CCNB1IP1 regulatory evolution underlies gradual increases in cortical size and folding in primates

The gradual expansion and folding of the cortex are key factors in human cognitive evolution, yet their molecular underpinnings remain not well understood. Here we identify cyclin B1 interacting protein 1 (CCNB1IP1) gene as a key regulator of human brain evolution using tree shrew as an outgroup. In primates, CCNB1IP1 acquired brain expression and gradually increased its expression during evolution, mirroring the increase of cortical size and folding. Comparative analysis of cis-regulatory elements reveals evolutionary changes underlying the increase of CCNB1IP1 expression. Overexpression of CCNB1IP1 affects the cell cycle, increasing the abundance of basal progenitors and neurons. Mechanistically, we demonstrated that CCNB1IP1 represses the transcription factor E2F1 through the ubiquitin-mediated degradation pathway. Moreover, CCNB1IP1 knock-in can develop cortical folding in otherwise smooth mouse brains. These findings reveal that evolutionary changes in CCNB1IP1 expression have contributed to the enlargement and folding of the primate cortex.