Abstract
Mutations are the root source of genetic variation and underlie the process of evolution. Although the rates at which mutations occur vary considerably between species, little is known about differences within species, or the genetic and molecular basis of these differences. Here we leveraged the power of the yeast Saccharomyces cerevisiae as a model system to uncover natural genetic variants that underlie variation in mutation rate. We developed a high-throughput fluctuation assay and used it to quantify mutation rates in natural yeast isolates and in 1008 segregant progeny from a cross between BY, a lab strain, and RM, a wine strain. We observed that mutation rate varies among yeast strains and is highly heritable (H2=0.46). We performed linkage mapping in the segregants and identified four quantitative trait loci (QTLs) underlying mutation rate variation in the cross. We fine-mapped two QTLs to the underlying causal genes, RAD5 and MKT1, that contribute to mutation rate variation. These genes also underlie sensitivity to the DNA damaging agents 4NQO and MMS, suggesting a connection between spontaneous mutation rate and mutagen sensitivity.
Author Summary Spontaneous mutation rate varies between species, as well as between individuals within species. The genetic basis for mutation rate variation within species is poorly understood. Part of the challenge is accurately measuring mutation rates in many individuals. We addressed this challenge by developing a high-throughput fluctuation assay, and we used this assay to identify and genetically dissect differences in mutation rate between yeast strains. To do so, we measured mutation rates in 1008 segregant progeny from a cross between a laboratory strain and a vineyard strain and used linkage analysis to map four genetic loci underlying the mutation rate variation in this cross. We then identified the genes and variants that underlie the two loci with largest contributions to mutation rate variation. These genes also affect sensitivity to DNA damaging agents, suggesting a connection between spontaneous mutation rate and mutagen sensitivity.