACCUC 4068
    1230 UUUGGCAU G GAUUUUAA 3634 UUAAAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCCAAA 4069
    1231 UUGGCAUG G AUUUUAAA 3635 UUUAAAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGCCAA 4070
    1240 AUUUUAAA G AAAUAGAA 3636 UUCUAUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUAAAAU 4071
    1246 AAGAAAUA G AAUUAAUU 3637 AAUUAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUUCUU 4072
    1255 AAUUAAUU G GCUCAGGU 3638 ACCUGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUUAAUU 4073
    1256 AUUAAUUG G CUCAGGUG 2321 CACCUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAUUAAU 4074
    1261 UUGGCUCA G GUGGAUUU 3639 AAAUCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGCCAA 4075
    1262 UGGCUCAG G UGGAUUUG 2322 CAAAUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAGCCA 4076
    1264 GCUCAGGU G GAUUUGGC 3640 GCCAAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUGAGC 4077
    1265 CUCAGGUG G AUUUGGCC 3641 GGCCAAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCUGAG 4078
    1270 GUGGAUUU G GCCAAGUU 3642 AACUUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAUCCAC 4079
    1271 UGGAUUUG G CCAAGUUU 2323 AAACUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAUCCA 4080
    1276 UUGGCCAA G UUUUCAAA 2324 UUUGAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGCCAA 4081
    1285 UUUUCAAA G CAAAACAC 2325 GUGUUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGAAAA 4082
    1295 AAAACACA G AAUUGACG 3643 CGUCAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGUUUU 4083
    1300 ACAGAAUU G ACGGAAAG 3644 CUUUCCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUUCUGU 4084
    1303 GAAUUGAC G GAAAGACU 3645 AGUCUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCAAUUC 4085
    1304 AAUUGACG G AAAGACUU 3646 AAGUCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUCAAUU 4086
    1308 GACGGAAA G ACUUACGU 3647 ACGUAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCCGUC 4087
    1315 AGACUUAC G UUAUUAAA 2326 UUUAAUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAAGUCU 4088
    1325 UAUUAAAC G UGUUAAAU 2327 AUUUAACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUUAAUA 4089
    1327 UUAAACGU G UUAAAUAU 2328 AUAUUUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGUUUAA 4090
    1342 AUAAUAAC G AGAAGGCG 3648 CGCCUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUAUUAU 4091
    1344 AAUAACGA G AAGGCGGA 3649 UCCGCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGUUAUU 4092
    1347 AACGAGAA G GCGGAGCG 3650 CGCUCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUCGUU 4093
    1348 ACGAGAAG G CGGAGCGU 2329 ACGCUCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCUCGU 4094
    1350 GAGAAGGC G GAGCGUGA 3651 UCACGCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUUCUC 4095
    1351 AGAAGGCG G AGCGUGAA 3652 UUCACGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCUUCU 4096
    1353 AAGGCGGA G CGUGAAGU 2330 ACUUCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCGCCUU 4097
    1355 GGCGGAGC G UGAAGUAA 2331 UUACUUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUCCGCC 4098
    1357 CGGAGCGU G AAGUAAAA 3653 UUUUACUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCUCCG 4099
    1360 AGCGUGAA G UAAAAGCA 2332 UGCUUUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCACGCU 4100
    1366 AAGUAAAA G CAUUGGCA 2333 UGCCAAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUACUU 4101
    1371 AAAGCAUU G GCAAAACU 3654 AGUUUUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUGCUUU 4102
    1372 AAGCAUUG G CAAAACUU 2334 AAGUUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAUGCUU 4103
    1381 CAAAACUU G AUCAUGUA 3655 UACAUGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGUUUUG 4104
    1387 UUGAUCAU G UAAAUAUU 2335 AAUAUUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGAUCAA 4105
    1396 UAAAUAUU G UUCACUAC 2336 GUAGUGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUAUUUA 4106
    1408 ACUACAAU G GCUGUUGG 3656 CCAACAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUGUAGU 4107
    1409 CUACAAUG G CUGUUGGG 2337 CCCAACAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUGUAG 4108
    1412 CAAUGGCU G UUGGGAUG 2338 CAUCCCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCAUUG 4109
    1415 UGGCUGUU G GGAUGGAU 3657 AUCCAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACAGCCA 4110
    1416 GGCUGUUG G GAUGGAUU 3658 AAUCCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAACAGCC 4111
    1417 GCUGUUGG G AUGGAUUU 3659 AAAUCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAACAGC 4112
    1420 GUUGGGAU G GAUUUGAU 3660 AUCAAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCCAAC 4113
    1421 UUGGGAUG G AUUUGAUU 3661 AAUCAAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCCCAA 4114
    1426 AUGGAUUU G AUUAUGAU 3662 AUCAUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAUCCAU 4115
    1432 UUGAUUAU G AUCCUGAG 3663 CUCAGGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAAUCAA 4116
    1438 AUGAUCCU G AGACCAGU 3664 ACUGGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAUCAU 4117
    1440 GAUCCUGA G ACCAGUGA 3665 UCACUGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGGAUC 4118
    1445 UGAGACCA G UGAUGAUU 2339 AAUCAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUCUCA 4119
    1447 AGACCAGU G AUGAUUCU 3666 AGAAUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGGUCU 4120
    1450 CCAGUGAU G AUUCUCUU 3667 AAGAGAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCACUGG 4121
    1459 AUUCUCUU G AGAGCAGU 3668 ACUGCUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGAGAAU 4122
    1461 UCUCUUGA G AGCAGUGA 3669 UCACUGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAAGAGA 4123
    1463 UCUUGAGA G CAGUGAUU 2340 AAUCACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCAAGA 4124
    1466 UGAGAGCA G UGAUUAUG 2341 CAUAAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCUCUCA 4125
    1468 AGAGCAGU G AUUAUGAU 3670 AUCAUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGCUCU 4126
    1474 GUGAUUAU G AUCCUGAG 3671 CUCAGGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAAUCAC 4127
    1480 AUGAUCCU G AGAACAGC 3672 GCUGUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAUCAU 4128
    1482 GAUCCUGA G AACAGCAA 3673 UUGCUGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGGAUC 4129
    1487 UGAGAACA G CAAAAAUA 2342 UAUUUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUCUCA 4130
    1496 CAAAAAUA G UUCAAGGU 2343 ACCUUGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUUUUG 4131
    1502 UAGUUCAA G GUCAAAGA 3674 UCUUUGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAACUA 4132
    1503 AGUUCAAG G UCAAAGAC 2344 GUCUUUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGAACU 4133
    1509 AGGUCAAA G ACUAAGUG 3675 CACUUAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGACCU 4134
    1515 AAGACUAA G UGCCUUUU 2345 AAAAGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAGUCUU 4135
    1517 GACUAAGU G CCUUUUCA 2346 UGAAAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUAGUC 4136
    1533 AUCCAAAU G GAAUUCUG 3676 CAGAAUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUUGGAU 4137
    1534 UCCAAAUG G AAUUCUGU 3677 ACAGAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUUGGA 4138
    1541 GGAAUUCU G UGAUAAAG 2347 CUUUAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAUUCC 4139
    1543 AAUUCUGU G AUAAAGGG 3678 CCCUUUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGAAUU 4140
    1549 GUGAUAAA G GGACCUUG 3679 CAAGGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUAUCAC 4141
