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On the subspecific origin of the laboratory mouse

Abstract

The genome of the laboratory mouse is thought to be a mosaic of regions with distinct subspecific origins. We have developed a high-resolution map of the origin of the laboratory mouse by generating 25,400 phylogenetic trees at 100-kb intervals spanning the genome. On average, 92% of the genome is of Mus musculus domesticus origin, and the distribution of diversity is markedly nonrandom among the chromosomes. There are large regions of extremely low diversity, which represent blind spots for studies of natural variation and complex traits, and hot spots of diversity. In contrast with the mosaic model, we found that most of the genome has intermediate levels of variation of intrasubspecific origin. Finally, mouse strains derived from the wild that are supposed to represent different mouse subspecies show substantial intersubspecific introgression, which has strong implications for evolutionary studies that assume these are pure representatives of a given subspecies.

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Figure 1: Frequency distribution of diagnostic subspecific SNPs.
Figure 2: SNP discovery bias.
Figure 3: Regions of intersubspecific introgression in the reference strains.
Figure 4: Subspecific origin of classical and hybrid strains.
Figure 5: Frequency distribution of the normalized variation in pairwise comparisons between classical strains.
Figure 6: Frequency and spatial distributions of the mean normalized genetic variation observed among 11 resequenced strains.

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References

  1. Paigen, K. One hundred years of mouse genetics: an intellectual history. I. The classical period (1902–1980). Genetics 163, 1–7 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Paigen, K. One hundred years of mouse genetics: an intellectual history. II. The molecular revolution (1981–2002). Genetics 163, 1227–1235 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Ferris, S.D., Sage, R.D. & Wilson, A.C. Evidence from mtDNA sequences that common laboratory strains of inbred mice are descended from a single female. Nature 295, 163–165 (1982).

    Article  CAS  PubMed  Google Scholar 

  5. Bishop, C.E., Boursot, P., Baron, B., Bonhomme, F. & Hatat, D. Most classical Mus musculus domesticus laboratory mouse strains carry a Mus musculus musculus Y chromosome. Nature 315, 70–72 (1985).

    Article  CAS  PubMed  Google Scholar 

  6. Nagamine, C.M. et al. The musculus-type Y chromosome of the laboratory mouse is of Asian origin. Mamm. Genome 3, 84–91 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Bonhomme, F., Guenet, J.-L., Dod, B., Moriwaki, K. & Bulfield, G. The polyphyletic of the laboratory inbred mice and their rate of evolution. J. Linn. Soc. 30, 51–58 (1987).

    Article  Google Scholar 

  8. Wade, C.M. et al. The mosaic structure of variation in the laboratory mouse genome. Nature 420, 574–578 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Wiltshire, T. et al. Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse. Proc. Natl. Acad. Sci. USA 100, 3380–3385 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pletcher, M.T. et al. Use of a dense single nucleotide polymorphism map for in silico mapping in the mouse. PLoS Biol. [online] 2, e393 (2004) (doi:10.1371/journal.pbio.0020393).

    Article  CAS  Google Scholar 

  11. Frazer, K.A. et al. Segmental phylogenetic relationships of inbred mouse strains revealed by fine-scale analysis of sequence variation across 4.6 Mb of mouse genome. Genome Res. 14, 1493–1500 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Petkov, P.M. et al. Evidence of a large-scale functional organization of mammalian chromosomes. PLoS Genet. [online] 1, e33 (2005) (doi:10.1371/journal.pgen.0010033).

    Article  CAS  Google Scholar 

  13. Yalcin, B. et al. Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice. Proc. Natl. Acad. Sci. USA 101, 9734–9739 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Harr, B. Genomic islands of differentiation between house mouse subspecies. Genome Res. 16, 730–737 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Harr, B. Regions of high differentiation–worth a check. Genome Res. 16, 1193–1194 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Boursot, P. & Belkhir, K. Mouse SNPs for evolutionary biology: beware of ascertainment biases. Genome Res. 16, 1191–1192 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Zhang, J. et al. A high-resolution multistrain haplotype analysis of laboratory mouse genome reveals three distinctive genetic variation patterns. Genome Res. 15, 241–249 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ideraabdullah, F.Y. et al. Genetic and haplotype diversity among wild derived mouse inbred strains. Genome Res. 14, 1880–1887 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Boissinot, S. & Boursot, P. Discordant phylogeographic patterns between the Y chromosome and mitochondrial DNA in the house mouse: selection on the Y chromosome? Genetics 146, 1019–1034 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bonhomme, F. et al. Species-wide distribution of highly polymorphic minisatellite markers suggests past and present genetic exchanges among House Mouse subspecies. Genome Biol. [online] 8, R80 (2007) (doi:10.1186/gb-2007-8-5-r80).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Frazer, K.A. et al. A sequence-based variation map of 8.27 million SNPs in inbred mouse strains. Nature, advance online publication 29 July 2007 (doi:10.1038/nature06067).

    Article  CAS  PubMed  Google Scholar 

  22. Genetic Variants and Strains of the Laboratory Mouse (Lyon, M.F., Rastan, S. & Brown, S.D.M., eds.) 3rd edn. (Oxford University Press, Oxford 1996).

