Diminishing Returns From Beneficial Mutations and Pervasive Epistasis Shape the Fitness Landscape for Rifampicin Resistance in Pseudomonas aeruginosa

作者：R. Craig MacLean, Gabriel G. Perron, Andy Gardner · 发表于：Genetics · 年份：2010 · DOI：10.1534/genetics.110.123083 · 被引用次数：208 · 研究领域：Evolution and Genetic Dynamics、Evolutionary Game Theory and Cooperation、Mathematical and Theoretical Epidemiology and Ecology Models

Because adaptation depends upon the fixation of novel beneficial mutations, the fitness effects of beneficial mutations that are substituted by selection are key to our understanding of the process of adaptation. In this study, we experimentally investigated the fitness effects of beneficial mutations that are substituted when populations of the pathogenic bacterium Pseudomonas aeruginosa adapt to the antibiotic rifampicin. Specifically, we isolated the first beneficial mutation to be fixed by selection when 96 populations of three different genotypes of P. aeruginosa that vary considerably in fitness in the presence of rifampicin were challenged with adapting to a high dose of this antibiotic. The simple genetics of rifampicin resistance allowed us to determine the genetic basis of adaptation in the majority of our populations. We show that the average fitness effects of fixed beneficial mutations show a simple and clear pattern of diminishing returns, such that selection tends to fix mutations with progressively smaller effects as populations approach a peak on the adaptive landscape. The fitness effects of individual mutations, on the other hand, are highly idiosyncratic across genetic backgrounds, revealing pervasive epistasis. In spite of this complexity of genetic interactions in this system, there is an overall tendency toward diminishing-returns epistasis. We argue that a simple overall pattern of diminishing-returns adaptation emerges, despite pervasive epistasis bet...