The interplay between epigenetic mechanisms and deleterious mutations: implications for fitness, evolution and conservation

This is a Preprint and has not been peer reviewed. This is version 1 of this Preprint. You must log in to post a comment. There are no comments or no comments have been made public for this article. This is a Preprint and has not been peer reviewed. This is version 1 of this Preprint. Add a Comment You must log in to post a comment. Comments There are no comments or no comments have been made public for this article. 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, likely 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. https://doi.org/10.32942/X2RM11 Biology, Ecology and Evolutionary Biology, Genetics, Genetics and Genomics, Genomics, Life Sciences, Molecular Genetics Epigenetics, DNA methylation, deleterious mutation, Genetic load Published: 2026-01-14 04:08 Last Updated: 2026-01-14 04:08 CC BY Attribution 4.0 International Conflict of interest statement: None Data and Code Availability Statement: Not applicable Language: English