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Title: Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment

The evolutionarily conserved splicing regulator neuro-oncological ventral antigen 1 (NOVA1) plays a key role in neural development and function.NOVA1also includes a protein-coding difference between the modern human genome and Neanderthal and Denisovan genomes. To investigate the functional importance of an amino acid change in humans, we reintroduced the archaic allele into human induced pluripotent cells using genome editing and then followed their neural development through cortical organoids. This modification promoted slower development and higher surface complexity in cortical organoids with the archaic version ofNOVA1. Moreover, levels of synaptic markers and synaptic protein coassociations correlated with altered electrophysiological properties in organoids expressing the archaic variant. Our results suggest that the human-specific substitution inNOVA1, which is exclusive to modern humans since divergence from Neanderthals, may have had functional consequences for our species’ evolution.

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Award ID(s):
1754451 2034037
Publication Date:
Journal Name:
Page Range or eLocation-ID:
Article No. eaax2537
American Association for the Advancement of Science (AAAS)
Sponsoring Org:
National Science Foundation
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