Neanderthalizing brain organoids

The evolution of the human brain reflects the interplay between genetic innovation and environmental pressures. Neuro-oncological ventral antigen 1 (NOVA1) is an evolutionarily conserved splicing regulator essential for neural development and harbors a protein-coding substitution unique to modern humans compared with Neanderthals and Denisovans. To investigate the functional consequences of this human-specific change, we reintroduced the archaic NOVA1 allele into human induced pluripotent stem cells and examined neural development using cortical organoids. Organoids expressing the archaic variant exhibited accelerated maturation, increased surface complexity, altered synaptic marker expression, and changes in electrophysiological properties, indicating that the extinct human NOVA1 allele contributes to accelerated and distinct cortical development. To explore potential evolutionary pressures underlying the selection of the modern allele, we assessed long-term environmental exposure to lead using fossilized teeth from multiple hominid species spanning over two million years. Our analysis reveals pervasive lead exposure across extinct and extant hominids, challenging the notion that lead toxicity is exclusively a modern phenomenon. Notably, lead exposure selectively disrupted FOXP2 expression in cortical and thalamic organoids carrying the archaic NOVA1 variant, implicating a gene critical for speech and language development. These findings were independently validated in NOVA1 humanized mouse models with altered vocalization. Together, these fossil, cellular, and molecular findings suggest that gene–environment interactions involving NOVA1 and environmental neurotoxins may have influenced neural circuit development, social behavior, and complex language capacity, potentially conferring a selective advantage to modern humans during evolution.