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

An unsolved mystery in biology is how human-specific traits were acquired during evolution. Here, we report that an evolutionary ancient non-coding element—human accelerated region 123 (HAR123)—has undergone rapid evolution specifically in the human lineage and confers human-specific functions. HAR123 is a neural enhancer that promotes the generation of human neuroectoderm and neural progenitor cells by upregulating the transcriptional repressor HIC1. The human and chimpanzee versions of HAR123 exhibit different properties, consistent with HAR123 being selected for new functions since the human-chimpanzee split. To address the in vivo functions of HAR123, we generated HAR123-knockout mice, which exhibit a specific defect in “re-learning.” Together, our study supports a model in which HAR123 has rapidly evolved in the human lineage to influence neural generation and, ultimately, cognitive flexibility. To examine the role of HAR123 in NPC generation, we performed single-cell RNA-sequencing (scRNAseq) analysis. For these experiments, we also compared the function of hHAR123 with chimpanzee (c) HAR123 and mouse (m) HAR123 by replacing hHAR123 with cHAR123 or mHAR123, respectively, in human embryonic stem cells (ESCs). We then differentiated these 3 genotypes of hESCs, along with HAR123-knock out (KO) hESCs, in parallel, using a standard NPC generation protocol.