Shifting epigenetic contexts influence regulatory variation and disease risk.

Epigenetic shifts are a hallmark of aging that impact transcriptional networks at regulatory level. These shifts may modify the effects of genetic regulatory variants during aging and contribute to disease pathomechanism. However, these shifts occur on the backdrop of epigenetic changes experienced throughout an individual's development into adulthood; thus, the phenotypic, and ultimately fitness, effects of regulatory variants subject to developmental- versus aging-related epigenetic shifts may differ considerably. Natural selection therefore may act differently on variants depending on their changing epigenetic context, which we propose as a novel lens through which to consider regulatory sequence evolution and phenotypic effects. Here, we define genomic regions subjected to altered chromatin accessibility as tissues transition from their fetal to adult forms, and subsequently from early to late adulthood. Based on these epigenomic datasets, we examine patterns of evolutionary constraint and potential functional impacts of sequence variation (e.g., genetic disease risk associations). We find that while the signals observed with developmental epigenetic changes are consistent with stronger fitness consequences (i.e., negative selection pressures), they tend to have weaker effects on genetic risk associations for aging-related diseases. Conversely, we see stronger effects of variants with increased local accessibility in adult tissues, strongest in young adult when compared to old. We propose a model for how epigenetic status of a region may influence the effects of evolutionary relevant sequence variation, and suggest that such a perspective on gene regulatory networks may elucidate our understanding of aging biology.