Little is known about the impact of genetic variation on mutation rates within species. We conducted a QTL scan for alleles that influence germline mutagenesis 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 locus on chromosome 4 accumulate C>A germline mutations at a 50% higher rate than those 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 B and DMutyh alleles are present in wild populations of Mus musculus domesticus, and likely represent the first documented example of segregating variation that modulates germline mutation rates in mammals.
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