Heritable epigenetic variation facilitates long-term maintenance of epigenetic and genetic variation

Understanding how genetic and phenotypic variation is maintained is a major problem in population and quantitative genetics. A variety of factors have been implicated to explain the maintenance of genetic variation in some contexts (e.g. balancing selection), but the potential role of epigenetic regulation to influence population dynamics has been understudied. It is well recognized that epigenetic regulation, including histone methylation, small RNA expression, and DNA methylation, helps to define differences between cell types and facilitate phenotypic plasticity. In recent years, empirical studies have shown the potential for epigenetic regulation to also be heritable for at least a few generations without selection, raising the possibility that differences in epigenetic regulation can act alongside genetic variation to shape evolutionary trajectories. Like genetic mutation, heritable differences in epigenetic regulation can arise spontaneously; these are termed ‘epimutations’. Epimutations differ from genetic mutations in two key ways – they occur at a higher rate, and the loci at which they occur often revert back to their original state within a few generations. Here, we present an extension of the standard population-genetic model with selection to incorporate epigenetic variation arising via epimutation. Our model assumes a diploid, sexually reproducing population with random mating. In addition to spontaneous genetic mutation, we included parameters for spontaneous epimutation and back-epimutation, allowing for four potential epialleles at a single locus (two genetic alleles, each with two epigenetic states), each of which affect fitness. We then analyzed the conditions under which stable epialleles were maintained. Our results show that highly reversible epialleles can be maintained in long-term equilibrium in a manner that depends primarily on the epimutation and back-epimutation rates, and for certain fitness parameters, alleles with high fitness can facilitate the maintenance of recessive deleterious alleles that would otherwise be purged from the population. This demonstrates that transient epigenetic regulation may be an important factor in the maintenance of both epigenetic and genetic variation in populations.