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

Bibliographic Collection: 
CARTA-Inspired Publication
Publication Type: Journal Article
Authors: Trujillo, Cleber A; Rice, Edward S; Schaefer, Nathan K; Chaim, Isaac A; Wheeler, Emily C; Madrigal, Assael A; Buchanan, Justin; Preissl, Sebastian; Wang, Allen; Negraes, Priscilla D; Szeto, Ryan A; Herai, Roberto H; Huseynov, Alik; Ferraz, Mariana S A; Borges, Fernando S; Kihara, Alexandre H; Byrne, Ashley; Marin, Maximillian; Vollmers, Christopher; Brooks, Angela N; Lautz, Jonathan D; Semendeferi, Katerina; Shapiro, Beth; Yeo, Gene W; Smith, Stephen E P; Green, Richard E; Muotri, Alysson R
Year of Publication: 2021
Journal: Science
Volume: 371
Issue: 6530
Date Published: 2021 02 12
Publication Language: eng
ISSN: 1095-9203
Keywords: Alleles, Alternative Splicing, Amino Acid Substitution, Animals, Binding Sites, Biological Evolution, Cell Proliferation, Cerebral Cortex, CRISPR-Cas Systems, Gene Expression Regulation, Developmental, Genetic Variation, Genome, Genome, Human, Haplotypes, Hominidae, Humans, Induced Pluripotent Stem Cells, Neanderthals, Nerve Net, Nerve Tissue Proteins, Neurons, Organoids, RNA-Binding Proteins, Synapses

The evolutionarily conserved splicing regulator neuro-oncological ventral antigen 1 () plays a key role in neural development and function. 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 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 , which is exclusive to modern humans since divergence from Neanderthals, may have had functional consequences for our species' evolution.

DOI: 10.1126/science.aax2537
Alternate Journal: Science