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A sequence-based variation map of 8.27 million SNPs in inbred mouse strains

Naturevolume 448, pages1050–1053 (2007)Cite this article

Abstract

A dense map of genetic variation in the laboratory mouse genome will provide insights into the evolutionary history of the species1 and lead to an improved understanding of the relationship between inter-strain genotypic and phenotypic differences. Here we resequence the genomes of four wild-derived and eleven classical strains. We identify 8.27 million high-quality single nucleotide polymorphisms (SNPs) densely distributed across the genome, and determine the locations of the high (divergent subspecies ancestry) and low (common subspecies ancestry) SNP-rate intervals2,3,4,5,6 for every pairwise combination of classical strains. Using these data, we generate a genome-wide haplotype map containing 40,898 segments, each with an average of three distinct ancestral haplotypes. For the haplotypes in the classical strains that are unequivocally assigned ancestry, the genetic contributions of theMus musculus subspecies—M. m. domesticus, M. m. musculus, M. m. castaneus and the hybridM. m. molossinus—are 68%, 6%, 3% and 10%, respectively; the remaining 13% of haplotypes are of unknown ancestral origin. The considerable regional redundancy of the SNP data will facilitate imputation of the majority of these genotypes in less-densely typed classical inbred strains to provide a complete view of variation in additional strains.

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Figure 1:Origin of modern classical strains.
Figure 2:Ancestral haplotype map for an 18-Mb region on chromosome 4.

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Acknowledgements

Work was supported by funding from the NIEHS. H.M.K. and E.E. are partially supported by the NSF. H.M.K. is partially supported by a Samsung Scholarship. E.E. is partially supported by the NIH. At Perlegen Sciences, we thank A. Kloek for assistance with manuscript preparation; B. Nguyen, X. Chen, P. Chu, R. Patel, P.-E. Jiao, R. Irikat and J. Kwon for assistance with DNA sample preparation and hybridization of the high-density oligonucleotide arrays; R, Vergara for primer handling; H. Huang and W. Barrett for designing the high-density arrays; T. Genschoreck and J. Sheehan for data quality control; and S. Osborn for assistance with website development and data delivery. At NIEHS, we thank D. A. Schwartz, K. Olden, S. Wilson, L. Birnbaumer, J. Bucher, W. T. Schrader and D. M. Klotz for constructive scientific discussions, and J. A. Lewis and T. Hardee for administrative support. At The Jackson Laboratory, we thank S. Deveau and JAX DNA Resources for DNA sample preparation.

Author Contributions L.L.S., J.M., C.L.P. and K.A.F. supervised the experiments. K.A.F., D.R.C., M.J.D., F.M.J., E.J.B. and M.A.B designed the study. H.M.K., E.E, C.M.W., D.A.H., G.B.N., R.V.G. and M.M.M. performed data analysis. K.A.F., with help from E.J.B., D.A.H., E.E. and C.M.W., wrote the manuscript.

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Authors and Affiliations

  1. Perlegen Sciences, 2021 Stierlin Court, Mountain View, California 94043, USA,

    Kelly A. Frazer, David A. Hinds, Erica J. Beilharz, Robert V. Gupta, Julie Montgomery, Matt M. Morenzoni, Geoffrey B. Nilsen, Charit L. Pethiyagoda, Laura L. Stuve & David R. Cox

  2. Department of Computer Science and Department of Human Genetics, University of California, Los Angeles, Los Angeles, California 90095, USA,

    Eleazar Eskin

  3. Department of Computer Science and Engineering, University of California, San Diego, La Jolla, California 92093, USA,

    Hyun Min Kang

  4. The Jackson Laboratory, Bar Harbor, Maine 04609, USA,

    Molly A. Bogue

  5. Toxicology Operations Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA,

    Frank M. Johnson

  6. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,

    Mark J. Daly & Claire M. Wade

  7. Center for Human Genetic Research, Massachussets General Hospital, 185 Cambridge St, Boston, Massachusetts 02114, USA,

    Mark J. Daly & Claire M. Wade

Authors
  1. Kelly A. Frazer

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  2. Eleazar Eskin

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  3. Hyun Min Kang

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  4. Molly A. Bogue

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  5. David A. Hinds

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  8. Julie Montgomery

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  9. Matt M. Morenzoni

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  10. Geoffrey B. Nilsen

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  11. Charit L. Pethiyagoda

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  12. Laura L. Stuve

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  13. Frank M. Johnson

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  14. Mark J. Daly

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  15. Claire M. Wade

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  16. David R. Cox

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Corresponding author

Correspondence toKelly A. Frazer.

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Competing interests

D.A.H., R.V.G., J.M., M.M.M., G.B.N., C.L.P., L.L.S. and D.R.C. are employed by Perlegen Sciences. K.A.F. is a former employee of Perlegen Sciences

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-7, Supplementary Tables S2-S16 and S21, Supplementary Discussion and additional references. (PDF 515 kb)

Supplementary Table S1

This file contains Supplementary Table S1 indicating sequences tiled on the arrays that were lightly-masked or unmasked. (XLS 1082 kb)

Supplementary Table S17

This file contains Supplementary Table S17 listing SNPs that produce nonsense mutations. (XLS 175 kb)

Supplementary Table S18

This file contains Supplementary Table S18 listing SNPs that produce altered translation start sites. (XLS 70 kb)

Supplementary Table S19

This file contains Supplementary Table S19 listing SNPs that produce altered translation stop sites. (XLS 61 kb)

Supplementary Table S20

This file contains Supplementary Table S20 listing SNPs that produce altered splice sites. (XLS 139 kb)

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Frazer, K., Eskin, E., Kang, H.et al. A sequence-based variation map of 8.27 million SNPs in inbred mouse strains.Nature448, 1050–1053 (2007). https://doi.org/10.1038/nature06067

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Editorial Summary

Putting mice on the HapMap

A major new resource is now available to geneticists working on the many mouse models that are used to study toxicity and human disease. The genomes of four wild-derived and eleven inbred laboratory mouse strains have been resequenced to create a comprehensive resource of DNA variation. About 8.3 million single base-pair differences known as single nucleotide polymorphisms (SNPs) were identified. The data are publicly available as a mouse 'HapMap' athttp://mouse.perlegen.com/. The density and quality of this set of SNP markers is unprecedented for a mammalian genome, and it will provide a powerful tool for identifying the genetic determinants of phenotypic variation in the mouse.

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