Collaborative Research: Risk and reward of high mutation rate: why large populations favor mutators while small populations inhibit them

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Genetic variation, the raw material for evolution, is ultimately generated by mutation. The rate of mutation is influenced by particular genes, e.g. for DNA replication and repair enzymes, which can themselves be altered by mutations. Some variants of those genes, known as mutators, increase the genomic rate of mutation. Even when mutators have no direct effect on survival and reproduction of the individual, they can experience indirect selection via genetic linkage to beneficial and deleterious mutations that occur elsewhere in the genome. This proposal explores a novel hypothesis that population size may have an effect on indirect selection experienced by mutators. Understanding the role of population size and spatial structure in shaping the evolution of mutation rate may resolve a longstanding empirical puzzle: why mutators frequently emerge in well-mixed microbial laboratory populations, yet are only sporadically found in nature. This project has important implications for understanding both natural and directed genetic changes in basic, health, conservation, and agriculture research. For example, this research may illuminate the role of mutators during disease progression of cancer tumors. The investigators will also work directly with K-12 teachers and students to improve their understanding of genetics and scientific inquiry. Building on several of their previous publications, the applicants present preliminary calculations and experimental results suggesting that large populations enrich for mutators and small populations inhibit them. In specific aim 1, the applicants propose to extend their calculations by developing computer simulations and mathematical analysis to model the evolution of mutators in complex and realistic scenarios, including spatially structured environments. In specific aim 2 the applicants propose to experimentally test their predictions in the laboratory by competing mutator and non-mutator strains of Saccharomyces cerevisiae yeast. Competitions will be monitored by fluorescence and conducted across a range of population sizes and spatial structures.