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

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.

SUMO and cellular adaptive mechanisms

“…The DNA sequencing of natural isolates of yeast strains, which tend to preferentially undergo asexual reproduction, revealed ~63% heterozygosity, suggesting some fitness advantage for this condition 42 . Higher levels of heterozygosity in yeast are observed under diverse stress conditions, such as exposure to the antifungal drug fluconazole, growth at high temperature, or incompatibility of the mismatch repair genes MLH1-PMS1 43 , 44 .…”

A stress response that allows highly mutated eukaryotic cells to survive and proliferate

“…Conservation of a response that allows pathogens to adopt hypermutator states with minimal fitness cost could be beneficial for evolution over short and long timescales. Indeed, many microbial pathogens, and even wild fungal populations, frequently adopt a hypermutator state (Bui et al, 2017;Guo et al, 2018;Raghavan et al, 2018). The alleles that govern this behavior have been retained across a considerable evolutionary distance (Bui et al, 2017), suggesting that it confers an adaptive advantage.…”

Advances in understanding the evolution of fungal genome architecture

“…Incompatibilities in the mismatch repair components Mlh1 and Pms1 have also been reported to contribute to hypermutation in S. cerevisiae laboratory strains 46 , 47 . Studies have identified several S. cerevisiae strains isolated from humans that encode these same MLH1 - PMS1 incompatible alleles 48 . Although the S. cerevisiae diploids with incompatible alleles isolated from humans were not hypermutators themselves, their meiotic progeny displayed a wide range of mutation rates and included hypermutators, thus providing an opportunity to produce progeny with variable fitness under stressful conditions 47 , 48 .…”

“…Studies have identified several S. cerevisiae strains isolated from humans that encode these same MLH1 - PMS1 incompatible alleles 48 . Although the S. cerevisiae diploids with incompatible alleles isolated from humans were not hypermutators themselves, their meiotic progeny displayed a wide range of mutation rates and included hypermutators, thus providing an opportunity to produce progeny with variable fitness under stressful conditions 47 , 48 . Another mechanism of hypermutation caused by a mutation in a DNA polymerase delta subunit was also described in C. neoformans ; this mechanism of hypermutation resulted in genome-wide increases in transition and transversion mutations but reduced viability and virulence 49 , 50 .…”