The role of histone modifications and transposable elements in the epigenetic regulation of gene dosage after gene duplication

The duplication of genes has long been recognized as a substrate for evolutionary novelty and adaptation, but the factors that govern fixation of paralogs soon after duplication are only partially understood. Duplication often leads to an increase in gene dosage, or the amount of functional gene product. For genes with which an increased dosage is harmful (i.e., triplosensitive genes), a dosage balancing mechanism needs to be present immediately after duplication if it is to evade negative selection. Previous research in vertebrates has demonstrated a potential role for epigenetic factors in allowing triplosensitive genes to increase in copy number by regulating their expression post-duplication. Here we expand this research by investigating the epigenetic landscape of duplicate genes in D. discoideum , a basal lineage separated from humans by over a billion years. We found that activating histone modifications are quickly lost in duplicate genes before gradually increasing in enrichment as paralogs age. For the repressive modification H3K9me3, we found it was enriched in the youngest paralogs, and that this enrichment was likely mediated by heterochromatin spread from transposable elements. We similarly found enrichment of H3K9me3 in young human duplicates, and again found transposable elements as a potential mediator. Finally, we leveraged recent genome-wide estimates of triplosensitivity in human genes to directly examine the relationship between this kind of dosage sensitivity and enrichment for repressive histone modifications. Interestingly, while we found no significant link between enrichment for the repressive mark H3K9me3 and triplosensitivity in human paralogs, we did find a significant association between triplosensitivity and transposon proximity. Our findings suggest that transposons may contribute to the epigenetic regulatory environment associated with dosage balancing of young duplicates in both protists and humans.