Highly Divergent Genomic Regions Underlying Human-Unique Traits

Abstract

The genetic basis of human-unique traits such as advanced cognitive capabilities is still largely unknown, despite the abundance of genetics and evolution research since around 1850. Previous research did not focus functional assays on the most extremely divergent genomic regions. Instead, it either focused on elements with existing function pre-human, or found elements with innovative function in one tissue at a time. To overcome these limitations, I searched for highly divergent genomic regions that have not only novel sequence but also innovative function in any tissue, leveraging technical innovations from telomere-to-telomere (T2T) genome resources to custom software tools. Building upon the initial set of Gapped HAQERs (Human Ancestor Quickly Evolved Regions), I identified the updated T2T and Consensus HAQER sets. The latest Consensus HAQER set aligned 20 T2T assemblies spanning great ape divergence and variation to define regions that diverged rapidly between the human-chimpanzee ancestor and an ancestral node of modern humans, incorporating population variation for the first time to reduce the likelihood of intraspecies variation appearing as interspecies divergence. Consensus HAQERs exhibit signatures of elevated mutation rates, ancient positive selection, bivalent regulatory function, are enriched in disease-linked loci, and often emerged in previously inaccessible repetitive DNA. Through multiplex, single-cell enhancer assays, I identify HAQERs as active enhancers in the developing brain and cardiomyocytes, highlighting their potential contributions to human-specific gene regulation across multiple tissues. Beyond HAQERs, I identified the preliminary set of an even more extremely divergent type of genomic regions called UHIs (Unique Human Insertions). UHIs are large insertions that emerged after the human-chimpanzee split, many of which have gene regulatory activity and may underlie human-unique traits. Overall, I take a 3-step approach to answer the question of “What makes us human”: identify highly divergent genomic regions, computationally analyze their sequence to uncover their evolutionary origins, and experimentally test their downstream functions. The 3 steps combine to tell the story of how human-unique traits are shaped.