Abstract
Maintaining germline genome integrity is essential and enormously complex. Although many proteins are involved in DNA replication, proofreading, and repair [1], mutator alleles have 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 of de novo mutations — 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 gene Mutyh that 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 overlaps Ogg1, a DNA glycosylase involved in the same base-excision repair network as Mutyh [4]. Its effect depended on the presence of a mutator allele near Mutyh, 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
tomsasani
tomsasani
aaronquinlan
Kelley__Harris
Funded by NIH/NHGRI R01HG012252
Funded by NIH/NIGMS R35GM133428; Burroughs Wellcome Career Award at the Scientific Interface; Searle Scholarship; Pew Scholarship; Sloan Fellowship; Allen Discovery Center for Cell Lineage Tracing
We have updated the manuscript in response to helpful feedback from peer reviewers. To avoid confusion, we have renamed the main method introduced in the manuscript (previously called “inter-haplotype distance,” or IHD) to be "aggregate mutation spectrum distance" (AMSD). We have also implemented a new bootstrap method for defining confidence intervals surrounding AMSD peaks, added additional detail about regulatory variation that may underlie the mutator locus we identified on chromosome 6, and performed a number of additional simulations to investigate the comparative power of AMSD and QTL mapping on mutation spectrum phenotypes. We have also made a number of minor edits to the text in response to reviewer comments, including explicit caveats about the applicability of AMSD to systems other than the BXD inbred laboratory mice. Finally, we have updated the title of the manuscript to emphasize the fact that our results are focused primarily on mutation spectrum, rather than mutation rate, variability in the BXDs.
