Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse

Abstract

Single-nucleotide polymorphisms (SNPs) have been the focus of much attention in human genetics because they are extremely abundant and well-suited for automated large-scale genotyping. Human SNPs, however, are less informative than other types of genetic markers (such as simple-sequence length polymorphisms or microsatellites) and thus more loci are required for mapping traits. SNPs offer similar advantages for experimental genetic organisms such as the mouse, but they entail no loss of informativeness because bi-allelic markers are fully informative in analysing crosses between inbred strains. Here we report a large-scale analysis of SNPs in the mouse genome. We characterized the rate of nucleotide polymorphism in eight mouse strains and identified a collection of 2,848 SNPs located in 1,755 sequence-tagged sites (STSs) using high-density oligonucleotide arrays. Three-quarters of these SNPs have been mapped on the mouse genome, providing a first-generation SNP map of the mouse. We have also developed a multiplex genotyping procedure by which a genome scan can be performed with only six genotyping reactions per animal.

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Figure 1: A SNP in A/J and C57BL/6J strains detected by hybridization to a high-density oligonucleotide array.
Figure 2: Distribution of SNPs between strain combinations.
Figure 3: Principle of gel-based length multiplex single base extension (LM–SBE).

References

  1. 1

    Dietrich, W.F. et al. A comprehensive genetic map of the mouse genome. Nature 380, 149–152 ( 1996).

    CAS  Article  Google Scholar 

  2. 2

    Nusbaum, C. et al. A YAC-based physical map of the mouse genome. Nature Genet. 22, 388–393 (1999).

    CAS  Article  Google Scholar 

  3. 3

    Ferris, K.D., Sage, R.D., Prager, E.M., Titte, U. & Wilson, A.C. Mitochondrial DNA evolution in mice. Genetics 105, 681– 721 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Wang, D.G. et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280, 1077–1082 (1998).

    CAS  Article  Google Scholar 

  5. 5

    Cargill, M. et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature Genet. 22, 231–238 (1999).

    CAS  Article  Google Scholar 

  6. 6

    Atchley, W.R. & Fitch, W. Genetic affinities of inbred mouse strains of uncertain origin. Mol. Biol. Evol. 10, 1150–1169 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Beck, J.A. et al. Genealogies of mouse inbred strains. Nature Genet. 24, 23–25 ( 2000).

    CAS  Article  Google Scholar 

  8. 8

    Van Etten, W.J. et al. Radiation hybrid map of the mouse genome. Nature Genet. 22, 384–387 ( 1999).

    CAS  Article  Google Scholar 

  9. 9

    Sage R.D. in The Mouse in Biomedical Research (eds Foster, H.L., Small, J.D. & Fox, J.G.) 40–90 (Academic, New York, 1981).

    Google Scholar 

  10. 10

    Syvanen, A.C. From gels to chips: “minisequencing” primer extension for analysis of point mutations and single nucleotide polymoprhisms. Hum. Mutat. 13, 1–10 (1999 ).

    CAS  Article  Google Scholar 

  11. 11

    Chee, M. et al. Accessing genetic information with high-density DNA arrays. Science 274, 610–614 ( 1996).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank H. Nguyen and R. Steen for assistance in RH mapping; the HTS group at Affymetrix Inc. for assistance with chip hybridizations; and J. Singer for providing the backcross DNAs. This research was supported by a research contract from Bristol-Myers Squibb, Millennium Pharmaceuticals Inc. and Affymetrix (E.S.L. and T.J.H.) and the National Institute of Health (HG01806). K.L. is the recipient of a scholarship from the Swedish Institute (4478/1998). J.N.H. is the recipient of a Howard Hughes Medical Institute Postdoctoral Fellowship for Physicians. T.J.H. is a recipient of a Clinician-Scientist award from the Medical Research Council of Canada.

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Correspondence to Kerstin Lindblad-Toh or Eric S. Lander.

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Lindblad-Toh, K., Winchester, E., Daly, M. et al. Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse. Nat Genet 24, 381–386 (2000). https://doi.org/10.1038/74215

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