A Wild-Derived Antimutator Drives Germline Mutation Spectrum Differences Among Laboratory Mouse Strains

Little is known about the impact of genetic variation on mutation rates within species. We conducted a search for alleles that modulate the germline mutation rate using a panel of recombinant inbred mouse lines descended from the laboratory strains C57BL/6J (B6) and DBA/2J (D2). Mice inheriting D haplotypes at a quantitative trait locus (QTL) on chromosome 4 accumulated C>A germline mutations at a 50% higher rate than strains with B haplotypes. The QTL contains coding variation in Mutyh, a DNA repair gene that underlies C>A-dominated mutational signatures with similar sequence context biases in human cancers. Both Mutyh alleles are present in wild populations of Mus musculus domesticus, and likely represent the first example of segregating variation that affects the germline mutation rate in a mammal.