Diversity Outbred Mice at 21: Maintaining Allelic Variation in the Face of Selection

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 the WSB/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.

Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size

“…One factor to consider when using the DO for genetic mapping is that allele frequency distributions could be distorted at particular regions due to selection or other effects (Chesler et al 2016). When a particular haplotype is low in frequency, random chance may cause that haplotype to have a significant effect and drive a QTL peak.…”

Effects of selection for ethanol preference on gene expression in the nucleus accumbens of HS‐CC mice

“…Using a selective breeding protocol, the meiotic drive locus and the associated WSB alleles have been eliminated from the DO population (Chesler et al . ). We have compared these DO mice with the HS‐CC; no difference was detected in either acute or chronic preference consumption (data not shown).…”

Male Infertility Is Responsible for Nearly Half of the Extinction Observed in the Mouse Collaborative Cross

“…A 500-kb region on the end of chromosome X containing the pseudoautosomal region (PAR) was excluded from the HMM. The reasons for exclusion include the variable length of the PAR region in the founder strains (White et al 2012), the fact that it recombines with chromosome Y, and the presence of de novo duplications or translocations discovered in the related Diversity Outbred (DO) population that can lead to apparent heterozygosity (Chesler et al 2016), which is disallowed in the eight-state model. We also incorporated a significant penalty against the fourth, seventh, and eighth positions of each line's funnel code into the HMM's transition probabilities.…”