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

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.