CA2268363A1 - An indexed library of cells containing genomic modifications and methods of making and utilizing the same - Google Patents

An indexed library of cells containing genomic modifications and methods of making and utilizing the same

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Publication number
CA2268363A1
CA2268363A1 CA002268363A CA2268363A CA2268363A1 CA 2268363 A1 CA2268363 A1 CA 2268363A1 CA 002268363 A CA002268363 A CA 002268363A CA 2268363 A CA2268363 A CA 2268363A CA 2268363 A1 CA2268363 A1 CA 2268363A1
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Canada
Prior art keywords
vector
foreign
cells
library
operatively positioned
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CA002268363A
Other languages
French (fr)
Other versions
CA2268363C (en
Inventor
Arthur Sands
Glenn Friedrich
Brian Zambrowicz
Allan Bradley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lexicon Pharmaceuticals Inc
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Individual
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Filing date
Publication date
Priority claimed from US08/726,867 external-priority patent/US6136566A/en
Priority claimed from US08/907,598 external-priority patent/US6139833A/en
Application filed by Individual filed Critical Individual
Publication of CA2268363A1 publication Critical patent/CA2268363A1/en
Application granted granted Critical
Publication of CA2268363C publication Critical patent/CA2268363C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1082—Preparation or screening gene libraries by chromosomal integration of polynucleotide sequences, HR-, site-specific-recombination, transposons, viral vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/102—Mutagenizing nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1051—Gene trapping, e.g. exon-, intron-, IRES-, signal sequence-trap cloning, trap vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/10041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/10043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2800/00—Nucleic acids vectors
    • C12N2800/60—Vectors containing traps for, e.g. exons, promoters
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2840/00—Vectors comprising a special translation-regulating system
    • C12N2840/20—Vectors comprising a special translation-regulating system translation of more than one cistron
    • C12N2840/203—Vectors comprising a special translation-regulating system translation of more than one cistron having an IRES
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2840/00—Vectors comprising a special translation-regulating system
    • C12N2840/44—Vectors comprising a special translation-regulating system being a specific part of the splice mechanism, e.g. donor, acceptor

Abstract

Methods and vectors (both DNA and retroviral) are provided for the construction of a Library of mutated cells. The Library will preferably contain mutations in essentially all genes present in the genome of the cells. The nature of the Library and the vectors allow for methods of screening for mutations in specific genes, and for gathering nucleotide sequence data from each mutated gene to provide a database of tagged gene sequences. Such a database provides a means to access the individual mutant cell clones contained in the Library. The invention includes the described Library, methods of making the same, and vectors used to construct the Library. Methods are also provided for accessing individual parts of the Library either by sequence or by pooling and screening. The invention also provides for the generation of non-human transgenic animals which are mutant for specific genes as isolated and generated from the cells of the Library.

Claims (28)

1. A library of cultured eucaryotic cells made by a process comprising the steps of:
a) treating a first group of cells to stably integrate a first vector that mediates the splicing of a foreign exon internal to a cellular transcript;
b) treating a second group of cells to stably integrate a second vector that mediates the splicing of a foreign exon 5' to an exon of a cellular transcript; and c) selecting for transduced cells that express the products encoded by the foreign exons.
2. A library according to claim 1 wherein said treating is transfection.
3. A library according to claim 1 wherein said treating is by infection.
4. A library according to claim 1 wherein said treating is by retrotransposition.
5. A library according to any one of claims 1 through 4 wherein said cells are animal cells.
6. A library according to claim 5 wherein said animal is mammalian.
7. A library according to claim 6 wherein said cells are rodent cells.
8. The use of a mutated cell from a library according to claim 6 to generate a non-human transgenic animal.
9. A vector for replacing the 3' end of an animal cell transcript with a foreign exon, comprising:
a) a selectable marker;