    1550 UGAUAAAG G GACCUUGG 3680 CCAAGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUAUCA 4142
    1551 GAUAAAGG G ACCUUGGA 3681 UCCAAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUUUAUC 4143
    1557 GGGACCUU G GAACAAUG 3682 CAUUGUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGUCCC 4144
    1558 GGACCUUG G AACAAUGG 3683 CCAUUGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGGUCC 4145
    1565 GGAACAAU G GAUUGAAA 3684 UUUCAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUGUUCC 4146
    1566 GAACAAUG G AUUGAAAA 3685 UUUUCAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUGUUC 4147
    1570 AAUGGAUU G AAAAAAGA 3686 UCUUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUCCAUU 4148
    1577 UGAAAAAA G AAGAGGCG 3687 CGCCUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUUUCA 4149
    1580 AAAAAGAA G AGGCGAGA 3688 UCUCGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCUUUUU 4150
    1582 AAAGAAGA G GCGAGAAA 3689 UUUCUCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUCUUU 4151
    1583 AAGAAGAG G CGAGAAAC 2348 GUUUCUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUUCUU 4152
    1585 GAAGAGGC G AGAAACUA 3690 UAGUUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUCUUC 4153
    1587 AGAGGCGA G AAACUAGA 3691 UCUAGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGCCUCU 4154
    1594 AGAAACUA G ACAAAGUU 3692 AACUUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAGUUUCU 4155
    1600 UAGACAAA G UUUUGGCU 2349 AGCCAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGUCUA 4156
    1605 AAAGUUUU G GCUUUGGA 3693 UCCAAAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAACUUU 4157
    1606 AAGUUUUG G CUUUGGAA 2350 UUCCAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAACUU 4158
    1611 UUGGCUUU G GAACUCUU 3694 AAGAGUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGCCAA 4159
    1612 UGGCUUUG G AACUCUUU 3695 AAAGAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAGCCA 4160
    1621 AACUCUUU G AACAAAUA 3696 UAUUUGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGAGUU 4161
    1636 UAACAAAA G GGGUGGAU 3697 AUCCACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUGUUA 4162
    1637 AACAAAAG G GGUGGAUU 3698 AAUCCACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUUGUU 4163
    1638 ACAAAAGG G GUGGAUUA 3699 UAAUCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUUUUGU 4164
    1639 CAAAAGGG G UGGAUUAU 2351 AUAAUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCUUUUG 4165
    1641 AAAGGGGU G GAUUAUAU 3700 AUAUAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCCCUUU 4166
    1642 AAGGGGUG G AUUAUAUA 3701 UAUAUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCCCUU 4167
    1673 AAUUCAUA G AGAUCUUA 3702 UAAGAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUGAAUU 4168
    1675 UUCAUAGA G AUCUUAAG 3703 CUUAAGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUAUGAA 4169
    1683 GAUCUUAA G CCAAGUAA 2352 UUACUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAAGAUC 4170
    1688 UAAGCCAA G UAAUAUAU 2353 AUAUAUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGCUUA 4171
    1702 UAUUCUUA G UAGAUACA 2354 UGUAUCUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAGAAUA 4172
    1705 UCUUAGUA G AUACAAAA 3704 UUUUGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACUAAGA 4173
    1717 CAAAACAA G UAAAGAUU 2355 AAUCUUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUUUUG 4174
    1722 CAAGUAAA G AUUGGAGA 3705 UCUCCAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUACUUG 4175
    1726 UAAAGAUU G GAGACUUU 3706 AAAGUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAUCUUUA 4176
    1727 AAAGAUUG G AGACUUUG 3707 CAAAGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAUCUUU 4177
    1729 AGAUUGGA G ACUUUGGA 3708 UCCAAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAAUCU 4178
    1735 GAGACUUU G GACUUGUA 3709 UACAAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGUCUC 4179
    1736 AGACUUUG G ACUUGUAA 3710 UUACAAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAGUCU 4180
    1741 UUGGACUU G UAACAUCU 2356 AGAUGUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGUCCAA 4181
    1752 ACAUCUCU G AAAAAUGA 3711 UCAUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGAUGU 4182
    1759 UGAAAAAU G AUGGAAAG 3712 CUUUCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUUUUCA 4183
    1762 AAAAUGAU G GAAAGCGA 3713 UCGCUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAUUUU 4184
    1763 AAAUGAUG G AAAGCGAA 3714 UUCGCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCAUUU 4185
    1767 GAUGGAAA G CGAACAAG 2357 CUUGUUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCCAUC 4186
    1769 UGGAAAGC G AACAAGGA 3715 UCCUUGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUUUCCA 4187
    1775 GCGAACAA G GAGUAAGG 3716 CCUUACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUUCGC 4188
    1776 CGAACAAG G AGUAAGGG 3717 CCCUUACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGUUCG 4189
    1778 AACAAGGA G UAAGGGAA 2358 UUCCCUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUUGUU 4190
    1782 AGGAGUAA G GGAACUUU 3718 AAAGUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUACUCCU 4191
    1783 GGAGUAAG G GAACUUUG 3719 CAAAGUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUACUCC 4192
    1784 GAGUAAGG G AACUUUGC 3720 GCAAAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUUACUC 4193
    1791 GGAACUUU G CGAUACAU 2359 AUGUAUCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGUUCC 4194
    1793 AACUUUGC G AUACAUGA 3721 UCAUGUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCAAAGUU 4195
    1800 CGAUACAU G AGCCCAGA 3722 UCUGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGUAUCG 4196
    1802 AUACAUGA G CCCAGAAC 2360 GUUCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUGUAU 4197
    1807 UGAGCCCA G AACAGAUU 3723 AAUCUGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCUCA 4198
    1812 CCAGAACA G AUUUCUUC 3724 GAAGAAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUCUGG 4199
    1821 AUUUCUUC G CAAGACUA 2361 UAGUCUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAAGAAAU 4200
    1825 CUUCGCAA G ACUAUGGA 3725 UCCAUAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGCGAAG 4201
    1831 AAGACUAU G GAAAGGAA 3726 UUCCUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAGUCUU 4202
    1832 AGACUAUG G AAAGGAAG 3727 CUUCCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUAGUCU 4203
    1836 UAUGGAAA G GAAGUGGA 3728 UCCACUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCCAUA 4204
    1837 AUGGAAAG G AAGUGGAC 3729 GUCCACUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUCCAU 4205
    1840 GAAAGGAA G UGGACCUC 2362 GAGGUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCUUUC 4206
    1842 AAGGAAGU G GACCUCUA 3730 UAGAGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUCCUU 4207
    1843 AGGAAGUG G ACCUCUAC 3731 GUAGAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACUUCCU 4208
    1852 ACCUCUAC G CUUUGGGG 2363 CCCCAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAGAGGU 4209
    1857 UACGCUUU G GGGCUAAU 3732 AUUAGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGCGUA 4210
    1858 ACGCUUUG G GGCUAAUU 3733 AAUUAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAGCGU 4211
    1859 CGCUUUGG G GCUAAUUC 3734 GAAUUAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAAAGCG 4212
    1860 GCUUUGGG G CUAAUUCU 2364 AGAAUUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAAAGC 4213
    1870 UAAUUCUU G CUGAACUU 2365 AAGUUCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGAAUUA 4214
