High-order epistasis shapes evolutionary trajectories

High-order epistasis—where the effect of a mutation is determined by interactions with two or more other mutations—makes small, but detectable, contributions to genotype-fitness maps. While epistasis between pairs of mutations is known to be an important determinant of evolutionary trajectories, the evolutionary consequences of high-order epistasis remain poorly understood. To determine the effect of high-order epistasis on evolutionary trajectories, we computationally removed high-order epistasis from experimental genotype-fitness maps containing all binary combinations of five mutations. We then compared trajectories through maps both with and without high-order epistasis. We found that high-order epistasis strongly shapes the accessibility and probability of evolutionary trajectories. A closer analysis revealed that the magnitude of epistasis, not its order, predicts is effects on evolutionary trajectories. We further find that high-order epistasis makes it impossible to predict evolutionary trajectories from the individual and paired effects of mutations. We therefore conclude that high-order epistasis profoundly shapes evolutionary trajectories through genotype-fitness maps.高阶上位性（high-order epistasis）——即突变的效应由其与两个或更多其他突变的相互作用所决定——对基因型-适应度图谱（genotype-fitness maps）具有微小但可检测的贡献。尽管已知成对突变间的上位性是进化轨迹的重要决定因素，但学界对高阶上位性的进化后果仍认知匮乏。为探明高阶上位性对进化轨迹的影响，我们从包含5种突变的全部二进制组合的实验基因型-适应度图谱中，通过计算手段移除了高阶上位性。随后我们对比了存在与不存在高阶上位性的图谱中的进化轨迹。研究发现，高阶上位性会显著影响进化轨迹的可达性与发生概率。进一步分析表明，上位性的强度而非其阶数，能够预测其对进化轨迹的影响。我们还发现，高阶上位性使得无法仅通过单个突变及成对突变的效应来预测进化轨迹。因此我们得出结论：高阶上位性会通过基因型-适应度图谱深刻塑造进化轨迹。