Reversion is Most Likely Under High Mutation Supply when Compensatory Mutations Do Not Fully Restore Fitness Costs

The dynamics of adaptation, reversion, and compensation have been central topics in microbial evolution, and several studies have attempted to resolve the population genetics underlying how these dynamics occur. However, questions remain regarding how certain features-the evolution of mutators and whether compensatory mutations alleviate costs fully or partially-may influence the evolutionary dynamics of compensation and reversion. In this study, we attempt to explain findings from experimental evolution by utilizing computational and theoretical approaches toward a more refined understanding of how mutation rate and the fitness effects of compensatory mutations influence adaptive dynamics. We find that high mutation rates increase the probability of reversion toward the wild type when compensation is only partial. However, the existence of even a single fully compensatory mutation is associated with a dramatically decreased probability of reversion to the wild type. These findings help to explain specific results from experimental evolution, where compensation was observed in nonmutator strains, but reversion (sometimes with compensation) was observed in mutator strains, indicating that real-world compensatory mutations are often unable to fully alleviate the costs associated with adaptation. Our findings emphasize the potential role of the supply and quality of mutations in crafting the dynamics of adaptation and reversal, with implications for theoretical population genetics and for biomedical contexts like the evolution of antibiotic resistance.