Abstract: A fundamental question in biology is: how did humans acquire their unique characteristics? What allows us to stand upright, while our primate ancestors walked on all fours? What brain alterations drove our increased intelligence and allowed us to perceive our own mortality? One of the mechanisms that has been hypothesized to be involved is changes in gene expression elicited by nucleotide alterations in non-coding regions of the human genome. In my talk, I will focus on a class of DNA sequences hypothesized to have this role. These human accelerated regions (HARs) are segments of DNA that exhibit 3 characteristics that—together—make them prime candidates for specifying human-specific traits by altering patterns of gene expression. First, HARs have rapidly changed in sequence specifically in the human lineage. Second, HARs are highly conserved in sequence in all mammals or vertebrates, indicating they that must have been selected for the ability to confer one or more function in higher organisms. Third, the vast majority of HARs are in the non-coding portion of animal genomes, indicating that most are likely to have a regulatory function.

While HARs are hypothesized to confer human-specific traits, this has yet to be demonstrated. In my talk, I will describe a HAR—called “HAR123”—that has properties consistent with such a role in the nervous system. We elected to focus on HAR123 because it is in the intron of a gene essential for a RNA turnover pathway—nonsense-mediated RNA decay (NMD)—that has roles in the nervous system and whose disruption causes neural disease. Through both in vitro and in vivo studies, we discovered that HAR123 is a conserved transcriptional enhancer that influences nervous system development and function. HAR123 promotes human neural progenitor cell (NPC) formation, influences the ratio of neurons and glial cells produced from NPCs, and functions in cognitive flexibility in vivo. We identified targets of HAR123 and found that one of these targets, HIC1, acts downstream of HAR123 to promote NPC generation. We also obtained evidence that HAR123 upregulates the expression of SMG6 in specific brain regions, raising the possibility that HAR123 evolved in the human lineage to regulate RNA turnover in a brain region-specific manner. Finally, we found that the human and chimpanzee orthologs of HAR123 subtly differ in their molecular and cellular effects, consistent with the possibility that HAR123 has evolved since the human-chimpanzee split to influence nervous system traits specific to humans.