Evolution of Enhancers through Duplication

Duplication is appreciated as a key source of genomic novelty. In this study, we examined putative enhancers in the human genome to investigate how duplication influences the evolution of these enhancers. We strictly identified a set of 3,336 confident duplicate enhancer pairs and examined their genomic and evolutionary features. We found that, compared to non-duplicated enhancers, duplicated enhancers tend to be longer, more pleiotropic, closer to genes, and harbor greater numbers and more diverse groups of transcription factor binding motifs. These attributes were more pronounced for evolutionarily older duplicate enhancers. Therefore, the regulatory potentials of enhancers may facilitate evolutionary maintenance of duplicated enhancers. Utilizing chimpanzee and rhesus macaque as outgroups, we found that between 30-40% of the examined duplicate enhancers exhibit evidence of asymmetric sequence evolution. Notably, the majority of the "accelerating enhancers" in such pairs gained enhancer activities in novel tissues, particularly in immune-related tissues. Moreover, the accelerating enhancers tended to harbor transcription factor binding motifs previously implicated in human evolution, and enriched in associations with immune functions and stress responses. These findings indicate that duplication may contribute to the proliferation of highly pleiotropic enhancers, as well as gaining novel enhancer activities, and contribute to rapid evolution of the immune system.