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Whole exome sequencing of wild-derived inbred strains of mice improves power to link phenotype and genotype

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Abstract

The house mouse is a powerful model to dissect the genetic basis of phenotypic variation, and serves as a model to study human diseases. Despite a wealth of discoveries, most classical laboratory strains have captured only a small fraction of genetic variation known to segregate in their wild progenitors, and existing strains are often related to each other in complex ways. Inbred strains of mice independently derived from natural populations have the potential to increase power in genetic studies with the addition of novel genetic variation. Here, we perform exome-enrichment and high-throughput sequencing (~8× coverage) of 26 wild-derived strains known in the mouse research community as the “Montpellier strains.” We identified 1.46 million SNPs in our dataset, approximately 19% of which have not been detected from other inbred strains. This novel genetic variation is expected to contribute to phenotypic variation, as they include 18,496 nonsynonymous variants and 262 early stop codons. Simulations demonstrate that the higher density of genetic variation in the Montpellier strains provides increased power for quantitative genetic studies. Inasmuch as the power to connect genotype to phenotype depends on genetic variation, it is important to incorporate these additional genetic strains into future research programs.

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Acknowledgements

We thank Charlie Nicolet and Selene Tyndale from the Epigenome Center at USC. Brent Young, Rachel Mangels, and Lorraine Provencio helped with molecular work. Matt Salomon and Rob Williams gave many helpful suggestions. Jean-Jacques Duquesne maintained the wild mouse repository in Montpellier. Funding was provided by the National Institutes of Health Grant #GM098536 (MDD), National Science Foundation Grant #1146525 (MDD), the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health Grant #HD073439 (JMG), and the University of Montana Genomics Core, supported by a grant from the M.J. Murdock Charitable Trust.

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Authors and Affiliations

  1. Molecular and Computational Biology, University of Southern California, 1050 Childs Way, Los Angeles, CA, 90089, USA

    Peter L. Chang, Emily Kopania, Sara Keeble & Matthew D. Dean

  2. Division of Biological Sciences, University of Montana, Missoula, MT, USA

    Emily Kopania, Sara Keeble, Brice A. J. Sarver, Erica Larson & Jeffrey M. Good

  3. Department of Biological Sciences, University of Denver, Denver, CO, 80210, USA

    Erica Larson

  4. Institut des Sciences de l’Evolution, CNRS UMR554, Université de Montpellier, Montpellier, France

    Annie Orth, Khalid Belkhir, Pierre Boursot & François Bonhomme

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  1. Peter L. Chang
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  2. Emily Kopania
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Correspondence to Matthew D. Dean.

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Illumina sequencing data are available in NCBI under the BioProject PRJNA326865.

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335_2017_9704_MOESM1_ESM.jpg

Supplementary Figure 1—Genealogical relationships among 26 Montpellier strains, 36 strains from dbSNP, and 67 wild-caught mice from Harr et al. (2016). Similar to Figure 1 but note that species names have changed to accommodate larger sample sizes. Strain names on a black box indicate novel Montpellier exomes sequenced in this study. Nodes labeled with small black circles were supported with at least 95% bootstrap support. Importantly, as seen in Fig. 1, the classical inbred strains cluster to the exclusion of wild-derived inbred strains (JPG 312 KB)

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Supplementary Figure 2—Principal components analysis of genetic variation among 26 Montpellier strains and 36 “classical inbred” strains. Colors follow Fig. 1 (PDF 29 KB)

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Supplementary Figure 3—Distribution of stop codons, arranged by the proportion of wild-type protein that remains (PDF 25 KB)

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Supplementary Figure 4—Proportion of wild-type protein truncated by early stop codons, separated by whether the early stop codon occurs on a facultative or constitutive exon (PDF 26 KB)

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Supplementary Figure 5—Examples of pairwise distribution of genetic divergence vs. haplotype length for 2 pairs of wild-derived inbred strains (PDF 45 KB)

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Chang, P.L., Kopania, E., Keeble, S. et al. Whole exome sequencing of wild-derived inbred strains of mice improves power to link phenotype and genotype. Mamm Genome 28, 416–425 (2017). https://doi.org/10.1007/s00335-017-9704-9

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