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Genetics. 2018 Dec;210(4):1253-1266. doi: 10.1534/genetics.118.301550. Epub 2018 Oct 22.

Incompatibilities in Mismatch Repair Genes MLH1-PMS1 Contribute to a Wide Range of Mutation Rates in Human Isolates of Baker's Yeast.

Author information

1
Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853-2703.
2
Université de Strasbourg, Centre National de la Recherche Scientifique, Laboratory of Molecular Genetics, Genomics and Microbiology (GMGM) UMR 7156, F-67000, France.
3
Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853-2703 eea3@cornell.edu.

Abstract

Laboratory baker's yeast strains bearing an incompatible combination of MLH1 and PMS1 mismatch repair alleles are mutators that can adapt more rapidly to stress, but do so at the cost of long-term fitness. We identified 18 baker's yeast isolates from 1011 surveyed that contain the incompatible MLH1-PMS1 genotype in a heterozygous state. Surprisingly, the incompatible combination from two human clinical heterozygous diploid isolates, YJS5845 and YJS5885, contain the exact MLH1 (S288c-derived) and PMS1 (SK1-derived) open reading frames originally shown to confer incompatibility. While these isolates were nonmutators, their meiotic spore clone progeny displayed mutation rates in a DNA slippage assay that varied over a 340-fold range. This range was 30-fold higher than observed between compatible and incompatible combinations of laboratory strains. Genotyping analysis indicated that MLH1-PMS1 incompatibility was the major driver of mutation rate in the isolates. The variation in the mutation rate of incompatible spore clones could be due to background suppressors and enhancers, as well as aneuploidy seen in the spore clones. Our data are consistent with the observed variance in mutation rate contributing to adaptation to stress conditions (e.g., in a human host) through the acquisition of beneficial mutations, with high mutation rates leading to long-term fitness costs that are buffered by mating or eliminated through natural selection.

KEYWORDS:

DNA mismatch repair; Saccharomyces cerevisiae; adaptation; genetic incompatibility; mutation rate; natural yeast isolates

PMID:
30348651
PMCID:
PMC6283166
[Available on 2019-12-01]
DOI:
10.1534/genetics.118.301550
[Indexed for MEDLINE]

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