A modified fluctuation assay reveals a natural mutator phenotype that drives mutation spectrum variation withinSaccharomyces cerevisiae

Although studies ofSaccharomyces cerevisiaehave 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 withinS. cerevisiae’s DNA repair pathways. Here, we use natural polymorphisms to detect historical mutation spectrum differences among several wild and domesticatedS. cerevisiaestrains. To determine whether these differences are likely caused by genetic mutation rate modifiers, we use a modified fluctuation assay with aCAN1reporter to measurede novomutation 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 geneOGG1, which excises 8-oxoguanine lesions that can cause C>A mutations if left unrepaired.