Understanding the causal effects of genetic mutations is essential for explaining fitness variation, forecasting evolutionary trajectories and assessing extinction risk, yet remains a fundamental challenge, particularly in natural populations. While amino acid substitutions can alter protein structure and function, mutations affecting gene regulation can also have significant fitness consequences. In this Opinion Piece, we argue that epigenetic mechanisms, given their central role in gene regulation, probably modulate the deleteriousness of mutations. Drawing on evidence from humans and model organisms, we identify three ways in which epigenetic mechanisms might interact with deleterious mutations. Specifically, we hypothesize that epigenetic regulation may: (i) be disrupted by deleterious mutations in non-coding regions and epigenetic regulator genes; (ii) buffer the expression of deleterious mutations; and (iii) contribute to the repair and purging of deleterious mutations. Advances in next- and third-generation sequencing and bioinformatics now allow these hypotheses to be empirically tested in wild populations. As many species face ongoing population declines, unravelling how epigenetic mechanisms influence the functional effects of mutations is vital for understanding fitness variation, guiding evolutionary predictions and informing conservation strategies.

This article is part of the theme issue ‘Ecological epigenetics at the intersection of behaviour and life history variation in non-model animals’.