INCOMPATIBILITIES IN MISMATCH REPAIR GENES MLH1-PMS1 CONTRIBUTE TO A WIDE RANGE OF MUTATION RATES IN HUMAN ISOLATES OF BAKER'S YEAST

Abstract

The mismatch repair (MMR) pathway maintains genome stability by repairing mutations incorporated in the genome during replication and recombination. While most microorganisms tend to have low mutation rates, a higher mutation rate can provide transient adaptive advantage to stress conditions by promoting adaptive mutations. Variants of the MMR genes, MLH1 and PMS1 from different yeast strains can display an incompatibility that results in a high mutation rate. MLH1 and PMS1 function as a heterodimer and the incompatibility is a result of single amino acid polymorphism in each protein. The incompatibility provides an adaptive advantage under stress but does so at the cost of long-term fitness. I identified 18 baker’s yeast isolates from 1011 yeast isolates surveyed that contain the incompatible MLH1-PMS1 genotype in a heterozygous state. I tested the mutation rates of two clinical heterozygous diploid isolates, YJS5885 and YJS5845, and their spore clones. While both of these isolates were non-mutators, their meiotic spore progeny displayed mutation rates that varied over a 340-fold range, and MLH1-PMS1 incompatibility was the major driver of high mutation rate. The range in mutation rates might be in part because these isolates are heterozygous for several genes that may be modifying the mutation rate. My data are consistent with the variance in mutation rate contributing to adaptation to stress conditions 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. Furthermore, I observed that one of the isolates was aneuploid and generated aneuploid spore clones at a high frequency. Aneuploidy also provides a transient adaptive advantage under stress conditions. Thus, I obtained evidence for mechanisms in clinical yeast isolates that may provide an adaptive advantage in the human body.