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

Trujillo CA, Rice ES, Schaefer NK, Chaim IA, Wheeler EC, Madrigal AA, Buchanan J, Preissl S, Wang A, Negraes PD, Szeto RA, Herai RH, Huseynov A, Ferraz MSA, Borges FS, Kihara AH, Byrne A, Marin M, Vollmers C, Brooks AN, Lautz JD, Semendeferi K, Shapiro B, Yeo GW, Smith SEP, Green RE, Muotri AR.

Science, 2021


The genomes of Neanderthals and modern humans are similar, but in order to understand the genetic variants a genome-wide analysis was performed.   The results identified NOVA1, as one of the few protein-coding differences between modern human and archaic hominin genomes that could affect human neurodevelopment.  This gene variant was introduced into human pluripotent stem cells using CRISPR/Cas9 genome-editing techniques and replaced the human variant with the Neanderthal version.  The resulting modified neurons were used to generate brain organoids.  The organoids showed alterations in neurodevelopment, proliferation and synaptic connectivity which resulted in differences in organoid morphology and neural network function.  The neurons in the ancestral organoids started to fire spikes of activity earlier than modern organoids but took longer to organize into waves.  The results suggest that the NOVA1 gene substitution may have had a functional consequence for the divergence of our modern species.