Mismatch Repair Incompatibilities in Diverse Yeast Populations

Abstract

An elevated mutation rate can provide cells with a source of mutations to adapt to changing environments. We identified a negative epistatic interaction involving naturally occurring variants in the and mismatch repair (MMR) genes of We hypothesized that this MMR incompatibility, created through mating between divergent, yields mutator progeny that can rapidly but transiently adapt to an environmental stress. Here we analyzed the and genes across 1010 natural isolates spanning a wide range of ecological sources (tree exudates,, fruits, and various fermentation and clinical isolates) and geographical sources (Europe, America, Africa, and Asia). We identified one homozygous clinical isolate and 18 heterozygous isolates containing the incompatible MMR genotype. The gene combination isolated from the homozygous clinical isolate conferred a mutator phenotype when expressed in the S288c laboratory background. Using a novel reporter to measure mutation rates, we showed that the overall mutation rate in the homozygous incompatible background was similar to that seen in compatible strains, indicating the presence of suppressor mutations in the clinical isolate that lowered its mutation rate. This observation and the identification of 18 heterozygous isolates, which can lead to MMR incompatible genotypes in the offspring, are consistent with an elevated mutation rate rapidly but transiently facilitating adaptation. To avoid long-term fitness costs, the incompatibility is apparently buffered by mating or by acquiring suppressors. These observations highlight effective strategies in eukaryotes to avoid long-term fitness costs associated with elevated mutation rates.

Natural mismatch repair mutations mediate phenotypic diversity and drug resistance inCryptococcus deuterogattii

“…In S. cerevisiae, incompatible alleles of PMS1 and MLH1 result in elevated mutation rates if present in combination (18,19). However, in the rare cases where the incompatible arrangement is found in nature, additional suppressors have arisen to restore wildtype mutation rate, suggesting that hypermutator phenotypes may not be tolerated over long periods of time (20,21). In addition, a recent study of Candida glabrata has demonstrated that a substantial proportion of clinical isolates (>50%) carry nonsynonymous mutations in the MSH2 gene, some causing elevated mutation rates similar to the null phenotype and others with intermediate changes in mutation rate (23).…”

Beyond speciation genes: an overview of genome stability in evolution and speciation

“…However, a mutator phenotype is predicted to be costly in the long term, due to the accumulation of deleterious mutations. Suppressor mutations within strains carrying incompatible alleles are thus likely to arise [32,but see 33 for a different interpretation]. This example illustrates how DNA repair pathways can be involved in reproductive isolation and potentially in adaptation.…”

Genetic suppression: Extending our knowledge from lab experiments to natural populations

“…After acceptance of this article, a pair of papers was published showing that known, naturally occurring genetic interaction between polymorphisms in two mismatch repair genes in yeast can be suppressed by genetic variants at other loci [70,71]. These studies provide yet another example of naturally occurring genetic suppression.…”