Mismatch Repair Incompatibilities in Diverse Yeast Populations

Area of Science:

• Genetics
• Evolutionary Biology
• Microbiology

Background:

• Elevated mutation rates can drive adaptation in changing environments.
• Naturally occurring variants in mismatch repair (MMR) genes MLH1 and PMS1 in Saccharomyces cerevisiae can interact negatively.
• MMR incompatibility may arise from mating divergent yeast strains, potentially creating mutator progeny for rapid adaptation.

Purpose of the Study:

• To investigate the prevalence and consequences of MLH1-PMS1 incompatibility in natural Saccharomyces cerevisiae isolates.
• To determine if MMR incompatibility confers a mutator phenotype and facilitates adaptation.
• To understand the mechanisms that mitigate long-term fitness costs associated with elevated mutation rates.

Main Methods:

• Analysis of MLH1 and PMS1 genes in 1010 S. cerevisiae natural isolates from diverse ecological and geographical sources.
• Identification of isolates with incompatible MMR genotypes (homozygous and heterozygous).
• Expression of MLH1-PMS1 from a homozygous clinical isolate in a laboratory strain (S288c) to assess the mutator phenotype using a novel mutation rate reporter.

Main Results:

• One homozygous and 18 heterozygous isolates with incompatible MMR genotypes were identified among natural isolates.
• The MLH1-PMS1 combination from the homozygous clinical isolate conferred a mutator phenotype in the S288c background.
• The homozygous incompatible strain showed a similar overall mutation rate to compatible strains, suggesting suppressor mutations lowered the rate.
• Heterozygous isolates can produce offspring with incompatible MMR genotypes, consistent with transient adaptation.

Conclusions:

• MMR incompatibility in S. cerevisiae can lead to a transient mutator phenotype, facilitating rapid adaptation.
• Mechanisms like mating or acquiring suppressor mutations buffer the long-term fitness costs of elevated mutation rates.
• Eukaryotes employ strategies to manage the trade-offs between adaptation and fitness costs associated with increased mutation rates.