  23. Yonekawa, H. et al. Hybrid origin of Japanese mice “Mus musculus molossinus”: evidence from restriction analysis of mitochondrial DNA. Mol. Biol. Evol. 5, 63–78 (1988).

    CAS  PubMed  Google Scholar 

  24. Sakai, T. et al. Origins of mouse inbred strains deduced from whole-genome scanning by polymorphic microsatellite loci. Mamm. Genome 16, 11–19 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Abe, K. et al. Contribution of Asian mouse subspecies Mus musculus molossinus to genomic constitution of strain C57BL/6J, as defined by BAC-end sequence-SNP analysis. Genome Res. 14, 2439–2447 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wade, C.M. & Daly, M.J. Genetic variation in laboratory mice. Nat. Genet. 37, 1175–1180 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Auffray, J.-C., Vanlerberghe, F. & Britton-Davidian, J. The house mouse progression in Eurasia: a palaeontological and archaeozoological approach. Biol. J. Linn. Soc. 41, 13–25 (1990).

    Article  Google Scholar 

  28. Din, W. et al. Origin and radiation of the house mouse: clues from nuclear genes. J. Evol. Biol. 9, 519–539 (1996).

    Article  CAS  Google Scholar 

  29. Prager, E.M., Orrego, C. & Sage, R.D. Genetic variation and phylogeography of central Asian and other house mice, including a major new mitochondrial lineage in Yemen. Genetics 150, 835–861 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Patil, N. et al. Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 294, 1719–1723 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Keightley, P.D., Lercher, M.J. & Eyre-Walker, A. Evidence for widespread degradation of gene control regions in hominid genomes. PLoS Biol. 3, 282–288 (2005).

    Article  CAS  Google Scholar 

  32. Forejt, J. Hybrid sterility in the mouse. Trends Genet. 12, 412–417 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Thrachtulec, Z. et al. Positional cloning of the hybrid sterility 1 gene: fine genetic mapping and evaluation of two candidate genes. Biol. J. Linn. Soc. 84, 637–641 (2005).

    Article  Google Scholar 

  34. Payseur, B.A. & Hoekstra, H.E. Signatures of reproductive isolation in patterns of single nucleotide diversity across inbred strains of mice. Genetics 171, 1905–1916 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Oka, A. et al. Disruption of genetic interaction between two autosomal regions and the x chromosome causes reproductive isolation between mouse strains derived from different subspecies. Genetics 175, 185–197 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Dai, J. et al. The absence of mitochondrial DNA diversity among common laboratory inbred mouse strains. J. Exp. Biol. 208, 4445–4450 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Tucker, P.K., Lee, B.K., Lundrigan, B.L. & Eicher, E.M. Geographic origin of the Y chromosomes in “old” inbred strains of mice. Mamm. Genome 3, 254–261 (1992).

    Article  CAS  PubMed  Google Scholar 

  38. Ferris, S.D. et al. Flow of mitochondrial DNA across a species boundary. Proc. Natl. Acad. Sci. USA 80, 2290–2294 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li, J. et al. Genomic segmental polymorphisms in inbred mouse strains. Nat. Genet. 36, 952–954 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Snijders, A.M. et al. Mapping segmental and sequence variations among laboratory mice using BAC array CGH. Genome Res. 15, 302–311 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Graubert, T.A. et al. A high-resolution map of segmental DNA copy number variation in the mouse genome. PLoS Genet. [online] 3, e3 (2007) (doi:10.1371/journal.pgen.0030003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Valdar, W. et al. Genome-wide genetic association of complex traits in heterogeneous stock mice. Nat. Genet. 38, 879–887 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. 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  PubMed  Google Scholar 

  44. Churchill, G.A. Stochastic models for heterogeneous DNA sequences. Bull. Math. Biol. 51, 79–94 (1989).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank S. Ahmed for technical assistance; K. Paigen, K. Broman and B. Payseur for helpful comments during the preparation of the manuscript; J. Felsenstein for advice and L. Wu for assistance with the phylogenetic tree computations and A. Smith for developing a genome browser format for displaying phylogenetic trees. CIM/Pas was provided by F. Bonhomme (University Mont Pellier II). This work was supported by the US National Institute of General Medical Sciences as part of the Center of Excellence in Systems Biology (1P50 GM076468).

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Contributions

This study was designed by F.P.-M.V. and G.A.C. The genome-wide analyses were carried out by H.Y. The sequence data used to determine the false-negative and false-positive rates and to confirm the presence and direction of intrasubspecific introgression were generated by T.A.B.

Corresponding author

Correspondence to Fernando Pardo-Manuel de Villena.

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The authors declare no competing financial interests.

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Supplementary Figures 1–6, Supplementary Note, Supplementary Table 1 (PDF 3338 kb)

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Yang, H., Bell, T., Churchill, G. et al. On the subspecific origin of the laboratory mouse. Nat Genet 39, 1100–1107 (2007). https://doi.org/10.1038/ng2087

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