Population size mediates the contribution of high-rate and large-benefit mutations to parallel evolution

Abstract

Both mutations with large benefits and mutations occurring at high rates may cause parallel evolution, but their contribution is expected to depend on population size. We show that small and large bacterial populations adapt to a novel antibiotic using similar numbers, but different types of mutations. Small populations repeatedly substitute similar high-rate structural variants, including the deletion of a nonfunctional {beta}-lactamase, and evolve modest resistance levels. Hundred-fold larger populations more frequently use the same low-rate, large-benefit point mutations, including those activating the {beta}-lactamase, and reach 50-fold higher resistance levels. Our results demonstrate a key role of clonal interference in mediating the contribution of high-rate and large-benefit mutations in populations of different size, facilitated by a tradeoff between rates and fitness effects of different mutation classes.