    1873 UUCUUGCU G AACUUCUU 3735 AAGAAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCAAGAA 4215
    1885 UUCUUCAU G UAUGUGAC 2366 GUCACAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGAAGAA 4216
    1889 UCAUGUAU G UGACACUG 2367 CAGUGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUACAUGA 4217
    1891 AUGUAUGU G ACACUGCU 3736 AGCAGUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAUACAU 4218
    1897 GUGACACU G CUUUUGAA 2368 UUCAAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGUCAC 4219
    1903 CUGCUUUU G AAACAUCA 3737 UGAUGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAGCAG 4220
    1914 ACAUCAAA G UUUUUCAC 2369 GUGAAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGAUGU 4221
    1924 UUUUCACA G ACCUACGG 3738 CCGUAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGAAAA 4222
    1931 AGACCUAC G GGAUGGCA 3739 UGCCAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAGGUCU 4223
    1932 GACCUACG G GAUGGCAU 3740 AUGCCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUAGGUC 4224
    1933 ACCUACGG G AUGGCAUC 3741 GAUGCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGUAGGU 4225
    1936 UACGGGAU G GCAUCAUC 3742 GAUGAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCCGUA 4226
    1937 ACGGGAUG G CAUCAUCU 2370 AGAUGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCCCGU 4227
    1948 UCAUCUCA G AUAUAUUU 3743 AAAUAUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGAUGA 4228
    1957 AUAUAUUU G AUAAAAAA 3744 UUUUUUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAUAUAU 4229
    1966 AUAAAAAA G AAAAAACU 3745 AGUUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUUUAU 4230
    1983 CUUCUACA G AAAUUACU 3746 AGUAAUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUAGAAG 4231
    1998 CUCUCAAA G AAACCUGA 3747 UCAGGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGAGAG 4232
    2005 AGAAACCU G AGGAUCGA 3748 UCGAUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUUUCU 4233
    2007 AAACCUGA G GAUCGACC 3749 GGUCGAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGGUUU 4234
    2008 AACCUGAG G AUCGACCU 3750 AGGUCGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCAGGUU 4235
    2012 UGAGGAUC G ACCUAACA 3751 UGUUAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUCCUCA 4236
    2026 ACACAUCU G AAAUACUA 3752 UAGUAUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUGUGU 4237
    2036 AAUACUAA G GACCUUGA 3753 UCAAGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAGUAUU 4238
    2037 AUACUAAG G ACCUUGAC 3754 GUCAAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUAGUAU 4239
    2043 AGGACCUU G ACUGUGUG 3755 CACACAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGUCCU 4240
    2047 CCUUGACU G UGUGGAAG 2371 CUUCCACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUCAAGG 4241
    2049 UUGACUGU G UGGAAGAA 2372 UUCUUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGUCAA 4242
    2051 GACUGUGU G GAAGAAAA 3756 UUUUCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACAGUC 4243
    2052 ACUGUGUG G AAGAAAAG 3757 CUUUUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACACAGU 4244
    2055 GUGUGGAA G AAAAGCCC 3758 GGGCUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCACAC 4245
    2060 GAAGAAAA G CCCAGAGA 2373 UCUCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUCUUC 4246
    2065 AAAGCCCA G AGAAAAAU 3759 AUUUUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCUUU 4247
    2067 AGCCCAGA G AAAAAUGA 3760 UCAUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGGCU 4248
    2074 AGAAAAAU G AACGACAC 3761 GUGUCGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUUUUCU 4249
    2078 AAAUGAAC G ACACACAU 3762 AUGUGUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUCAUUU 4250
    2087 ACACACAU G UUAGAGCC 2374 GGCUCUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGUGUGU 4251
    2091 ACAUGUUA G AGCCCUUC 3763 GAAGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAACAUGU 4252
    2093 AUGUUAGA G CCCUUCUG 2375 CAGAAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUAACAU 4253
    2101 GCCCUUCU G AAAAAGUA 3764 UACUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGGGC 4254
    2107 CUGAAAAA G UAUCCUGC 2376 GCAGGAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUUCAG 4255
    2114 AGUAUCCU G CUUCUGAU 2377 AUCAGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAUACU 4256
    2120 CUGCUUCU G AUAUGCAG 3765 CUGCAUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGCAG 4257
    2125 UCUGAUAU G CAGUUUUC 2378 GAAAACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAUCAGA 4258
    2128 GAUAUGCA G UUUUCCUU 2379 AAGGAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAUAUC 4259
    2153 UAAAAUCU G CUAGGGAA 2380 UUCCCUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUUUUA 4260
    2157 AUCUGCUA G GGAAUAUC 3766 GAUAUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAGCAGAU 4261
    2158 UCUGCUAG G GAAUAUCA 3767 UGAUAUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAGCAGA 4262
    2159 CUGCUAGG G AAUAUCAA 3768 UUGAUAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUAGCAG 4263
    2170 UAUCAAUA G AUAUUUAC 3769 GUAAAUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUGAUA 4264
    2192 AUUUUAAU G UUUCCUUU 2381 AAAGGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUAAAAU 4265
    2230 AUCUUUCU G CAGAAACA 2382 UGUUUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAAGAU 4266
    2233 UUUCUGCA G AAACAGAA 3770 UUCUGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAGAAA 4267
    2239 CAGAAACA G AAAGGUUU 3771 AAACCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUUCUG 4268
    2243 AACAGAAA G GUUUUCUU 3772 AAGAAAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCUGUU 4269
    2244 ACAGAAAG G UUUUCUUC 2383 GAAGAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUCUGU 4270
    2258 UUCUUUUU G CUUCAAAA 2384 UUUUGAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAAGAA 4271
    2292 UUUUUCCU G GCUCAUCU 3773 AGAUGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAAAAA 4272
    2293 UUUUCCUG G CUCAUCUC 2385 GAGAUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGAAAA 4273
    2326 UUUUUAAA G ACAGAGUC 3774 GACUCUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUAAAAA 4274
    2330 UAAAGACA G AGUCUCGC 3775 GCGAGACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCUUUA 4275
    2332 AAGACAGA G UCUCGCUC 2386 GAGCGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGUCUU 4276
    2337 AGAGUCUC G CUCUGUUG 2387 CAACAGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGACUCU 4277
    2342 CUCGCUCU G UUGCCCAG 2388 CUGGGCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGCGAG 4278
    2345 GCUCUGUU G CCCAGGCU 2389 AGCCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACAGAGC 4279
    2350 GUUGCCCA G GCUGGAGU 3776 ACUCCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCAAC 4280
    2351 UUGCCCAG G CUGGAGUG 2390 CACUCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGGCAA 4281
    2354 CCCAGGCU G GAGUGCAA 3777 UUGCACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUGGG 4282
    2355 CCAGGCUG G AGUGCAAU 3778 AUUGCACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCUGG 4283
    2357 AGGCUGGA G UGCAAUGA 2391 UCAUUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGCCU 4284
    2359 GCUGGAGU G CAAUGACA 2392 UGUCAUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUCCAGC 4285
    2364 AGUGCAAU G ACACAGUC 3779 GACUGUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUGCACU 4286
    2370 AUGACACA G UCUUGGCU 2393 AGCCAAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGUCAU 4287
