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Subspecific origin and haplotype diversity in the laboratory mouse

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Abstract

Here we provide a genome-wide, high-resolution map of the phylogenetic origin of the genome of most extant laboratory mouse inbred strains. Our analysis is based on the genotypes of wild-caught mice from three subspecies of Mus musculus. We show that classical laboratory strains are derived from a few fancy mice with limited haplotype diversity. Their genomes are overwhelmingly Mus musculus domesticus in origin, and the remainder is mostly of Japanese origin. We generated genome-wide haplotype maps based on identity by descent from fancy mice and show that classical inbred strains have limited and non-randomly distributed genetic diversity. In contrast, wild-derived laboratory strains represent a broad sampling of diversity within M. musculus. Intersubspecific introgression is pervasive in these strains, and contamination by laboratory stocks has played a role in this process. The subspecific origin, haplotype diversity and identity by descent maps can be visualized using the Mouse Phylogeny Viewer (see URLs).

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Figure 1: Overall contribution of each subspecies to the genome of wild and laboratory mice.
Figure 2: Subspecific origin and haplotype diversity of chromosomes 6 and X.
Figure 3: Intersubspecific introgression and contamination by classical strains in the wild-derived inbred strains.
Figure 4: Identification of donor strains.

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Acknowledgements

This work was supported by the National Institute of General Medical Sciences (NIGMS) Centers of Excellence in Systems Biology program, grant GM-076468, by a US National Institutes of Health (NIH) grant to M.W.N. (R01 GM74245), by a grant to F.B. (ISEM 2010-141) and by a Czech Science Foundation grant to J.P. (206-08-0640). J.P.D. was partially supported by NIH Training Grant Number GM067553-04, University of North Carolina (UNC) Bioinformatics and Computational Biology Training Grant. J.P.D., R.J.B. and T.A.B. are partially supported by an NIH grant to F.P.-M.d.V. (P50 MH090338). We also thank F. Oyola for help annotating the samples genotyped in this study.

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F.P.-M.d.V., G.A.C. and H.Y. conceived the study design and wrote the paper. H.Y., J.R.W., J.P.D., L.M. and C.E.W. carried out the bioinformatics analyses. J.P.D., T.A.B. and R.J.B. prepared the samples and conducted the targeted PCR amplification and sequencing. F.B., P.B., A.H.-T.Y., M.W.N., J.P. and P.T. provided biological samples. All authors contributed to the interpretation of the results and the writing of the manuscript.

Corresponding authors

Correspondence to Gary A Churchill or Fernando Pardo-Manuel de Villena.

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The authors declare no competing financial interests.

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Supplementary Figures 1–10 and Supplementary Tables 2–6. (PDF 7417 kb)

Supplementary Table 1

Sample summary (XLSX 90 kb)

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Yang, H., Wang, J., Didion, J. et al. Subspecific origin and haplotype diversity in the laboratory mouse. Nat Genet 43, 648–655 (2011). https://doi.org/10.1038/ng.847

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