Network and Evolutionary Analysis of Human Epigenetic Regulators to Unravel Disease Associations.

We carried out a system-level analysis of epigenetic regulators (ERs) and detailed the protein-protein interaction (PPI) network characteristics of disease-associated ERs. We found that most diseases associated with ERs can be clustered into two large groups, cancer diseases and developmental diseases. ER genes formed a highly interconnected PPI subnetwork, indicating a high tendency to interact and agglomerate with one another. We used the disease module detection (DIAMOnD) algorithm to expand the PPI subnetworks into a comprehensive cancer disease ER network (CDEN) and developmental disease ER network (DDEN). Using the transcriptome from early mouse developmental stages, we identified the gene co-expression modules significantly enriched for the CDEN and DDEN gene sets, which indicated the stage-dependent roles of ER-related disease genes during early embryonic development. The evolutionary rate and phylogenetic age distribution analysis indicated that the evolution of CDEN and DDEN genes was mostly constrained, and these genes exhibited older evolutionary age. Our analysis of human polymorphism data revealed that genes belonging to DDEN and Seed-DDEN were more likely to show signs of recent positive selection in human history. This finding suggests a potential association between positive selection of ERs and risk of developmental diseases through the mechanism of antagonistic pleiotropy.