    2375 ACAGUCUU G GCUCACUG 3780 CAGUGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGACUGU 4288
    2376 CAGUCUUG G CUCACUGC 2394 GCAGUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGACUG 4289
    2383 GGCUCACU G CAACUUCU 2395 AGAAGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUGAGCC 4290
    2392 CAACUUCU G CCUCUUGG 2396 CCAAGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAAGUUG 4291
    2399 UGCCUCUU G GGUUCAAG 3781 CUUGAACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGAGGCA 4292
    2400 GCCUCUUG G GUUCAAGU 3782 ACUUGAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGAGGC 4293
    2401 CCUCUUGG G UUCAAGUG 2397 CACUUGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAAGAGG 4294
    2407 GGGUUCAA G UGAUUCUC 2398 GAGAAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAACCC 4295
    2409 GUUCAAGU G AUUCUCCU 3783 AGGAGAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUGAAC 4296
    2418 AUUCUCCU G CCUCAGCC 2399 GGCUGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGAAU 4297
    2424 CUGCCUCA G CCUCCUGA 2400 UCAGGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGGCAG 4298
    2431 AGCCUCCU G AGUAGCUG 3784 CAGCUACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGGCU 4299
    2433 CCUCCUGA G UAGCUGGA 2401 UCCAGCUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAGGAGG 4300
    2436 CCUGAGUA G CUGGAUUA 2402 UAAUCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACUCAGG 4301
    2439 GAGUAGCU G GAUUACAG 3785 CUGUAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUACUC 4302
    2440 AGUAGCUG G AUUACAGG 3786 CCUGUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUACU 4303
    2447 GGAUUACA G GCAUGUGC 3787 GCACAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUAAUCC 4304
    2448 GAUUACAG G CAUGUGCC 2403 GGCACAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUAAUC 4305
    2452 ACAGGCAU G UGCCACCC 2404 GGGUGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCCUGU 4306
    2454 AGGCAUGU G CCACCCAC 2405 GUGGGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAUGCCU 4307
    2476 UAAUUUUU G UGUUUUUA 2406 UAAAAACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAAAUUA 4308
    2478 AUUUUUGU G UUUUUAAU 2407 AUUAAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAAAAU 4309
    2490 UUAAUAAA G ACAGGGUU 3788 AACCCUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUAUUAA 4310
    2494 UAAAGACA G GGUUUCAC 3789 GUGAAACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUCUUUA 4311
    2495 AAAGACAG G GUUUCACC 3790 GGUGAAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUCUUU 4312
    2496 AAGACAGG G UUUCACCA 2408 UGGUGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGUCUU 4313
    2506 UUCACCAU G UUGGCCAG 2409 CUGGCCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGGUGAA 4314
    2509 ACCAUGUU G GCCAGGCU 3791 AGCCUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACAUGGU 4315
    2510 CCAUGUUG G CCAGGCUG 2410 CAGCCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAACAUGG 4316
    2514 GUUGGCCA G GCUGGUCU 3792 AGACCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCAAC 4317
    2515 UUGGCCAG G CUGGUCUC 2411 GAGACCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGCCAA 4318
    2518 GCCAGGCU G GUCUCAAA 3793 UUUGAGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUGGC 4319
    2519 CCAGGCUG G UCUCAAAC 2412 GUUUGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCUGG 4320
    2532 AAACUCCU G ACCUCAAG 3794 CUUGAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGUUU 4321
    2540 GACCUCAA G UAAUCCAC 2413 GUGGAUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAGGUC 4322
    2551 AUCCACCU G CCUCGGCC 2414 GGCCGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUGGAU 4323
    2556 CCUGCCUC G GCCUCCCA 3795 UGGGAGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAGGCAGG 4324
    2557 CUGCCUCG G CCUCCCAA 2415 UUGGGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGGCAG 4325
    2567 CUCCCAAA G UGCUGGGA 2416 UCCCAGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGGGAG 4326
    2569 CCCAAAGU G CUGGGAUU 2417 AAUCCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUUGGG 4327
    2572 AAAGUGCU G GGAUUACA 3796 UGUAAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCACUUU 4328
    2573 AAGUGCUG G GAUUACAG 3797 CUGUAAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCACUU 4329
    2574 AGUGCUGG G AUUACAGG 3798 CCUGUAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGCACU 4330
    2581 GGAUUACA G GGAUGAGC 3799 GCUCAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUAAUCC 4331
    2582 GAUUACAG G GAUGAGCC 3800 GGCUCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUAAUC 4332
    2583 AUUACAGG G AUGAGCCA 3801 UGGCUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGUAAU 4333
    2586 ACAGGGAU G AGCCACCG 3802 CGGUGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCCUGU 4334
    2588 AGGGAUGA G CCACCGCG 2418 CGCGGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUCCCU 4335
    2594 GAGCCACC G CGCCCAGC 2419 GCUGGGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUGGCUC 4336
    2596 GCCACCGC G CCCAGCCU 2420 AGGCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGUGGC 4337
    2601 CGCGCCCA G CCUCAUCU 2421 AGAUGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCGCG 4338
    2614 AUCUCUUU G UUCUAAAG 2422 CUUUAGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAGAGAU 4339
    2622 GUUCUAAA G AUGGAAAA 3803 UUUUCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUAGAAC 4340
    2625 CUAAAGAU G GAAAAACC 3804 GGUUUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUUUAG 4341
    2626 UAAAGAUG G AAAAACCA 3805 UGGUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCUUUA 4342
    2664 CUAUUAAU G AAUCAAUC 3806 GAUUGAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUAAUAG 4343
    2702 UUUCUACC G CUUUUAGG 2423 CCUAAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUAGAAA 4344
    2709 CGCUUUUA G GCCAAAAA 3807 UUUUUGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAAAGCG 4345
    2710 GCUUUUAG G CCAAAAAA 2424 UUUUUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAAAAGC 4346
    2721 AAAAAAAU G UAAGAUCG 2425 CGAUCUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUUUUUU 4347
    2725 AAAUGUAA G AUCGUUCU 3808 AGAACGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUACAUUU 4348
    2729 GUAAGAUC G UUCUCUGC 2426 GCAGAGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUCUUAC 4349
    2736 CGUUCUCU G CCUCACAU 2427 AUGUGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGAACG 4350
    2746 CUCACAUA G CUUACAAG 2428 CUUGUAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUGUGAG 4351
    2754 GCUUACAA G CCAGCUGG 2429 CCAGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUAAGC 4352
    2758 ACAAGCCA G CUGGAGAA 2430 UUCUCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCUUGU 4353
    2761 AGCCAGCU G GAGAAAUA 3809 UAUUUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGGCU 4354
    2762 GCCAGCUG G AGAAAUAU 3810 AUAUUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCUGGC 4355
    2764 CAGCUGGA G AAAUAUGG 3811 CCAUAUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCAGCUG 4356
    2771 AGAAAUAU G GUACUCAU 3812 AUGAGUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAUUUCU 4357
    2772 GAAAUAUG G UACUCAUU 2431 AAUGAGUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUAUUUC 4358
    2796 AAAAAAAA G UGAUGUAC 2432 GUACAUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUUUUU 4359
    2798 AAAAAAGU G AUGUACAA 3813 UUGUACAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUUUUU 4360

