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

Abstract

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.

A natural mutator allele shapes mutation spectrum variation in mice

“…Our discovery of a genetic modifier of the murine C>A mutation rate provides new support for the long-standing theoretical prediction that multicellular eukaryotes have a limited ability to optimize their germline replication fidelity 1 . Our work shows that common mutator alleles, previously identified only in microorganisms such as Saccharomyces cerevisiae 39,40 , also shape vertebrate genetic diversity.…”

Nonparametric coalescent inference of mutation spectrum history and demography

“…They found that human triplet spectra distinctly cluster by continental ancestry group and that historical pulses in mutation activity influence the distribution of allele frequencies in certain mutation types. The divergence of mutation spectra among human continental groups has been replicated in independently generated datasets (7,16), and similar patterns have been observed in other species, including great apes (17), mice (18), and yeast (19). Some of the mutation spectrum divergence between mice and yeast lineages has been mapped to mutator alleles (19,20).…”

Heterogeneous mutation rates and spectra in yeast hybrids

“…Both approaches have been used in different contexts with model organisms. In yeast, mutation rates and spectra have been shown to differ within and between species (Nguyen et al 2020; Jiang et al 2021), between environmental factors such as mild (Liu and Zhang 2019) and severe stressors (Shor et al 2013) and vary depending on ploidy (Sharp et al 2018) or sequence context (Ma et al 2012). A wide array of genes, notably involved in DNA repair, have been shown to influence the mutation landscape (Demogines et al 2008; Lang et al 2013; Serero et al 2014; Stirling et al 2014; Gou et al 2019; Loeillet et al 2020).…”