Mutation rate variability as a driving force in adaptive evolution

TL;DR

This study explores how variability in mutation rates influences bacterial adaptation and antibiotic resistance, revealing that extreme stress levels amplify the impact of hypermutation on resistance fixation.

Contribution

It demonstrates how mutation rate variability affects resistance evolution, especially under specific environmental stresses, linking biophysical fitness to population dynamics.

Findings

Hypermutation significantly influences resistance fixation under certain stress conditions.

Genetic hitchhiking propagates high-mutation rate cells with high-fitness mutations.

Resistance evolution is most sensitive to mutation rate changes when selective advantage is weak.

Abstract

Mutation rate is a key determinant of the pace as well as outcome of evolution, and variability in this rate has been shown in different scenarios to play a key role in evolutionary adaptation and resistance evolution under stress caused by selective pressure. Here we investigate the dynamics of resistance fixation in a bacterial population with variable mutation rates and show that evolutionary outcomes are most sensitive to mutation rate variations when the population is subject to environmental and demographic conditions that suppress the evolutionary advantage of high-fitness subpopulations. By directly mapping a biophysical fitness function to the system-level dynamics of the population we show that both low and very high, but not intermediate, levels of stress in the form of an antibiotic result in a disproportionate effect of hypermutation on resistance fixation. We demonstrate how this behavior is directly tied to the extent of genetic hitchhiking in the system, the propagation of high-mutation rate cells through association with high-fitness mutations. Our results indicate a substantial role for mutation rate flexibility in the evolution of antibiotic resistance under conditions that present a weak advantage over wildtype to resistant cells.