Physical constraints on epistasis

TL;DR

This paper shows that the physical dynamics of biological systems, especially slow collective modes, can constrain epistasis, reducing complexity and influencing evolvability.

Contribution

It demonstrates that slow physical modes lead to global epistasis, providing a mechanistic explanation for observed epistatic patterns in proteins and regulatory networks.

Findings

Physical dynamics constrain mutational effects.

Epistasis arises from global non-linearity on linear traits.

Constraints reduce the ruggedness of the sequence-to-function map.

Abstract

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 non-linearity applied to an underlying linear trait, i.e., 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.