    Input Sequence = NM_002759. Cut Site = G/.

    Arm Length = 8. Core Sequence = GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG

    NM_002759 (Homo sapiens protein kinase, interferon-inducible double stranded RNA dependent (PRKR), mRNA.; 2808 bp)
  • TABLE XIII
    Human IKK-gamma and PKR Nucleic Acid and Target molecules
    Seq
    Gene Pos Target Seq ID RPI# Enzymatic Nucleic Acid ID
    PKR 563 UUUACAUUUCAAGUU 7771 24072 aSaScSuSugacUGAuGaggccguuaggccGaaAuguaaa B 7884
    PKR 571 UCAAGUUAUAAUAGA 7772 24073 uScSuSaSuuacUGAuGaggccguuaggccGaaAacuugaB 7885
    PKR 644 GCCAAAUUAGCUGUU 7773 24074 aSaScSaSgcucUGAuGaggccguuaggccGaaAuuuggcB 7886
    PKR 645 CCAAAUUAGCUGUUG 7774 24075 cSaSaScSagccUGAuGaggccguuaggccGaaAauuuggB 7887
    PKR 1259 UUGGCUCAGGUGG 7775 24076 cScSaScScucUGAuGaggccguuaggccGaaAgccaaB 7888
    PKR 1259 AUUGGCUCAGGUGGA 7776 24077 uScScSaSccucUGAuGaggccguuaggccGaaAgccaauB 7889
    PKR 1538 UGGAAUUCUGUGA 7777 24078 uScSaScSagcUGAuGaggccguuaggccGaaAuuccaB 7890
    PKR 1538 AUGGAAUUCUGUGAU 7778 24079 aSuScSaScagcUGAuGaggccguuaggccGaaAuuccauB 7891
    PKR 1678 AGAGAUCUUAAGC 7779 24080 gScSuSuSaacUGAuGaggccguuaggccGaaAucucuB 7892
    PKR control GACGAUUGCAAUC 7780 24081 gSaSuSuSgccUAGuGacgccguuaggcgGaaAucgucB 7893
    PKR control ACACCGUUGGAUCGC 7781 24082 gScSgSaSucccUAGuGaggccguuaggccGaalcgguguB 7894
    PKR 764 UUGCCCAGAAGAA 7782 24153 uSuScSuSuccUGAuGaggccguuaggccGaalggcaaB 7895
    PKR 1540 GGAAUUCUGUGAUAA 7783 24154 uSuSaSuScaccUGAuGaggccguuaggccGaalaauuccB 7896
    PKR 1679 GAGAUCUUAAGCC 7784 24155 gSgScSuSuacUGAuGaggccguuaggccGaalaucucB 7897
    PKR 1679 AGAGAUCUUAAGCCA 7785 24156 uSgSgScSuuacUGAuGaggccguuaggccGaalaucucuB 7898
    PKR Control ACUGGCAUACAUG 7786 24157 cSaSuSgSuacUAGuGacgccguuaggcgGaaIccaguB 7899
    PKR Control CAUUCGCUAAAUGAG 7787 24158 cSuScSaSuuucUAGuGacgccguuaggcgGaalcgaaugB 7900
    PKR 1348 GAGAAGGCGGAGC 7788 24210 gScSuScScggccgaaagg C gagugaGgu C ucuucucB 7901
    PKR Control CCGUACGUUAAGA 7789 24211 uScSuSuSaagccgaaagg C u C ugGagugagguacggB 7902
    PKR Control ACGAAGAGUUACCUU 7790 24212 aSaSgSgSuaagccgaaagg C u C ugGagugagucuucguB 7903
    PKR 1224 AGAGGUUUGGCAUGG 7791 24416 ccaugccCUGAUGAggccguuaggccGAAAaccucuB 7904
    PKR 1556 GGGACCUUGGAACAA 7792 24417 uuguuccCUGAUGAggccguuaggccGAAAggucccB 7905
    PKR 1780 AAGGAGUAAGGGAAC 7793 24418 guucccuCUGAUGAggccguuaggccGAAAcuccuuB 7906
    PKR 2296 CCUGGCUCAUCUCUU 7794 24419 aagagauCUGAUGAggccguuaggccGAAAgccaggB 7907
    PKR 2732 GAUCGUUCUCUGCCU 7795 24420 aggcagaCUGAUGAggccguuaggccGAAAacgaucB 7908
    PKR 198 UACUCGCUGUCUGUC 7796 24421 gacagacCUGAUGAggccguuaggccGAAlcgaguaB 7909
    PKR 322 GCAGUUCUUCCAUCU 7797 24422 agauggaCUGAUGAggccguuaggccGAAlaacugcB 7910
    PKR 1805 AUGAGCCCAGAACAG 7798 24423 cuguucuCUGAUGAggccguuaggccGAAlgcucauB 7911
    PKR 2297 CUGGCUCAUCUCUUU 7799 24424 aaagagaCUGAUGAggccguuaggccGAAlagccagB 7912
    PKR 2733 AUCGUUCUCUGCCUC 7800 24425 gaggcagCUGAUGAggccguuaggccGAAlaacgauB 7913
    PKR 199 ACUCGCUGUCUGUCA 7801 24426 ugacagagccgaaagg C gagugaGGu C uagcgaguB 7914
    PKR 810 CGGGGGUGCAUGGGC 7802 24427 gcccauggccgaaagg C gagugaGGu C uacccccgB 7915
    PKR 904 ACAAUUGGCCGCUAA 7803 24428 uuagcgggccgaaagg C gagugaGGu C ucaauuguB 7916
    PKR 966 ACUACCUGUCCUCUG 7804 24429 cagaggagccgaaagg C gagugaGGu C uagguaguB 7917
    PKR 992 ACUACGUGUGAGUCC 7805 24430 ggacucagccgaaagg C gagugaGGu C uacguaguB 7918
    PKR 396 UGCGUGCAUUUUGGA 7806 24431 uccaaaaGGCTAGCTACAACGAgcacgcaB 7919
    PKR 966 ACUACCUGUCCUCUG 7804 24432 cagaggaGGCTAGCTACAACGAagguaguB 7920
