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Synergistic Fitness Interactions and a High Frequency of Beneficial Changes Among Mutations Accumulated Under Relaxed Selection in Saccharomyces cerevisiae

Spontaneous mutations were accumulated for ∼4800 generations in 48 lines of yeast protected from effective selection by frequent passage through single-cell bottlenecks. Changes in fitness were evaluated by direct competition with matched parental stocks differing only at a selectively neutral marker locus. Average fitness declined by ∼5% over the course of the experiment. The rate of change increased sharply in later generations, strongly suggesting synergistic epistasis. Divergence among lines increased rapidly relative to the change in average fitness and also at an accelerating pace. Both results are well matched by a model assuming that fitness cost increases exponentially (approximately second order) with the number of accumulated mutations. This result is consistent with fitness loss due primarily to interactions between specific pairs of gene products. I also estimate that ∼25% of the mutations with detectable fitness effects were beneficial. This result can be explained by the fact that the effects of most mutations are small relative to the distance from a local fitness optimum.