Microbial evolution. Global epistasis makes adaptation predictable despite sequence-level stochasticity

Abstract

Epistatic interactions between mutations can make evolutionary trajectories contingent on the chance occurrence of initial mutations. We used experimental evolution in Saccharomyces cerevisiae to quantify this contingency, finding differences in adaptability among 64 closely related genotypes. Despite these differences, sequencing of 104 evolved clones showed that initial genotype did not constrain future mutational trajectories. Instead, reconstructed combinations of mutations revealed a pattern of diminishing-returns epistasis: Beneficial mutations have consistently smaller effects in fitter backgrounds. Taken together, these results show that beneficial mutations affecting a variety of biological processes are globally coupled; they interact strongly, but only through their combined effect on fitness. As a consequence, fitness evolution follows a predictable trajectory even though sequence-level adaptation is stochastic.

Figure 1

Fitness evolution. (A) The distribution of mean population fitness over time, relative to DivAnc. Inset shows inter-population fitness variation over time. (B) Fraction of the variance between lines in fitness increment after 250 and 500 generations of the Adaptation phase that is attributable to each indicated component. All variance components are significant (Table S3). (C) Relationship between Founder fitness and population fitness after 250 and 500 generations of Adaptation. (D) Relationship between Founder fitness and the mean fitness of the 10 independent lines descended from that Founder, after 250 and 500 generations of Adaptation. Error bars show ±1 standard error of the mean (sem).

Figure 2

Sequence-level evolution. (A) Mutations from the Adaptation phase arranged by type. (B) Clones descended from different Founders acquired on average about the same number of putatively functional mutations (see also Fig. S5, S6). (C) Convergence and parallelism at the gene (top, orange) and GO Slim (bottom, blue) levels. Cell color represents the average number of mutations shared by two clones descended from the Founders indicated in the row and column headers. Founders are ordered from least-fit (left, bottom) to most-fit (right, top). Row and column width represents the number of clones sequenced. (D) Mutations in multihit genes and the Founder backgrounds in which they were observed (top); putatively functional mutations that determine the Founder background (bottom). Asterisks indicate genes mutated in both Diversification and Adaptation phases.

Figure 3

Diminishing returns epistasis among specific mutations. The fitness effect of knocking out genes gat2, whi2, and sfl1 declines with the fitness of the background strain. The ho knockout is a negative control. Error bars show ±1 sem over biological replicates.