Reciprocal Sign Epistasis between Frequently Experimentally Evolved Adaptive Mutations Causes a Rugged Fitness Landscape

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Abstract
The fitness landscape captures the relationship between genotype and evolutionary fitness and is a pervasive metaphor used to describe the possible evolutionary trajectories of adaptation. However, little is known about the actual shape of fitness landscapes, including whether valleys of low fitness create local fitness optima, acting as barriers to adaptive change. Here we provide evidence of a rugged molecular fitness landscape arising during an evolution experiment in an asexual population of Saccharomyces cerevisiae. We identify the mutations that arose during the evolution using whole-genome sequencing and use competitive fitness assays to describe the mutations individually responsible for adaptation. In addition, we find that a fitness valley between two adaptive mutations in the genes MTH1 and HXT6/HXT7 is caused by reciprocal sign epistasis, where the fitness cost of the double mutant prohibits the two mutations from being selected in the same genetic background. The constraint enforced by reciprocal sign epistasis causes the mutations to remain mutually exclusive during the experiment, even though adaptive mutations in these two genes occur several times in independent lineages during the experiment. Our results show that epistasis plays a key role during adaptation and that inter-genic interactions can act as barriers between adaptive solutions. These results also provide a new interpretation on the classic Dobzhansky-Muller model of reproductive isolation and display some surprising parallels with mutations in genes often associated with tumors. How organisms adapt to their environment is of central importance in biology, but the molecular underpinnings of adaptation are difficult to discover. Fitness landscapes illustrate possible steps adaptive evolution can take to increase the evolutionary fitness of individuals within a population, and the shape of the fitness landscape determines the accessibility of the fittest point on the landscape. On a rugged landscape, negative interactions between mutations cause fitness valleys separating fitness peaks, which can constrain adaptation and act as an adaptive barrier. Here, we comprehensively characterized the fitness of mutations that arose in clones during a yeast experimental evolution and found that mutations in two loci, MTH1 and HXT6/HXT7, arose multiple times independently and are individually adaptive. However, when forced to co-occur, the double mutant has a lower fitness than either single mutant and even the wild-type strain. This negative interaction forces these two mutations to remain mutually exclusive during the experimental evolution and results in a rugged fitness landscape, where genetic constraint prevents lineages carrying the MTH1 mutation from reaching the higher fitness peak of HXT6/HXT7. These results show that genetic interactions are central in shaping a very active portion of this fitness landscape.