From Bad to Good: Fitness Reversals and the Ascent of Deleterious Mutations

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Abstract
Deleterious mutations are considered a major impediment to adaptation, and there are straightforward expectations for the rate at which they accumulate as a function of population size and mutation rate. In a simulation model of an evolving population of asexually replicating RNA molecules, initially deleterious mutations accumulated at rates nearly equal to that of initially beneficial mutations, without impeding evolutionary progress. As the mutation rate was increased within a moderate range, deleterious mutation accumulation and mean fitness improvement both increased. The fixation rates were higher than predicted by many population-genetic models. This seemingly paradoxical result was resolved in part by the observation that, during the time to fixation, the selection coefficient (s) of initially deleterious mutations reversed to confer a selective advantage. Significantly, more than half of the fixations of initially deleterious mutations involved fitness reversals. These fitness reversals had a substantial effect on the total fitness of the genome and thus contributed to its success in the population. Despite the relative importance of fitness reversals, however, the probabilities of fixation for both initially beneficial and initially deleterious mutations were exceedingly small (on the order of 10−5 of all mutations). Mutations are the fuel of natural selection. It is widely believed that most mutations are deleterious, that is, they harm the organisms in which they occur. Thus, biologists would like to understand how deleterious mutations impact evolution. Most of the theoretical work on this problem makes an important assumption: mutations that start bad stay bad. It may be possible, however, for an initially bad mutation to become good (beneficial) by interacting with subsequent mutations. In this study, Cowperthwaite, Bull, and Meyers show that such “fitness reversals” are surprisingly common and can lead to the fixation of initially deleterious mutations. Perhaps mutations that undergo such changes serve as stepping stones for greater evolutionary progress.