Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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 between beneficial mutations, because many beneficial mutations are available, and while the fitness landscape is rugged at the fine scale, it is smooth and regular when we consider the average over possible routes to adaptation. In the context of antibiotic resistance, these results show that acquiring mutations that confer low levels of antibiotic resistance does not impose any constraint on the ability to evolve high levels of resistance.

Original publication




Journal article



Publication Date





1345 - 1354


Biological Evolution, Drug Resistance, Microbial, Epistasis, Genetic, Genetic Fitness, Genotype, Mutation, Pseudomonas aeruginosa, Rifampin