TY - JOUR TI - Global epistasis emerges from a generic model of a complex trait AU - Reddy, Gautam AU - Desai, Michael M A2 - Barkai, Naama A2 - Petrov, Dmitri A A2 - Crona, Kristina A2 - Krug, Joachim VL - 10 PY - 2021 DA - 2021/03/29 SP - e64740 C1 - eLife 2021;10:e64740 DO - 10.7554/eLife.64740 UR - https://doi.org/10.7554/eLife.64740 AB - Epistasis between mutations can make adaptation contingent on evolutionary history. Yet despite widespread ‘microscopic’ epistasis between the mutations involved, microbial evolution experiments show consistent patterns of fitness increase between replicate lines. Recent work shows that this consistency is driven in part by global patterns of diminishing-returns and increasing-costs epistasis, which make mutations systematically less beneficial (or more deleterious) on fitter genetic backgrounds. However, the origin of this ‘global’ epistasis remains unknown. Here, we show that diminishing-returns and increasing-costs epistasis emerge generically as a consequence of pervasive microscopic epistasis. Our model predicts a specific quantitative relationship between the magnitude of global epistasis and the stochastic effects of microscopic epistasis, which we confirm by reanalyzing existing data. We further show that the distribution of fitness effects takes on a universal form when epistasis is widespread and introduce a novel fitness landscape model to show how phenotypic evolution can be repeatable despite sequence-level stochasticity. KW - epistasis KW - complex trait KW - predictability JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -