title: 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 theMLH1andPMS1mismatch repair (MMR) genes ofSaccharomyces cerevisiaeWe hypothesized that this MMR incompatibility, created through mating between divergentS. cerevisiae, yields mutator progeny that can rapidly but transiently adapt to an environmental stress. Here we analyzed theMLH1andPMS1genes across 1010S. cerevisiaenatural isolates spanning a wide range of ecological sources (tree exudates,Drosophila, 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. TheMLH1-PMS1gene 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.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853-2703.
authors.forename: Duyen T
authors.initials: DT
authors.lastname: Bui
authors.affiliation: Université de Strasbourg, Centre National de la Recherche Scientifique, Génétique Moléculaire, Génomique, Microbiologie, Unité Mixte de Recherche, 7156, F-67000 Strasbourg, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Friedrich
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853-2703.
authors.forename: Najla
authors.initials: N
authors.lastname: Al-Sweel
authors.affiliation: Institute for Research on Cancer and Ageing of Nice, 06107 Nice, France.
authors.forename: Gianni
authors.initials: G
authors.lastname: Liti
authors.affiliation: Université de Strasbourg, Centre National de la Recherche Scientifique, Génétique Moléculaire, Génomique, Microbiologie, Unité Mixte de Recherche, 7156, F-67000 Strasbourg, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schacherer
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853-2703.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Aquadro
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853-2703 eea3@cornell.edu.
authors.forename: Eric
authors.identifier: 0000-0002-5011-9339
authors.initials: E
authors.lastname: Alani
mesh_terms: D053843:DNA Mismatch Repair; D019143:Evolution, Molecular; D000068617:Genetic Background; D056084:Genetic Fitness; D006720:Homozygote; D000070957:MutL Protein Homolog 1 / Q000235:genetics; D000070956:MutL Proteins / Q000235:genetics; D059645:Mutation Rate; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
chemical_list: C088859:MLH1 protein, S cerevisiae; C088858:PMS1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins
keywords: DNA mismatch repair; Saccharomyces cerevisiae; adaptation; experimental evolution; genetic incompatibility; mutator phenotype; natural yeast isolates