Cis-Regulatory Evolution of CCNB1IP1 Driving Gradual Increase of Cortical Size and Folding in primates.

Neocortex expansion has a concerted relationship with folding, underlying evolution of human cognitive functions. However, molecular mechanisms underlying this significant evolutionary process remains unknown. Here, using tree shrew as an outgroup of primates, we identify a new regulator which acquired its expression before the emergence of primates. Following the evolution of cis-regulatory elements, the CCNB1IP1 expression has steadily increased over the course of primate brain evolution, mirroring the gradual increase of neocortex. Mechanistically, we elucidated that CCNB1IP1 expression can cause an increase in neural progenitors through shortening G1 phase. Consistently, the CCNB1IP1 knock-in mouse model exhibited traits associated with enhanced learning and memory abilities. Together, our study reveals how changes in expression may have contributed to the gradual evolution in primate brain.