    PKR 1563 UGGAACAAUGGAUUG 7807 24433 caauccaGGCTAGCTACAACGAuguuccaB 7921
    PKR 2297 CUGGCUCAUCUCUUU 7799 24434 aaagagaGGCTAGCTACAACGAgagccagB 7922
    PKR 2543 UCAAGUAAUCCACCU 7808 24435 agguggaGGCTAGCTACAACGAuacuugaB 7923
    PKR 604 AGGUGAAGGUAGAUC 7809 24436 gaucuacGgaggaaacuc CCUUC aaggacaucguc C GGGuucaccuB 7924
    PKR 903 AACAAUUGGCCGCUA 7810 24437 uagcggcGgaggaaacuc CCUUC aaggacaucguc C GGGaauuguuB 7925
    PKR 966 ACUACCUGUCCUCUG 7804 24438 cagaggaGgaggaaacuc CCUUC aaggacaucguc C GGGagguaguB 7926
    PKR 1186 CCUUCCUGACAUGAA 7811 24439 uucauguGgaggaaacuc CCUUC aaggacaucguc C GGGaggaaggB 7927
    PKR 2292 UUUUCCUGGCUCAUC 7812 24440 gaugagcGgaggaaacuc CCUUC aaggacaucguc C GGGaggaaaaB 7928
    IKKg 427 AGUUCCUCAUGUGCA 7813 24083 uSgScSaScaucUGAuGaggccguuaggccGaaAggaacu B 7929
    IKKg 1067 GCGGAUAUCUACA 7814 24084 uSgSuSaSgacUGAuGaggccguuaggccGaaAuccgc B 7930
    IKKg 1067 GGCGGAUAUCUACAA 7815 24085 uSuSgSuSagacUGAuGaggccguuaggccGaaAuccgcc B 7931
    IKKg 1069 CGGAUAUCUACAAGG 7816 24086 cScSuSuSguacUGAuGaggccguuaggccGaaAuauccg B 7932
    IKKg 1071 AUAUCUACAAGGC 7817 24087 gScScSuSugcUGAuGaggccguuaggccGaaAgauau B 7933
    IKKg 1390 UACAUGUCAUGGAGU 7818 24088 aScSuScScaucUGAuGaggccguuaggccGaaAcaugua B 7934
    IKKg 1402 AGUGCAUUGAGUAGG 7819 24089 cScSuSaScuccUGAuGaggccguuaggccGaaAugcacu B 7935
    IKKg control ACGACUCGGAGCU 7820 24090 aSgScSuScccUAGuGacgccguuaggcgGaaAgucgu B 7936
    IKKg control UCUGAGUCAGGCGAC 7821 24091 gSuScSgSccucUAGuGacgccguuaggcgGaaAcucaga B 7937
    IKKg 195 UGCAGCCCAGUGG 7822 24159 cScSaScSugcUGAuGaggccguuaggccGaalcugca B 7938
    IKKg 196 GCAGCCCAGUGGU 7823 24160 aScScSaScucUGAuGaggccguuaggccGaalgcugc B 7939
    IKKg 303 CCCUCCAGCGCUG 7824 24161 cSaSgScSgccUGAuGaggccguuaggccGaalgaggg B 7940
    IKKg 324 AGAAUCAAGAGCU 7825 24162 aSgScSuScucUGAuGaggccguuaggccGaalauucu B 7941
    IKKg 324 GAGAAUCAAGAGCUC 7826 24163 gSaSgScSucucUGAuGaggccguuaggccGaalauucuc B 7942
    IKKg 556 GAUGGCUGAGGAC 7827 24164 gSuScScSuccUGAuGaggccguuaggccGaalccauc B 7943
    IKKg 556 AGAUGGCUGAGGACA 7828 24165 uSgSuScScuccUGAuGaggccguuaggccGaalccaucu B 7944
    IKKg 568 ACAAGGCCUCUGUGA 7829 24166 uScSaScSagacUGAuGaggccguuaggccGaalccuugu B 7945
    IKKg 571 GGCCUCUGUGAAA 7830 24167 uSuSuScSaccUGAuGaggccguuaggccoaalaggcc B 7946
    IKKg 580 UGAAAGCCCAGGUGA 7831 24168 uScSaScScugcUGAuGaggccguuaggccGaalcuuuca B 7947
    IKKg 749 GUGGACCAGCUGC 7832 24169 gScSaSgScucUGAuGaggccguuaggccGaaluccac B 7948
    lKKg 927 UGCAGCUGGAAGA 7833 24170 uScSuSuScccUGAuGaggccguuaggccGaalcugca B 7949
    lKKg 927 AUGCAGCUGGAAGAU 7834 24171 aSuScSuSucccUGAuGaggccguuaggccGaalcugcau B 7950
    IKKg 1012 GGAGGCCGAGCAG 7835 24172 cSuSgScSuccUGAuGaggccguuaggccGaalccucc B 7951
    IKKg 1012 AGGAGGCCGAGCAGC 7836 24173 gScSuSgScuccUGAuGaggccguuaggccGaalccuccu B 7952
    IKKg 1020 AGCAGCACAAGAU 7837 24174 aSuScSuSugcUGAuGaggccguuaggccGaalcugcu B 7953
    IKKg 1020 GAGCAGCACAAGAUU 7838 24175 aSaSuScSuugcUGAuGaggccguuaggccGaalcugcuc B 7954
    IKKg 1022 GCAGCACAAGAUUGU 7839 24176 aScSaSaSucucUGAuGaggccguuaggccGaalugcugc B 7955
    IKKg 1070 GGAUAUCUACAAGGC 7840 24177 gScScSuSugucUGAuGaggccguuaggccGaalauaucc B 7956
    IKKg 1143 AGGAGCAGCUGGA 7841 24178 uScScSaSgccUGAuGaggccguuaggccGaalcuccu B 7957
    IKKg 1350 AAGUGCCAGUAUCAG 7842 24179 cSuSgSaSuaccUGAuGaggccguuaggccGaalgcacuu B 7958
    IKKg 1391 CAUGUCAUGGAGU 7843 24180 aScSuScScacUGAuGaggccguuaggccGaalacaug B 7959
    IKKg 1391 ACAUGUCAUGGAGUG 7844 24181 cSaScSuSccacUGAuGaggccguuaggccGaalacaugu B 7960
