Molecular evolution in light of regulatory-coding epistasis

Predicting the fitness effects of mutations is central to understanding molecular evolution and interpreting genome sequence data. Such predictions remain challenging due to the inter-dependent roles of coding and non-coding genetic variation. While coding mutations alter protein structure, stability, activity, and sometimes abundance, regulatory mutations modulate gene expression timing and levels. Because coding and regulatory variation are thought to independently impact features of protein function, their combined effects or complex phenotypes are often unexpected. In particular, regulatory-coding epistasis, whereby the fitness effect of a coding mutation depends on the regulatory background, can reshape fitness landscapes and influence adaptive trajectories. In this review, we explore how variation in protein abundance and activity jointly shape fitness, constrain adaptation, and impact molecular evolution. Drawing on examples from systematic studies carried out in unicellular organisms, we speculate on a fitness function integrating abundance and activity and discuss the broader implications of these interactions for evolutionary dynamics, genetic disease, and phenotypic diversity.