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Precis on forward genetics in mice

Mutations have been the driving force behind some of the most important discoveries in immunology, and the growing speed with which they can be found has impelled the use of random mutagenesis to create new immunological phenotypes in mice. Here we describe how phenotypes are created, detected and ascribed to genetic change.

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Figure 1: Inbreeding protocols for generating homozygous mutations.
Figure 2: Steps in positional cloning of a recessive phenotype.
Figure 3: Integrated system for mutation identification.

References

  1. Robin, N.H. & Nadeau, J.H. Disorganization in mice and humans. Am. J. Med. Genet. 101, 334–338 (2001).

    Article  CAS  Google Scholar 

  2. Lehoczky, J.A. et al. Description and genetic mapping of Polypodia: an X-linked dominant mouse mutant with ectopic caudal limbs and other malformations. Mamm. Genome 17, 903–913 (2006).

    Article  CAS  Google Scholar 

  3. Hoebe, K. et al. Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nat. Immunol. 4, 1223–1229 (2003).

    Article  CAS  Google Scholar 

  4. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    Article  CAS  Google Scholar 

  5. Brunkow, M.E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).

    Article  CAS  Google Scholar 

  6. Royer-Pokora, B. et al. Cloning the gene for an inherited human disorder–chronic granulomatous disease–on the basis of its chromosomal location. Nature 322, 32–38 (1986).

    Article  CAS  Google Scholar 

  7. Hoebe, K. et al. CD36 is a sensor of diacylglycerides. Nature 433, 523–527 (2005).

    Article  CAS  Google Scholar 

  8. Tabeta, K. et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat. Immunol. 7, 156–164 (2006).

    Article  CAS  Google Scholar 

  9. Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J.M. & Hoffmann, J.A. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983 (1996).

    Article  CAS  Google Scholar 

  10. Staskawicz, B.J., Ausubel, F.M., Baker, B.J., Ellis, J.G. & Jones, J.D. Molecular genetics of plant disease resistance. Science 268, 661–667 (1995).

    Article  CAS  Google Scholar 

  11. Beutler, B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430, 257–263 (2004).

    Article  CAS  Google Scholar 

  12. Hoffmann, J.A. The immune response of Drosophila. Nature 426, 33–38 (2003).

    Article  CAS  Google Scholar 

  13. Waterston, R.H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).

    Article  CAS  Google Scholar 

  14. Vidal, S.M., Malo, D., Vogan, K., Skamene, E. & Gros, P. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell 73, 469–485 (1993).

    Article  CAS  Google Scholar 

  15. Churchill, G.A. et al. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat. Genet. 36, 1133–1137 (2004).

    Article  CAS  Google Scholar 

  16. Concepcion, D., Seburn, K.L., Wen, G., Frankel, W.N. & Hamilton, B.A. Mutation rate and predicted phenotypic target sizes in ethylnitrosourea-treated mice. Genetics 168, 953–959 (2004).

    Article  CAS  Google Scholar 

  17. Rinchik, E.M. & Carpenter, D.A. N-ethyl-N-nitrosourea mutagenesis of a 6- to 11-cM subregion of the Fah-Hbb interval of mouse chromosome 7: completed testing of 4557 gametes and deletion mapping and complementation analysis of 31 mutations. Genetics 152, 373–383 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kile, B.T. et al. Functional genetic analysis of mouse chromosome 11. Nature 425, 81–86 (2003).

    Article  CAS  Google Scholar 

  19. Crozat, K. et al. Analysis of the MCMV resistome by ENU mutagenesis. Mamm. Genome 17, 398–406 (2006).

    Article  CAS  Google Scholar 

  20. Ding, S. et al. Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice. Cell 122, 473–483 (2005).

    Article  CAS  Google Scholar 

  21. Horie, K. et al. Characterization of Sleeping Beauty transposition and its application to genetic screening in mice. Mol. Cell. Biol. 23, 9189–9207 (2003).

    Article  CAS  Google Scholar 

  22. Luo, G., Ivics, Z., Izsvak, Z. & Bradley, A. Chromosomal transposition of a Tc1/mariner-like element in mouse embryonic stem cells. Proc. Natl. Acad. Sci. USA 95, 10769–10773 (1998).

    Article  CAS  Google Scholar 

  23. Crozat, K. et al. Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d:a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. J. Exp. Med. 204, 853–863 (2007).

    Article  CAS  Google Scholar 

  24. Keays, D.A., Clark, T.G., Campbell, T.G., Broxholme, J. & Valdar, W. Estimating the number of coding mutations in genotypic and phenotypic driven N-ethyl-N-nitrosourea (ENU) screens: revisited. Mamm. Genome 18, 123–124 (2007).

    Article  Google Scholar 

  25. Keays, D.A., Clark, T.G. & Flint, J. Estimating the number of coding mutations in genotypic- and phenotypic-driven N-ethyl-N-nitrosourea (ENU) screens. Mamm. Genome 17, 230–238 (2006).

    Article  CAS  Google Scholar 

  26. Auwerx, J. et al. The European dimension for the mouse genome mutagenesis program. Nat. Genet. 36, 925–927 (2004).

    Article  CAS  Google Scholar 

  27. Austin, C.P. et al. The knockout mouse project. Nat. Genet. 36, 921–924 (2004).

    Article  CAS  Google Scholar 

  28. Blewitt, M.E. et al. An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. Proc. Natl. Acad. Sci. USA 102, 7629–7634 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

Supported by the National Institutes of Health (P01 AI070167).

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Beutler, B., Du, X. & Xia, Y. Precis on forward genetics in mice. Nat Immunol 8, 659–664 (2007). https://doi.org/10.1038/ni0707-659

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