Effects of genotype on rates of substitution during experimental evolution

Rates of molecular evolution may vary widely between populations, yet the causes of this variation are still incompletely understood. Genetic differences between populations may make an important contribution to variation in rates of evolution, owing to differences in fitness, population size, mutation rates, or in the distribution of fitness effects (DFE) of available beneficial mutations. By whole genome sequencing of Escherichia coli populations experimentally evolved in the presence of a quinolone antibiotic, we found that rates of substitution varied by genotype, with evidence for a contribution from a genotype’s starting fitness. Subsequent targeted sequencing showed that genotypes with high average substitution rates were more likely to undergo the simultaneous fixation of several mutations, consistent with theoretical models of multiple mutation dynamics. Moreover, patterns of substitution were indicative of epistatic relationships between known resistance mutations.不同种群间的分子进化速率差异悬殊，然而该差异的成因仍未完全阐明。种群间的遗传差异可能对进化速率的变异产生重要贡献，这源于适合度、种群规模、突变率，或是可获得的有益突变的适合度效应分布（distribution of fitness effects, DFE）存在差异。本研究对在喹诺酮类抗生素环境下经实验进化的大肠杆菌（Escherichia coli）种群开展全基因组测序，结果发现不同基因型的替换速率存在差异，且证据表明基因型的初始适合度对此存在贡献。后续靶向测序结果显示，平均替换速率较高的基因型更易发生多个突变的同时固定，这与多突变动态的理论模型相符。此外，替换模式也反映出已知耐药突变之间存在上位性关系。