Reintroduction of the archaic variant of <i>NOVA1</i> in cortical organoids alters neurodevelopment.
Cleber A Trujillo, Edward S Rice, Nathan K Schaefer, Isaac A Chaim, Emily C Wheeler, Assael A Madrigal, Justin Buchanan, Sebastian Preissl, Allen Wang, Priscilla D Negraes, Ryan A Szeto, Roberto H Herai, Alik Huseynov, Mariana S A Ferraz, Fernando S Borges, Alexandre H Kihara, Ashley Byrne, Maximillian Marin, Christopher Vollmers, Angela N Brooks, Jonathan D Lautz, Katerina Semendeferi, Beth Shapiro, Gene W Yeo, Stephen E P Smith, Richard E Green, Alysson R Muotri
Science (New York, N.Y.) · 2021 · Vol. 371 (6530)
Abstract
The evolutionarily conserved splicing regulator neuro-oncological ventral antigen 1 (<i>NOVA1</i>) plays a key role in neural development and function. <i>NOVA1</i> also 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 of <i>NOVA1</i> 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 in <i>NOVA1</i>, which is exclusive to modern humans since divergence from Neanderthals, may have had functional consequences for our species' evolution.
Potentially related datasets 1
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
| Accession | Source | Title |
|---|---|---|
| PRJNA670687 | PRJNA · BioProject | No title in the index |
Funding 11 grants
| Grant | Funder |
|---|---|
| U24 HG009889 | NHGRI NIH HHS (United States) |
| S10 OD026929 | NIH HHS (United States) |
| R01 HG004659 | NHGRI NIH HHS (United States) |
| U41 HG009889 | NHGRI NIH HHS (United States) |
| U19 MH107367 | NIMH NIH HHS (United States) |
| K12 GM068524 | NIGMS NIH HHS (United States) |
| R01 HL137223 | NHLBI NIH HHS (United States) |
| R01 MH121487 | NIMH NIH HHS (United States) |
| R01 MH113545 | NIMH NIH HHS (United States) |
| K01 AA026911 | NIAAA NIH HHS (United States) |
| T32 HG008345 | NHGRI NIH HHS (United States) |