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Neanderthal Gene Variant Alters Neurodevelopment in Human Brain Organoids

NEW YORK – An international team of researchers reintroduced an archaic variant of the neuro-oncological ventral antigen 1 (NOVA1) gene into cortical organoids and found that this Neanderthal-associated variant promoted slower development and higher surface complexity in the brain models.

In a paper published on Thursday in Science, the researchers said that NOVA1 is an evolutionarily conserved splicing regulator that plays a key role in neural development and function. The gene regulates alternative splicing in the developing nervous system and is a master regulator of splicing genes responsible for synapse formation. Altered NOVA1 splicing activity in humans is associated with neurological disorders, underscoring its role in neural function.

The modern human variant of NOVA1 includes a protein-coding difference that differentiates it from the gene variant carried by Neanderthals and Denisovans. In order to investigate the functional importance of the amino acid change in humans, the researchers reintroduced the archaic allele into human induced pluripotent cells (iPSCs) using genome editing and then followed their neural development into cortical organoids with the archaic version of NOVA1.

Aside from the altered neurodevelopment, the researchers also observed levels of synaptic markers and synaptic proteins that correlated with altered electrophysiological properties in organoids expressing the archaic variant, suggesting that the modern substitution in NOVA1 may have had functional consequences for human evolution.

"From an evolutionary perspective, the fact that all modern humans now carry the current variant strongly suggests that it creates a positive selective pressure," corresponding author Alysson Muotri, a researcher at the University of California, San Diego's Kavli Institute for Brain and Mind, said in an email. "The observation that organoids carrying the archaic version produces neurons that are more active early on goes along with the idea that complex brains require long developmental maturation. It is no surprise a baby chimp can outsmart a human newborn. Thus, it is possible that our extinct relatives would have shorter cognitive maturation compared to us."

The researchers compared human genetic data from the 1000 Genomes Project, the Simons Genome Diversity Project dataset (SGDP), and from two high-coverage Neanderthal genomes and one high-coverage Denisovan genome. To investigate the functional importance of the NOVA1 substitution, they used CRISPR-Cas9 to introduce the archaic variant of NOVA1 into the genome of iPSCs derived from two neurotypical human individuals with distinct genetic backgrounds. They then derived functional cortical organoids from edited and unedited control iPSC lines and assessed the impact of the NOVA1 archaic variant on human neural cells and found that the archaic-variant organoids were smaller in diameter than those expressing human-variant NOVA1 organoids during the proliferative and maturation stages.

To explore other potential morphological differences, they then extracted 2D organoid outlines using automatic image processing to generate 3D surface models of the organoids, finding that the archaic models revealed increased surface complexity at the proliferative stages.

To determine the molecular and cellular changes underlying the reduced size and increased surface rugosity of the archaic models, the investigators then assessed cell proliferation, cell cycle, apoptosis, and cell-type composition. They found that the archaic models had a higher number of apoptotic cells than the human-variant organoid models and that the archaic organoid cells proliferated more slowly than the human model cells because of a reduced number of neural progenitor cells.

Overall, they noted, this suggested that the reduction of organoid size and the increased surface complexity could be linked to alterations in proliferation and cell death.

The researchers also collected and sequenced RNA from cortical organoids at one and two months into development in order to capture potential alterations in gene expression and alternative splicing, and they identified 277 differentially expressed genes between the archaic and human organoid models, many of which are involved in neural developmental processes.

Collectively, they said, the data suggests that expression of the archaic NOVA1 variant leads to modified synaptic protein interactions, affecting glutamatergic signaling, differences in neuronal connectivity, and higher heterogeneity of neurons regarding their electrophysiological profiles.

Muotri noted that a limitation of the study is the inability of the brain organoid model to more directly mimic an adult brain, so they may not yet be directly useful for studying conditions such as Alzheimer's disease or Parkinson's disease. However, she added, even late onset diseases might have neurodevelopmental alterations.

"My lab and others are improving the model to accelerate maturation by adding senescent factors or growing these organoids at the International Space Station," she wrote. "Thus, I think in the future we will have better models for these conditions."

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