Selection on mutators in experimental Saccharomyces cerevisiae populations: Recombination, clonal interference, and the evolution of mutation rates

The first part of this dissertation presents an experimental investigation of mutator dynamics in asexual and—for the first time—sexual populations of Saccharomyces cerevisiae. To examine the effect of recombination on a mutator allele msh2Δ, I propagated thirty replicate yeast populations with and without recombination while tracking msh2Δ frequency. Mutators increased in frequency at the expense of wild types in all asexual diploid populations in 150 generations of propagation. Over the same period of time, mutators declined toward loss in all sexual diploid populations as well as in haploid populations propagated asexually. The decline of msh2Δ in sexual populations is consistent with the predicted effect of recombination that is expected to erode mutator associations with beneficial mutations, inhibiting mutator hitchhiking. I also show that the msh2Δ mutator has a high and immediate realized cost that is alone sufficient to explain its decline in sexual populations. I postulate that this cost is indirect; namely, that it is due to a very high rate of recessive lethal or strongly deleterious mutation. My results prompt me to speculate that the short-term cost of highly deleterious recessive mutations can be as important as recombination in preventing mutator hitchhiking in some sexual populations. The second part of this dissertation examines the effect of total population size on mutator dynamics in asexual populations of yeast. Mutators quickly hitchhike to fixation in smaller populations, but mutator fixation requires more and more time as population size increases; this observed delay in mutator hitchhiking is consistent with the expected effect of clonal interference. Interestingly, despite their higher beneficial mutation supply rate, mutators are supplanted by the wild type in very large populations. I postulate that this striking reversal in mutator dynamics is caused by an interaction between clonal interference, the fitness cost of the mutator allele, and infrequent large-effect beneficial mutations in the experimental populations. This work thus identifies a potential set of circumstances under which mutator hitchhiking can be inhibited in natural asexual populations, despite recent theoretical predictions that such populations should have a net tendency to evolve ever-higher genomic mutation rates