Although studies of Saccharomyces cerevisiae have provided many insights into mutagenesis and DNA repair, most of this work has focused on a few laboratory strains. Much less is known about the phenotypic effects of natural variation within S. cerevisiae's DNA repair pathways. Here, we use natural polymorphisms to detect historical mutation spectrum differences among several wild and domesticated S. cerevisiae strains. To determine whether these differences are likely caused by genetic mutation rate modifiers, we use a modified fluctuation assay with a CAN1 reporter to measure de novo mutation rates and spectra in 16 of the analyzed strains. We measure a 10-fold range of mutation rates and identify two strains with distinctive mutation spectra. These strains, known as AEQ and AAR, come from the panel's 'Mosaic beer' clade and share an enrichment for C>A mutations that is also observed in rare variation segregating throughout the genomes of several Mosaic beer and Mixed origin strains. Both AEQ and AAR are haploid derivatives of the diploid natural isolate CBS 1782, whose rare polymorphisms are enriched for C>A as well, suggesting that the underlying mutator allele is likely active in nature. We use a plasmid complementation test to show that AAR and AEQ share a mutator allele in the DNA repair gene OGG1, which excises 8-oxoguanine lesions that can cause C>A mutations if left unrepaired.

Mutations are the source of genetic variation and a prerequisite for evolution. Despite their fundamental importance, however, their rarity makes them expensive and difficult to detect, which has limited our ability to measure the extent to which mutational processes vary within and between species. Here, we use the 1011 Saccharomyces cerevisiae collection to measure variation of mutation rates and spectra among strains isolated from a variety of natural and human-related environments. The mutation spectra of variants segregating in different S. cerevisiae populations exhibit differences in the relative numbers of specific transition and transversion types, a pattern reminiscent of previously observed mutation spectrum differences between populations of humans, great apes, and mice. Such natural variation is thought to reveal historical differences in the activity of particular mutational processes, but is also potentially complicated by other forces such as admixture, genetic drift, and selection. In order to directly test how much of the observed mutation spectrum variation is caused by heritable differences between extant strains of S. cerevisiae, we developed an experimental pipeline to assay de novo mutation rates and spectra of individual strains, using the reporter gene CAN1. We found a 10-fold range of mutation rate variation among 16 haploid strains surveyed. While many strains exhibit similar mutation spectra, two related strains from the panel’s “Mosaic beer” clade, known as AEQ and AAR, share a distinctive mutation spectrum enrichment for C>A mutations. This C>A enrichment found through our experimental pipeline mirrors an enrichment of C>A mutations in rare variants segregating throughout the genomes of AEQ and AAR as well as additional Mosaic beer strains. We deduce that a major axis of S. cerevisiae mutation spectrum variation is likely driven by one or more naturally occurring mutator alleles whose action is measurable in a controlled laboratory environment.

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