DCHS1 Modulates Forebrain Proportions in Modern Humans via a Glycosylation Change

Comparative anatomical studies of primates and extinct hominins, including Neanderthals, show that the modern human brain is characterised by a disproportionately enlarged neocortex relative to the striatum. To explore the molecular basis of this difference, we screened for missense mutations that are unique to modern humans and occur at high frequency and that alter post-translational sites. One such mutation was identified in DCHS1, a protocadherin family gene, and it was found to disrupt an N-glycosylation site in modern humans. Using CRISPR/Cas9-editing we introduced into human-induced pluripotent stem cells (hiPSCs) this ancestral DCHS1 variant present in Neanderthals and other primates, representing the ancestral state before the modern human-specific substitution. Leveraging hiPSCs-derived neural organoids, we observed an expansion of striatal progenitors at the expense of the neocortex, mirroring the anatomical distribution seen in non-human primates. We further identify the ephrin receptor EPHA4 as a binding partner of DCHS1 and show that modern human-specific alterations in DCHS1 modulate EPHA4-ephrin signalling, contributing to a gradual shift in the neocortex-to-striatum ratio - a hallmark of brain organisation in our species.