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Understanding how beneficial mutations affect fitness is crucial to our understanding of adaptation by natural selection. Here, using adaptation to the antibiotic rifampicin in the opportunistic pathogen Pseudomonas aeruginosa as a model system, we investigate the underlying distribution of fitness effects of beneficial mutations on which natural selection acts. Consistent with theory, the effects of beneficial mutations are exponentially distributed where the fitness of the wild type is moderate to high. However, when the fitness of the wild type is low, the data no longer follow an exponential distribution, because many beneficial mutations have large effects on fitness. There is no existing population genetic theory to explain this bias towards mutations of large effects, but it can be readily explained by the underlying biochemistry of rifampicin-RNA polymerase interactions. These results demonstrate the limitations of current population genetic theory for predicting adaptation to severe sources of stress, such as antibiotics, and they highlight the utility of integrating statistical and biophysical approaches to adaptation.

Original publication




Journal article


PLoS Genet

Publication Date





Anti-Bacterial Agents, DNA-Directed RNA Polymerases, Mutation, Phenotype, Pseudomonas aeruginosa, Rifampin, Selection, Genetic