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. Overall design: To identify HAR123-regulated genes potentially important for NPC generation, we performed bulk RNA sequencing (RNAseq) analysis on HAR123-KO, hHAR123, cHAR123, and mHAR123 cells. Since HAR123 is critical for promoting NPC generation derived from ESCs, we performed RNAseq analysis at both the ESC and neuroectoderm stages of these 4 genotypes.