A natural mutator allele shapes mutation spectrum variation in mice

Area of Science:

• Genetics
• Genomics
• Evolutionary Biology

Background:

• Germline mutation rates and spectra exhibit variability across species.
• Identifying common genetic modifiers of mutation rates in natural populations remains a challenge.

Purpose of the Study:

• To identify genetic loci that influence germline mutagenesis.
• To investigate the role of genetic variation in modulating mutation rates in mammals.

Main Methods:

• Utilized the BXD recombinant inbred mouse lines, derived from C57BL/6J and DBA/2J strains.
• Analyzed de novo mutations accumulated over 50 years on a known genetic background.
• Investigated quantitative trait loci (QTL) on chromosome 4 associated with mutation rates.

Main Results:

• Mice with D haplotypes at a chromosome 4 QTL showed a 50% higher rate of C>A germline mutations compared to those with B haplotypes.
• This increased mutation rate was linked to the C>A-dominated mutational signature SBS18.
• The identified QTL haplotypes encode different alleles of the DNA repair gene Mutyh.

Conclusions:

• Common genetic variation, specifically different Mutyh alleles, modulates germline mutagenesis in mice.
• Mutyh alleles found in both laboratory strains and wild mouse populations (Mus musculus domesticus) suggest natural selection may act on mutation rates.
• This finding provides evidence for genetic control of mutation rates in a model mammalian species and has implications for understanding heritable cancer predisposition.