Mutation rate variation in the yeast, Saccharomyces cerevisiae

Mutation is a fundamental process in biology. Mutation is necessary for evolution and lies at the heart of human disease. Variation in the rate at which mutations are produced can have profound consequences. Microorganisms that generate mutations at a higher rate have a selective advantage when adapting to novel environments, and this may play an important role in pathogenesis. An increase in the mutation rate of somatic cells may be a necessary step in the evolution of cancer, and individuals who inherit an elevated mutation rate are predisposed to developing the disease. For these reasons, the study of mutation rate variation has attracted great attention and impacted our understanding of nearly every aspect of biology from the dynamics of evolution, the mechanisms of bacterial pathogenesis, the functioning of the immune system, and the development of cancer. Despite its importance, the degree to which mutation rate can vary and the mechanisms underlying this variation are not entirely understood. A common method used to measure mutation rate is the fluctuation assay. I have increased the throughput of this assay and used it to characterize mutation rate variation in the budding yeast, Saccharomyces cerevisiae. I show that mutation rate is robust to variation in the duration of the cell cycle, but varies between strain backgrounds, between environments, and within the genome. I show that mutation rate varies between two common laboratory yeast strains and that mutation rate is increased under osmotic stress, consistent with the hypothesis that high salt induces strand breaks. In addition, I show that the mutation rate in the yeast genome is correlated with replication timing, consistent with a model regarding the temporal segregation of two modes of DNA damage tolerance during replication: error-free DNA damage tolerance and translesion synthesis. In support of this model, I show that elimination of translesion synthesis reduces mutation rate variation within the genome.