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

Mutations with large fitness benefits and mutations occurring at high rates may both cause parallel evolution, but their contribution is predicted to depend on population size. Moreover, high-rate and large-benefit mutations may have different long-term adaptive consequences. We show that small and 100-fold larger bacterial populations evolve resistance to a beta-lactam antibiotic by using similar numbers, but different types of mutations. Small populations frequently substitute similar high-rate structural variants and loss-of-function point mutations, including the deletion of a low-activity beta-lactamase, and evolve modest resistance levels. Large populations more often use low-rate, large-benefit point mutations affecting the same targets, including mutations activating the beta-lactamase and other gain-of-function mutations, leading to much higher resistance levels. Our results demonstrate the separation by clonal interference of mutation classes with divergent adaptive consequences, causing a shift from high-rate to large-benefit mutations with increases in population size. Population size influences mutation supply but may also influence what types of mutations eventually become fixed. Here, Schenk et al. show that small and large experimentally evolving bacteria populations predictably fix different types of mutations, with greater antibiotic resistance emerging in large populations.

Automated summary

This study shows that small and large bacterial populations evolving resistance to β-lactam antibiotics fix different types of mutations, leading to greater antibiotic resistance in large populations.