    IKKg Control CACGUCUGCGGAA 7845 24182 uSuScScSgccUAGuGacgccguuaggcgGaalacgug B 7961
    IKKg Control UCGGAACCAGGUCUG 7846 24183 cSaSgSaSccucUAGuGacgccguuaggcgGaaluuccga B 7962
    IKKg 304 CCCUCCAGCGCUGCC 7847 24213 gSgScSaSgcggccgaaagg C gagugaGgu C uuggagggB 7963
    IKKg 306 CUCCAGCGCUGCCUG 7848 24214 cSaSgSgScaggccgaaagg C gagugaGgu C ugcuggagB 7964
    IKKg 309 AGCGCUGCCUGGA 7849 24215 uScScSaSgggccgaaagg C gagugaGgu C uagcgcuB 7965
    IKKg 328 UCAAGAGCUCCGA 7850 24216 uScSgSgSaggccgaaagg C gagugaGgu C uucuugaB 7966
    IKKg 328 AUCAAGAGCUCCGAG 7851 24217 cSuScSgSgaggccgaaagg C gagugaGgu C uucuugauB 7967
    IKKg 572 GCCUCUGUGAAAG 7852 24218 cSuSuSuScagccgaaagg C gagugaGgu C uagaggcB 7968
    IKKg 572 GGCCUCUGUGAAAGC 7853 24219 gScSuSuSucagccgaaagg C gagugaGgu C uagaggccB 7969
    IKKg 705 UGGAGAGUGAGCG 7854 24220 cSgScSuScagccgaaagg C gagugaGgu C uucuccaB 7970
    IKKg 1028 CAAGAUUGUGAUGGA 7855 24221 uScScSaSucagccgaaagg C gagugaGgu C uaaucuugB 7971
    IKKg 1222 GAGGAAGCGGCAU 7856 24222 aSuSgScScggccgaaagg C gagugaGgu C uuuccucB 7972
    IKKg 1222 UGAGGAAGCGGCAUG 7857 24223 cSaSuSgSccggccgaaagg C gagugaGgu C uuuccucaB 7973
    IKKg 1351 AGUGCCAGUAUCAGG 7858 24224 cScSuSgSauagccgaaagg C gagugaGgu C uuggcacuB 7974
    IKKg Control ACUCCGGCGUAGA 7859 24225 uScSuSaScggccgaaagg C u C ugGagugagcggaguB 7975
    IKKg Control GUGACGCGUGUCACA 7860 24226 uSgSuSgSacagccgaaaggCuCugGagugaggcgucacB 7976
    IKKg 438 UGCAAGUUCCAGGAG 7861 24463 cuccuggCUGAUGAggccguuaggccGAAAcuugcaB 7977
    IKKg 1167 AGGGAGUACAGCAAA 7862 24464 uuugcugCUGAUGAggccguuaggccGAAAcucccuB 7978
    IKKg 1273 CCUACCUCUCCUCUC 7863 24465 gagaggaCUGAUGAggccguuaggccGAAAgguaggB 7979
    IKKg 1639 CGCUGCUCUUUUUGU 7864 24466 acaaaaaCUGAUGAggccguuaggccGAAAgcagcgB 7980
    IKKg 1781 GGCAGCUCUUCCUCC 7865 24467 ggaggaaCUGAUGAggccguuaggccGAAAgcugccB 7981
    IKKg 741 AGCGUGCAGGUGGAC 7866 24468 guccaccCUGAUGAggccguuaggccGAAlcacgcuB 7982
    IKKg 1158 CAGCUGCAGAGGGAG 7867 24469 cucccucCUGAUGAggccguuaggccGAAlcagcugB 7983
    IKKg 1272 GCCUACCUCUCCUCU 7868 24470 agaggagCUGAUGAggccguuaggccGAAlguaggcB 7984
    IKKg 1650 UUGUUCCCUUCUGUC 7869 24471 gacagaaCUGAUGAggccguuaggccGAAlgaacaaB 7985
    IKKg 1834 UGCUGCCCUCUUACC 7870 24472 gguaagaCUGAUGAggccguuaggccGAAlgcagcaB 7986
    IKKg 52 CAGAGAAGUGAGGAC 7871 24473 guccucagccgaaagg C gagugaGGu C uuucucugB 7987
    IKKg 124 CAUCGAGGUCCCAUC 7872 24474 gaugggagccgaaagg C gagugaGGu C ucucgaugB 7988
    IKKg 1338 UUCUGCUGUCCCAAG 7873 24475 cuugggagccgaaagg C gagugaGGu C uagcagaaB 7989
    IKKg 1633 CUGACUCGCUGCUCU 7874 24476 agagcaggccgaaagg C gagugaGGu C ugagucagB 7990
    IKKg 1655 CCCUUCUGUCUGCUC 7875 24477 gagcagagccgaaagg C gagugaGGu C uagaagggB 7991
    IKKg 52 CAGAGAAGUGAGGAC 7871 24478 guccucaGGCTAGCTACAACGAuucucugB 7992
    IKKg 216 GCAGCAGAUCAGGAC 7876 24479 guccugaGGCTAGCTACAACGAcugcugcB 7993
    IKKg 538 UGAAGAGAUGCCAGC 7877 24480 gcuggcaGGCTAGCTACAACGAcucuucaB 7994
    IKKg 868 UCCAAGAAUACGACA 7878 24481 ugucguaGGCTAGCTACAACGAucuuggaB 7995
    IKKg 940 AUCUCAAACAGCAGC 7879 24482 gcugcugGGCTAGCTACAACGAuugagauB 7996
    IKKg 52 CAGAGAAGUGAGGAC 7871 24483 guccucaGgaggaaacuc CCUUC aaggacaucgucCGGGuucucugB 7997
    IKKg 215 GGCAGCAGAUCAGGA 7880 24484 uccugauGgaggaaacuc CCUUC aaggacaucgucCGGGugcugccB 7998
    IKKg 817 CGGAGGAGAAGAGGA 7881 24485 uccucuuGgaggaaacuc CCUUC aaggacaucgucCGGGuccuccgB 7999
    IKKg 986 ACAGGAGGUGAUCGA 7882 24486 ucgaucaGgaggaaacuc CCUUC aaggacaucgucCGGGcuccuguB 8000
    IKKg 1826 CCUGGGAGUGCUGCC 7883 24487 ggcagcaGgaggaaacuc CCUUC aaggacaucgucCGGGucccaggB 8001

