The origin of mutational epistasis

Abstract

The interconnected processes of protein folding, mutations, epistasis, and evolution have all been the subject of extensive analysis throughout the years due to their signifcance for structural and evolutionary biology. The origin (molecular basis) of epistasis—the non-additive interactions between mutations—is still, nonetheless, unknown. The existence of a new perspective on protein folding, a problem that needs to be conceived as an ‘analytic whole’, will enable us to shed light on the origin of mutational epistasis at the simplest level—within proteins—while also uncovering the reasons why the genetic background in which they occur, a key component of molecular evolution, could foster changes in epistasis efects. Additionally, because mutations are the source of epistasis, more research is needed to determine the impact of post-translational modifcations, which can potentially increase the proteome’s diversity by several orders of magnitude, on mutational epistasis and protein evolvability. Finally, a protein evolution thermodynamic-based analysis that does not consider specifc mutational steps or epistasis efects will be briefy discussed. Our study explores the complex processes behind the evolution of proteins upon mutations, clearing up some previously unresolved issues, and providing direction for further research.