Mutation-biased adaptation is consequential even in large bacterial populations

Adaptive variation is typically presented to selection in a biased manner, owing to vast differences in effective mutation rates across genomes, organisms and environments. Yet, how strongly and how generally such bias shapes adaptation remains poorly understood. Here we used a well-known experimental system in which two Escherichia coli mutator variants evolve antibiotic resistance via two mutationally favored, but genetically distinct routes. Through simulations and experiments, we show that the scaling of mutation-biased adaptation with population size is complex, highly dependent on biological details, and—most critically—on how closely mutation bias aligns with selection. Contrary to the common view, we find that mutation-biased adaptation may not wane in large populations but instead intensify depending on the nature of the bias. Crucially, we demonstrate that distinct mutation biases can produce markedly different collateral sensitivity profiles to multiple antibiotics, even at large population sizes. These findings suggest that mutation-biased adaptation may not only be widespread but also have far-reaching and unpredictable consequences both within and beyond the original selective context.