RT Journal Article SR Electronic T1 Global Epistasis Makes Adaptation Predictable Despite Sequence-Level Stochasticity JF bioRxiv FD Cold Spring Harbor Laboratory SP 001784 DO 10.1101/001784 A1 Sergey Kryazhimskiy A1 Daniel P. Rice A1 Elizabeth R. Jerison A1 Michael M. Desai YR 2014 UL http://biorxiv.org/content/early/2014/01/13/001784.abstract AB Epistasis can make adaptation highly unpredictable, rendering evolutionary trajectories contingent on the chance effects of initial mutations. We used experimental evolution in Saccharomyces cerevisiae to quantify this effect, finding dramatic differences in adaptability between 64 closely related genotypes. Despite these differences, sequencing of 105 evolved clones showed no significant effect of initial genotype on future sequence-level evolution. Instead, reconstruction experiments revealed a consistent pattern of diminishing returns epistasis. Our results suggest that many beneficial mutations affecting a variety of biological processes are globally coupled: they interact strongly, but only through their combined effect on fitness. Sequence-level adaptation is thus highly stochastic. Nevertheless, fitness evolution is strikingly predictable because differences in adaptability are determined only by global fitness-mediated epistasis, not by the identity of individual mutations.