    A, G, C, U = Ribo

    A, G, C, T (italic) = deoxy

    lower case = 2′-O-methyl

    s = phosphorothioate 3′-internucleotide linkage

    U = 2′-deoxy-2′-C-allyl uridine

    U = 2′-deoxy-2′-Amino uridine

    C = 2′-deoxy-2′-Amino cytidine

    I = Inosine

    B = inverted deoxyabasic derivative

Claims (16)

1. A chemically modified double stranded siRNA molecule that down regulates expression of a protein kinase PKR gene via RNA interference (RNAi), wherein:
a) each strand of said siRNA molecule is independently about 18 to about 28 nucleotides in length; and
b) one strand of said siRNA molecule comprises nucleotide sequence having sufficient complementarity to an RNA of said protein kinase PKR gene for the siRNA molecule to direct cleavage of said RNA via RNA interference.
2. The siRNA molecule of claim 1, wherein each strand of the siRNA molecule comprises about 18 to about 28 nucleotides, and wherein each strand comprises at least about 14 to 24 nucleotides that are complementary to the nucleotides of the other strand.
3. The siRNA molecule of claim 1, wherein said siNA molecule is assembled from two separate oligonucleotide fragments wherein a first fragment comprises the sense strand and a second fragment comprises the antisense strand of said siNA molecule.
4. The siRNA molecule of claim 3, wherein said sense strand is connected to the antisense strand via a linker molecule.
5. The siRNA molecule of claim 4, wherein said linker molecule is a polynucleotide linker.
6. The siRNA molecule of claim 4, wherein said linker molecule is a non-nucleotide linker.
7. The siRNA molecule of claim 1, wherein said siRNA molecule comprises at least one 2′-sugar modification.
8. The siRNA molecule of claim 1, wherein said siRNA molecule comprises at least one nucleic acid base modification.
9. The siRNA molecule of claim 1, wherein said siRNA molecule comprises at least one phosphate backbone modification.
10. The siRNA molecule of claim 7, wherein said 2′-sugar modification is a 2′-deoxy-2′-fluoro modification.
11. The siRNA molecule of claim 7, wherein said 2′-sugar modification is a 2′-O-methyl modification.
12. The siRNA molecule of claim 7, wherein said 2′-sugar modification is a 2′-deoxy modification.
13. The siRNA molecule of claim 3, wherein said second fragment comprises a terminal cap moiety at a 5′-end, a 3′-end, or both of the 5′ and 3′ ends of said second strand.
14. The siRNA molecule of claim 13, wherein said terminal cap moiety is an inverted deoxy abasic moiety.
15. The siRNA molecule of claim 3, wherein said first fragment comprises a phosphorothioate internucleotide linkage at the 3′ end of said first strand.
16. A composition comprising the siRNA molecule of claim 1 in a pharmaceutically acceptable carrier or diluent.
US11/255,139 2001-04-05 2005-10-20 Enzymatic nucleic acid treatment of diseases or conditions related to levels of IKK-gamma and PKR Abandoned US20060154271A1 (en)

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US09/827,395 US20030113891A1 (en) 2000-02-11 2001-04-05 Method and reagent for the inhibition of NOGO and NOGO receptor genes
US29441201P 2001-05-29 2001-05-29
US31531501P 2001-08-28 2001-08-28
PCT/US2002/010512 WO2002081628A2 (en) 2001-04-05 2002-04-03 Modulation of gene expression associated with inflammation proliferation and neurite outgrowth, using nucleic acid based technologies
US10/156,306 US7022828B2 (en) 2001-04-05 2002-05-28 siRNA treatment of diseases or conditions related to levels of IKK-gamma
US11/255,139 US20060154271A1 (en) 2001-04-05 2005-10-20 Enzymatic nucleic acid treatment of diseases or conditions related to levels of IKK-gamma and PKR

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US10/156,306 Expired - Fee Related US7022828B2 (en) 2001-04-05 2002-05-28 siRNA treatment of diseases or conditions related to levels of IKK-gamma
US10/206,693 Abandoned US20050261212A1 (en) 2000-02-11 2002-07-26 RNA interference mediated inhibition of NOGO and NOGO receptor gene expression using short interfering RNA
US10/224,005 Abandoned US20030143732A1 (en) 2001-04-05 2002-08-20 RNA interference mediated inhibition of adenosine A1 receptor (ADORA1) gene expression using short interfering RNA
US10/226,992 Abandoned US20030148507A1 (en) 2001-04-05 2002-08-23 RNA interference mediated inhibition of prostaglandin D2 receptor (PTGDR) and prostaglandin D2 synthetase (PTGDS) gene expression using short interfering RNA
US10/230,006 Abandoned US20030191077A1 (en) 2001-04-05 2002-08-28 Method and reagent for the treatment of asthma and allergic conditions
US11/255,139 Abandoned US20060154271A1 (en) 2001-04-05 2005-10-20 Enzymatic nucleic acid treatment of diseases or conditions related to levels of IKK-gamma and PKR

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US10/156,306 Expired - Fee Related US7022828B2 (en) 2001-04-05 2002-05-28 siRNA treatment of diseases or conditions related to levels of IKK-gamma
US10/206,693 Abandoned US20050261212A1 (en) 2000-02-11 2002-07-26 RNA interference mediated inhibition of NOGO and NOGO receptor gene expression using short interfering RNA
US10/224,005 Abandoned US20030143732A1 (en) 2001-04-05 2002-08-20 RNA interference mediated inhibition of adenosine A1 receptor (ADORA1) gene expression using short interfering RNA
US10/226,992 Abandoned US20030148507A1 (en) 2001-04-05 2002-08-23 RNA interference mediated inhibition of prostaglandin D2 receptor (PTGDR) and prostaglandin D2 synthetase (PTGDS) gene expression using short interfering RNA
US10/230,006 Abandoned US20030191077A1 (en) 2001-04-05 2002-08-28 Method and reagent for the treatment of asthma and allergic conditions

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