Evolution of mutation rates is determined by short term costs and long term benefits in proofreading polymerases

The nature of evolution is subject to evolution itself, through changes in modifier traits such as mutation and recombination rates. Mutation rate modifiers ("mutators") are frequently observed in both natural and experimental populations of microbes. However, little is known about the biophysical constraints that shape their long-term evolution. Here we study the evolution of mutation rates in proofreading polymerases using a self-replicating plasmid system in yeast. We find that a reversal of the classical speed-accuracy trade-off implies that mutator polymerases have distinct fitnesses on different timescales: variants leading to high mutation rates confer a long term benefit for their lineage but are often selected against in the short term due to their lower processivity. We determine the range of environmental conditions that select for mutators in the context of such biophysical constraints, and demonstrate that varying environments over time can select for mutators even when no static intermediate environments can. These results show how pleiotropic biophysical interactions between short- and long-term fitness can alter modifier selection in unexpected ways.