Divergence, Mutation, Function, Selection: The Evolution of the Human Genome

Abstract

Searches for the genetic underpinnings of uniquely human traits have focused on human-specific divergence in conserved genomic regions, which reflects adaptive modifications of existing functional elements. However, the study of conserved regions excludes novel functional elements that descended from previously neutral regions. In this work, I integrate comparative genomic analyses with human population variation data to reveal that rapid divergence rate is associated with positive selection in human evolutionary history. Encouraged by this finding, I identified 1581 Human Ancestor Quickly Evolved Regions (HAQERs), which represent the fastest-evolved regions of the human genome. HAQERs rapidly diverged in an episodic burst of directional positive selection prior to the human-Neanderthal split before transitioning to constraint within hominins. HAQERs are enriched for bivalent chromatin states, particularly in gastrointestinal and neurodevelopmental tissues, and genetic variants linked to neurodevelopmental disease. I led a collaborative effort to develop scSTARR-seq as a multiplex single-cell in vivo enhancer assay to discover that rapid sequence divergence in HAQERs generated hominin-unique enhancers in the developing cerebral cortex. I propose that a lack of pleiotropic constraints and elevated mutation rates poised HAQERs for rapid adaptation and subsequent susceptibility to disease.