b) a splice acceptor site operatively positioned 5' to the initiation codon of said selectable marker;
c) a polyadenylation site operatively positioned 3' to said selectable marker;
d) said vector not comprising a promoter element operatively positioned 5' of the coding region of said selectable marker; and e) said vector not comprising a splice donor sequence operatively positioned between the 3' end of the coding region of said selectable marker and said polyadenylation site.
10. A vector for inserting foreign mutagenic polynucleotide sequence internal to animal cell transcripts, comprising:
a) a foreign exon;
b) a splice acceptor sequence operatively positioned 5' to the foreign exon;
c) a splice donor site operatively positioned 3' to said foreign exon;
d) a sequence comprising a nested set of stop codons in each of the three reading frames located between the 3' end of said foreign exon and said splice donor site;
e) said vector not comprising a polyadenylation site operatively positioned 3' to said foreign exon; and f) said vector not comprising a promoter element operatively positioned 5' to the coding region of said foreign exon.
11. A vector for attaching a foreign exon upstream from the 3' end of an animal cell transcript, comprising:
a) a selectable marker;
b) a promoter element operatively positioned 5' to said selectable marker;
c) a splice donor site operatively positioned 3' to said selectable marker; and d) said vector not comprising a transcription terminator or polyadenylation site operatively positioned relative to the coding region of said selectable marker; and e) said vector not comprising a splice acceptor site operatively positioned between said promoter element and the initiation codon of said selectable marker.
12. A vector according to claim 11 wherein said vector additionally comprises a foreign mutagenic polynucleotide sequence located upstream from said promoter.
13. A vector according to claim 12 wherein said vector additionally comprises a splice acceptor operatively positioned upstream from said foreign mutagenic polynucleotide sequence.
14. A vector according to claim 13 wherein said foreign mutagenic polynucleotide sequence comprises a polyadenylation site.
15. A vector according to claim 14, wherein said foreign mutagenic polynucleotide sequence additionally comprises stop codons in all three reading frames.
16. A vector according to claim 12 in which a first recombinase recognition sequence is present upstream from said promoter and a second recombinase recognition sequence is present downstream from said promoter.
17. A vector according to any one of claims 9, 10, or 11 wherein said vector is a viral vector.
18. A vector according to claim 17 wherein said viral vector is a retroviral vector.
19. The use of a vector according to claim 9 to produce a library of mutated animal cells.
20. The use of a vector according to claim 10 to produce mutated animal cells.
21. The use of a vector according to claim 11 to produce mutated animal cells.
22. The use of a vector according to claim 11 to effect homologous recombination in an animal cell.
23. A stably transduced animal cell that incorporates a vector according to claim 16.
24. A method of deleting a region of vector DNA from a cell according to claim 23, comprising:
a) providing a recombinase activity to the cell; and b) selecting for cells that lack the desired region of vector DNA.
25. A method of adding a region of DNA to a cell according to claim 23, comprising:
a) introducing the DNA to be added into the cell;
a) providing a recombinase activity to the cell; and b) selecting for cells that incorporate the added DNA.
26. A method of effecting the inducible expression of a desired gene, comprising:
a) providing a cell according to claim 23 with a recombinase gene that is expressed by an inducible promoter;
and b) inducing said inducible promoter.
27. A method of gene discovery comprising:
a) adding a foreign polynucleotide to a population of target cells such that the foreign polynucleotide is inserted throughout the genomes of the target cells; and b) activating control elements encoded by the foreign polynucleotides that activate or repress the expression of target cell genes that flank the integrated foreign polynucleotides, and identifying the regions of the target cell genome into which the foreign polynucleotides have integrated.
28. A library of cultured animal cells that stably integrate vectors according to claims 10 or 11.
CA2268363A 1996-10-04 1997-10-03 An indexed library of cells containing genomic modifications and methods of making and utilizing the same Expired - Lifetime CA2268363C (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US08/726,867 US6136566A (en) 1996-10-04 1996-10-04 Indexed library of cells containing genomic modifications and methods of making and utilizing the same
US08/726,867 1996-10-04
US72896396A 1996-10-11 1996-10-11
US08/728,963 1996-10-11
US08/907,598 US6139833A (en) 1997-08-08 1997-08-08 Targeted gene discovery
PCT/US1997/017791 WO1998014614A1 (en) 1996-10-04 1997-10-03 An indexed library of cells containing genomic modifications and methods of making and utilizing the same

Publications (2)

Publication Number Publication Date
CA2268363A1 true CA2268363A1 (en) 1998-04-09
CA2268363C CA2268363C (en) 2012-07-10

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CA2268363A Expired - Lifetime CA2268363C (en) 1996-10-04 1997-10-03 An indexed library of cells containing genomic modifications and methods of making and utilizing the same

Country Status (9)

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US (2) US6207371B1 (en)
EP (1) EP0994962B1 (en)
JP (1) JP2002503083A (en)
AT (1) ATE419381T1 (en)
AU (1) AU744030B2 (en)
CA (1) CA2268363C (en)
DE (1) DE69739192D1 (en)
DK (1) DK0994962T3 (en)
WO (1) WO1998014614A1 (en)

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EP0994962B1 (en) 2008-12-31
AU4805697A (en) 1998-04-24
US20090149336A1 (en) 2009-06-11
AU744030B2 (en) 2002-02-14
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