An ancient enhancer rapidly evolving in the human lineage promotes neural development and cognitive flexibility

The genetic changes driving the evolution of humans since the human-chimpanzee split have been elusive. Here, we report a promising candidate in a chromosomal region linked with neurological defects-17p13.3. We show that this 442-nucleotide sequence-human-accelerated region (HAR) 123-is a conserved neural enhancer that promotes neural progenitor cell (NPC) formation. While present in all mammals, HAR123 has rapidly evolved since humans diverged from chimpanzees. The human and chimpanzee HAR123 orthologs exhibit subtle differences in their neural developmental effects, and the human HAR123 ortholog uniquely regulates many genes involved in neural differentiation. We identified direct targets of the HAR123 enhancer and showed that HIC1 acts downstream of HAR123 to promote human NPC formation. HAR123-knockout mice exhibit a defect in cognitive flexibility and a shift in neural-glia ratio in specific regions of the hippocampus. Our study has implications for neurodevelopmental disorders, which are often accompanied by altered neural-glia ratio and have been linked with HARs.