title: Known mutator alleles do not markedly increase mutation rate in clinicalSaccharomyces cerevisiaestrains.
abstract: Natural selection has the potential to act on all phenotypes, including genomic mutation rate. Classic evolutionary theory predicts that in asexual populations, mutator alleles, which cause high mutation rates, can fix due to linkage with beneficial mutations. This phenomenon has been demonstrated experimentally and may explain the frequency of mutators found in bacterial pathogens. By contrast, in sexual populations, recombination decouples mutator alleles from beneficial mutations, preventing mutator fixation. In the facultatively sexual yeastSaccharomyces cerevisiae, segregating alleles ofMLH1andPMS1have been shown to be incompatible, causing a high mutation rate when combined. These alleles had never been found together naturally, but were recently discovered in a cluster of clinical isolates. Here we report that the incompatible mutator allele combination only marginally elevates mutation rate in these clinical strains. Genomic and phylogenetic analyses provide no evidence of a historically elevated mutation rate. We conclude that the effect of the mutator alleles is dampened by background genetic modifiers. Thus, the relationship between mutation rate and microbial pathogenicity may be more complex than once thought. Our findings provide rare observational evidence that supports evolutionary theory suggesting that sexual organisms are unlikely to harbour alleles that increase their genomic mutation rate.
authors.affiliation: Department of Biology, Duke University, Durham, NC, USA.
authors.forename: Daniel A
authors.identifier: http://orcid.org/0000-0002-2329-2216
authors.initials: DA
authors.lastname: Skelly
authors.affiliation: Department of Biology, Duke University, Durham, NC, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Magwene
authors.affiliation: Department of Biology, The College of William and Mary, Williamsburg, VA, USA.
authors.forename: Brianna
authors.initials: B
authors.lastname: Meeks
authors.affiliation: Department of Biology, The College of William and Mary, Williamsburg, VA, USA hamurphy@wm.edu.
authors.forename: Helen A
authors.identifier: http://orcid.org/0000-0002-4363-4543
authors.initials: HA
authors.lastname: Murphy
mesh_terms: D000483:Alleles; D019143:Evolution, Molecular; D009154:Mutation; D059645:Mutation Rate; D010802:Phylogeny; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D012641:Selection, Genetic
keywords: Saccharomyces cerevisiae; genetic background; mutation rate; mutators