Diversity outbred mice at 21: Maintaining allelic variation in the face of selection

Elissa J. Chesler, Daniel M. Gatti, Andrew P. Morgan, Marge Strobel, Laura Trepanier, Denesa Oberbeck, Shannon McWeeney, Robert Hitzemann, Martin Ferris, Rachel McMullan, Amelia Clayshultle, Timothy A. Bell, Fernando Pardo Manuel de Villena, Gary A. Churchill

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Multi-parent populations (MPPs) capture and maintain the genetic diversity from multiple inbred founder strains to provide a resource for high-resolution genetic mapping through the accumulation of recombination events over many generations. Breeding designs that maintain a large effective population size with randomized assignment of breeders at each generation can minimize the impact of selection, inbreeding, and genetic drift on allele frequencies. Small deviations from expected allele frequencies will have little effect on the power and precision of genetic analysis, but a major distortion could result in reduced power and loss of important functional alleles. We detected strong transmission ratio distortion in the Diversity Outbred (DO) mouse population on chromosome 2, caused by meiotic drive favoring transmission of the WSB/EiJ allele at the R2d2 locus. The distorted region harbors thousands of polymorphisms derived from the seven non-WSB founder strains and many of these would be lost if the sweep was allowed to continue. To ensure the utility of the DO population to study genetic variation on chromosome 2, we performed an artificial selection against WSB/EiJ alleles at the R2d2 locus.Here, we report that we have purged theWSB/EiJ allele from the drive locus while preserving WSB/EiJ alleles in the flanking regions. We observed minimal disruption to allele frequencies across the rest of the autosomal genome. However, there was a shift in haplotype frequencies of the mitochondrial genome and an increase in the rate of an unusual sex chromosome aneuploidy. The DO population has been restored to genome-wide utility for genetic analysis, but our experience underscores that vigilant monitoring of similar genetic resource populations is needed to ensure their long-term utility.

Original languageEnglish (US)
Pages (from-to)3893-3902
Number of pages10
JournalG3: Genes, Genomes, Genetics
Volume6
Issue number12
DOIs
StatePublished - Jan 1 2016

Keywords

  • Aneuploidy
  • Meiotic drive
  • Multiparent Advanced Generation Inter-Cross (MAGIC)
  • Multiparental populations MPP
  • Transmission ratio distortion

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Chesler, E. J., Gatti, D. M., Morgan, A. P., Strobel, M., Trepanier, L., Oberbeck, D., McWeeney, S., Hitzemann, R., Ferris, M., McMullan, R., Clayshultle, A., Bell, T. A., de Villena, F. P. M., & Churchill, G. A. (2016). Diversity outbred mice at 21: Maintaining allelic variation in the face of selection. G3: Genes, Genomes, Genetics, 6(12), 3893-3902. https://doi.org/10.1534/g3.116.035527