Department of Physics, University of Chicago, Chicago, IL.
Mol Biol Evol. 2020 Oct 1;37(10):2865-2874. doi: 10.1093/molbev/msaa124.
Living systems evolve one mutation at a time, but a single mutation can alter the effect of subsequent mutations. The underlying mechanistic determinants of such epistasis are unclear. Here, we demonstrate that the physical dynamics of a biological system can generically constrain epistasis. We analyze models and experimental data on proteins and regulatory networks. In each, we find that if the long-time physical dynamics is dominated by a slow, collective mode, then the dimensionality of mutational effects is reduced. Consequently, epistatic coefficients for different combinations of mutations are no longer independent, even if individually strong. Such epistasis can be summarized as resulting from a global nonlinearity applied to an underlying linear trait, that is, as global epistasis. This constraint, in turn, reduces the ruggedness of the sequence-to-function map. By providing a generic mechanistic origin for experimentally observed global epistasis, our work suggests that slow collective physical modes can make biological systems evolvable.
生物系统是逐次发生突变而进化的，但单个突变会改变后续突变的效应。这种上位性的潜在机械决定因素尚不清楚。在这里，我们证明了生物系统的物理动力学可以普遍限制上位性。我们分析了蛋白质和调控网络的模型和实验数据。在每一种情况下，我们都发现如果长时间的物理动力学主要由缓慢的集体模式主导，那么突变效应的维度就会降低。因此，即使单个突变的效应很强，不同突变组合的上位性系数也不再独立。这种上位性可以概括为应用于基础线性特征的全局非线性，即全局上位性。这种约束反过来又降低了序列到功能映射的崎岖程度。通过为实验观察到的全局上位性提供通用的机械起源，我们的工作表明，缓慢的集体物理模式可以使生物系统具有进化能力。
