Maintaining germline genome integrity is essential and enormously complex. Although many proteins are involved in DNA replication, proofreading, and repair [1],mutator alleleshave largely eluded detection in mammals.DNA replication and repair proteins often recognize sequence motifs or excise lesions at specific nucleotides. Thus, we might expect that the spectrum ofde novomutations — the frequencies of C>T, A>G, etc. — will differ between genomes that harbor either a mutator or wild-type allele. Previously, we used quantitative trait locus mapping to discover candidate mutator alleles in the DNA repair geneMutyhthat increased the C>A germline mutation rate in a family of inbred mice known as the BXDs [2,3].In this study we developed a new method to detect alleles associated with mutation spectrum variation and applied it to mutation data from the BXDs. We discovered an additional C>A mutator locus on chromosome 6 that overlapsOgg1, a DNA glycosylase involved in the same base-excision repair network asMutyh[4]. Its effect depended on the presence of a mutator allele nearMutyh, and BXDs with mutator alleles at both loci had greater numbers of C>A mutations than those with mutator alleles at either locus alone. Our new methods for analyzing mutation spectra reveal evidence of epistasis between germline mutator alleles and may be applicable to mutation data from humans and other model organisms.