Intraspecific sequence variation and complete genomes refine the identification of rapidly evolved regions in humans.

Abstract

Humans exhibit significant phenotypic differences from other great apes, yet pinpointing the underlying genetic changes has been limited by incomplete reference genomes and a reliance on single assemblies to represent a species. We aligned 20 telomere-to-telomere (T2T) assemblies spanning great ape divergence and variation to define 1,596 Consensus HAQERs (consensus human ancestor quickly evolved regions), regions that diverged rapidly between the human-chimpanzee ancestor and an ancestral node of modern humans. Unlike prior HAQER sets, Consensus HAQERs incorporate population variation, thereby reducing the likelihood of intraspecies variation appearing as interspecies divergence. Consensus HAQERs exhibit signatures of elevated mutation rates, ancient positive selection, and bivalent regulatory function; are enriched in disease-linked loci; and often emerged in previously inaccessible repetitive DNA. Through multiplex, single-cell enhancer assays, we identify HAQERs as active enhancers in the developing brain and cardiomyocytes, and we highlight their potential contributions to human-specific gene regulation across multiple tissues.