Dissecting the evolution of human enhancer sequences

Abstract

Divergent regulation of gene expression is a major driver of species divergence, however, the relationship between gene regulatory sequence evolution and its functional effects on gene expression are poorly understood. This dissertation attempts to bridge the gap between evolutionary history, function, and variation in human enhancer sequences. I integrate comparative genomics, evolutionary, and functional reporter assay data to determine the origins of sequences with enhancer functions in humans. Functional genomics data is then used to interpret the features linked to distinct evolutionary histories. To determine the genetic mechanisms that produce functional gene regulatory divergence between humans and their close relative, rhesus macaques, I systematically dissect cis-DNA sequence and trans-cellular environment attributes that differ across all active regulatory elements in human and rhesus macaque lymphoblastoid cell models. Together, this body of work expands on previous knowledge of enhancer sequence evolution and links to function, revises the proposed nucleation model of enhancer sequence evolution, and reveals the widespread effects of trans-species-specific cellular environments on divergent regulatory activity.