Journal home
Advance online publication
Current issue
Archive
Press releases
Free Association (blog)
Supplements
Focuses
Guide to authors
Online submissionOnline submission
For referees
Free online issue
Contact the journal
Subscribe
Advertising
work@npg
Reprints and permissions
About this site
For librarians
 
NPG Resources
Nature
Nature Biotechnology
Nature Cell Biology
Nature Medicine
Nature Methods
Nature Reviews Cancer
Nature Reviews Genetics
Nature Reviews Molecular Cell Biology
news@nature.com
Nature Conferences
RNAi Gateway
NPG Subject areas
Biotechnology
Cancer
Chemistry
Clinical Medicine
Dentistry
Development
Drug Discovery
Earth Sciences
Evolution & Ecology
Genetics
Immunology
Materials Science
Medical Research
Microbiology
Molecular Cell Biology
Neuroscience
Pharmacology
Physics
Browse all publications
New Technology
Nature Genetics  16, 19 - 27 (1997)
doi:10.1038/ng0597-19

Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice

Elizabeth M. Simpson1, Carol C. Linder1, Evelyn E. Sargent1, Muriel T. Davisson1, Larry E. Mobraaten1 & John J. Sharp1

1The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA. e-mail: ccl@jax.org.

Targeted mutagenesis in mice, a powerful tool for the analysis of gene function and human disease, makes extensive use of 129 mouse substrains. Although all are named 129, we document that outcrossing of these substrains, both deliberate and accidental, has lead to extensive genetic variability among substrains and embryonic stem cells derived from them. This clearer understanding of 129 substrain variability allows consideration of its negative impact on targeting technology, including: homologous recombination frequencies, preparation of inbred animals, and availability of appropriate controls. Based on these considerations we suggest a number of recommendations for future experimental design.

