Archaic NOVA1 alters FOXP2-expressing neurons upon lead exposure

A complex interplay between genetics and environmental factors shapes the evolution of cognitive function and brain architecture. Notably, 61 protein-coding genes, including neuro-oncological ventral antigen 1 (NOVA1), distinguish modern humans from extinct hominins like Neanderthals and Denisovans. When reintroduced into human brain organoids, the archaic variant of NOVA1 altered neural development. However, the selective pressures that favored the modern NOVA1 allele remain elusive. Single-cell proteomics-based mass spectrometry and single-cell transcriptomics analysis from dissociated brain organoids of Homo sapiens model and Neanderthal control and treated organoid were used in this study. Here, we demonstrate that lead exposure disproportionately impacts cell populations in brain organoids carrying the archaic NOVA1 variant. Importantly, this exposure suppresses FOXP2 expression in cortical neurons, implicating language and speech abnormalities in humans carrying the archaic genetic variant. Single-cell proteomics data corroborate those findings as proteins related to apoptosis induced DNA fragmentation, RHO GTPases activate PAKs, NABA ECM regulators, dopamine receptor signaling pathway, substantia nigra development, protein localization to chromatin, antiviral mechanism by IFN-stimulated genes and synapse organization were impaired in lead treat brain organoids. Our findings unveil a potential evolutionary advantage of the modern NOVA1 allele, mitigating the deleterious effect of lead toxicity.