REFERENCES
  1. Deng, C. & Capecchi, M.R. Reexamination of Gene Targeting Frequency as a Function of the Extent of Homology between the Targeting Vector and the Target Locus. Mol. Cell.Biol. 12, 3365−3371 (1992). | ChemPort |
  2. Festing, M.F.W. Inbred strains of mice. Mouse Genome 94, 523−677 (1996).
  3. Stevens, L.C. A new inbred subline of mice (129/terSv) with a high incidence of spontaneous congenital testicular teratomas. J. Natl. CancerInst. 50, 235−242 (1973). | ChemPort |
  4. Stevens, L.C. Spontaneous testicular teratomas in an inbred strain of mice. Proc. Natl. Acad. Sci. USA 40, 1080−1087 (1954).
  5. Stevens, L.C. & Hummel, K.P.A description of spontaneous congenital testicular teratomas in strain 129 mice. J. Natl. Cancer Inst. 18, 719−747 (1957). | PubMed  | ChemPort |
  6. Kuehn, M.R., Bradley, A., Robertson, E.J. & Evans, M.J. A potential animal model for Lesch-Nyhan syndrome through introduction of HPRT mutations into mice. Nature 326, 295−301(1987). | PubMed  | ChemPort |
  7. Asada, Y Varnum, D.S., Frankel, W.N. & Nadeau, J.H. A potential animal modelfor Lesch-Nyhan syndrome through introduction of HPRT mutations into mice. Nature 363−368 (1994). | ChemPort |
  8. Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Monk, M. HPRT-deficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured. Nature 326, 292−295 (1987). | Article | PubMed  | ISI | ChemPort |
  9. Magin, T.M., McWhir, J. & Melton, D.W.A new mouse embryonic stem cell line with good germ line contribution and gene targeting frequency. Nucl. Acids Res. 20, 3795−3796 (1992). | PubMed  | ISI | ChemPort |
  10. Knudson, C.M., Tung, K.S., Tourtellotte, W.G., Brown, G.A. & Korsmeyer, S.J. Baxdeficient mice with lymphoid hyperplasia and male germ cell death. Science 270, 96−99 (1995). | PubMed  | ISI | ChemPort |
  11. Shipley, J.M., Wesselschmidt, R.L., Kobayashi, D.K., Shapiro, S.D Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc. Natl. Acad. Sci. USA 93, 3942−3946 (1996). | Article | PubMed  | ChemPort |
  12. Doetschman, T.C., Eistetter, H., Katz, M., Schmidt, W. & Kemler, R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood island and myocardium. J. Embryol. Exp. Morph. 87, 27−45 (1985). | PubMed  | ISI | ChemPort |
  13. Robertson, E., Bradley, A., Kuehn, M. & Evans, M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector. Nature 323, 445−448 (1986). | PubMed  | ISI | ChemPort |
  14. McMahon, A.P. & Bradley, A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell. 62, 1073−1085 (1990). | Article | PubMed  | ISI | ChemPort |
  15. Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 64, 693−702 (1991). | PubMed  | ISI | ChemPort |
  16. Li, E., Bestor, T. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 69, 915−926 (1992). | Article | PubMed  | ISI | ChemPort |
  17. Nagy, A., Rossant, J., Nagy, R., Abramownewerly, W. & Roder, J.C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl. Acad. Sci. USA 90, 8424−8428 (1993). | PubMed  | ChemPort |
  18. Schwartzberg, P.L., Goff, S.P. & Robertson, E.J. Germ-line transmission of a c-abl mutation produced by targeted gene disruption of ES cells. Science. 246, 799−803 (1989). | PubMed  | ISI | ChemPort |
  19. Bailey, D.W. Four approaches to estimating the number of histocompatibility loci in mice. Transplant Proc.. 2, 32−38 (1970). | PubMed  | ISI | ChemPort |
  20. Bailey, D.W. How pure are inbred strains of mice? Immun. Today. 3, 210−214 (1982). | ISI |
  21. Stevens, L.C., Mouse News Letter (companion issue Inbred Strains of Mice)61, 38−39 (1979).
  22. Bultman, S.J. et al. Molecular analysis of reverse mutations from nonagouti (a) to black-and-tan (at) and white-bellied agouti (AW) reveals alternative forms of agouti transcripts. Genes Dev. 8, 481−490 (1994). | PubMed  | ISI | ChemPort |
  23. Stevens, L.C., Mouse News Letter (Companion Issue Inbred Strains of Mice). 57, 35−36 (1977).
  24. Dietrich, W.F. et al. A comprehensive genetic map of the mouse genome. Nature 380, 149−152 (1996). | Article | PubMed  | ISI | ChemPort |
  25. Silver, L.M. Mouse genetics: concepts and applications 1−362 (Oxford University Press, New York 1995).
  26. Mouse Genome Database. Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, Maine. World Wide Web (URL: http://www. informatics.jax.org/) (Oct. 1996).
  27. Wehner, J.M. & Silva, A. Importance of strain differences in evaluations of learning and memory processes in null mutants. Ment. Retard. Dev. Disabil. 4, 1−6 (1996).
  28. Sadlack, B. et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25, 3053−3059 (1995). | PubMed  | ISI | ChemPort |
  29. Sibilia, M. & Wagner, E.F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234−238 (1995). | PubMed  | ISI | ChemPort |
  30. Threadgill, D.W. et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269, 230−234 (1995). | PubMed  | ISI | ChemPort |
  31. Skarnes, W.C., Auerbach, B.A. & Joyner, A.L. A gene trap approach in mouse embryonic stem cells: the lacZ reported is activated by splicing, reflects endogenous gene expression, and is mutagenic in mice. Genes Dev.. 6, 903−918 (1992). | PubMed  | ISI | ChemPort |
  32. Zuberi, A.R., Christianson, G.J. & Roopenian, D.C. Allele sizes at Chromosome 2 Mit loci from 129/J, 129/Ola, C57BL/10J, and the autoimmune-prone mouse strains BXSB/MpJ-Vaa, MRL/MpJ, SJL/J and NZB/B1NJ. Mouse Genome 94, 152−154 (1996).
  33. Matouk, C., Gosselin, D., Malo, D., Skamene, E. & Radzioch, D. PCR-analyzed microsatellites for the inbred mouse strain 129/Sv, the strain most commonly used in gene knockout technology. Mamm. Genome 7, 603−605 (1996). | Article | PubMed  | ISI | ChemPort |
  34. Dietrich, W.F.A complete genetic map of the mouse and its application to the study of mouse models of human disease 1−219 (Massachusetts Institute of Technology, Cambridge, 1993).
  35. Kontgen, F., Suss, G., Stewart, C., Steinmetz, M. & Bluethmann, H. Targeted Disruption of the MHC class-ll Aa Gene in C57BL/6 Mice. Int. Immunol. 5, 957−964 (1993). | PubMed  | ISI | ChemPort |
  36. Ledermann, B. & Burki, K. Establishment of a germ-line competent C57BL/6 embryonic stem cell line.. Exp. Cell Res. 197, 254−258 (1991). | PubMed  | ISI | ChemPort |
  37. Kawase, E. et al. Strain difference in establishment of mouse embryonic stem (ES) cell lines. Int. J. Dev. Biol. 38, 385−90 (1994). | PubMed  | ISI | ChemPort |
  38. McWhir, J. et al. Selective ablation of differentiated cells permits cell lines from murine embryos with a non-permissive genetic background. Nature Genet. 14, 223−226 (1996). | Article | PubMed  | ISI | ChemPort |
  39. Esaki, K & Takeshi, T ICLAS Manual for genetic monitoring of inbred mice 1-187 (Univeristy of Tokyo Press, Tokyo, 1984).
  40. Sagai, T & Moriwaki, K A simplified micro-method for cytotoxicity testing using a flat-type titration plate for the detection of H-2 antigens. Microbiol. Immunol. 25, 1327−1234 (1981).
  41. Bailey, D.W. & Usama, B.A rapid method of grafting skin on tails of mice. plast. Reconstr. Surg. Transplant.Bull. 25, 424−425 (1960).
  42. Silvers, W.K. The coat colors of mice 1−379 (Springer-Verlag, New York, 1979).
 Top
 Top
Abstract
Previous | Next
Table of contents
Download PDFDownload PDF
Send to a friendSend to a friend
Save this linkSave this link

natureevents

References
Export citation
Export references
natureproducts

Search buyers guide:

 
ADVERTISEMENT
 
Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
Journal home | Advance online publication | Current issue | Archive | Press releases | Supplements | Focuses | For authors | Online submission | Permissions | For referees | Free online issue | About the journal | Contact the journal | Subscribe | Advertising | work@npg | naturereprints | About this site | For librarians
Nature Publishing Group, publisher of Nature, and other science journals and reference works©1997 Nature Publishing Group | Privacy policy