A gene called NOVA1, which plays a role in regulating the formation of synapses between neurons, could hold the key to understanding how we differ from our Neanderthal cousins. Researchers created human brain organoids with a Neanderthal and Denisovan variant of the gene, resulting in neurons that matured faster than neurons with a modern sequence did, developing synapses that fired at a higher rate, according to a study published yesterday (February 11) in Science.
“This is amongst the first studies of its kind to investigate how specific changes in the DNA of modern humans influences brain development,” Duke University’s Debra Silver, a developmental neurobiologist who did not participate in the research, tells Science.
“It’s an extraordinary paper with some extraordinary claims,” developmental biologist Gray Camp of the University of Basel in Switzerland notes to Nature. Camp was also not involved in the current study but reported with colleagues last year an analysis of Neanderthal gene variants, which modern humans still carry, in human stem cell–derived brain organoids.
In human pluripotent stem cells, University of California, San Diego, neuroscientist Alysson Muotri and his colleagues used the CRISPR-Cas9 gene editing system to change a single base pair in NOVA1, effectively converting the modern gene into an archaic version. The researchers then grew the cells in culture conditions to induce the growth of brain-like organoids up to 5 millimeters in diameter. Comparing them with organoids containing all modern DNA, Muotri tells Nature, the difference was obvious, with the CRISPR’d organoids being smaller with convoluted, rather than smooth, surfaces. “As soon as we saw the shape of the organoids, we knew that we were on to something.”
Muotri and his colleagues chose NOVA1 because they found that it is one of just 61 genes with modern sequences not found in the Neanderthal genome—nor in the genome of Denisovans, another archaic group of hominins—and because it has a prominent regulatory role in neurodevelopment. Dysfunction in the gene and its associated pathways has been linked with neurological conditions such as schizophrenia and autism.
In addition to the structural differences in the organoids, the team found that the archaic gene induced significant changes in the expression of 277 genes, including those involved in neurodevelopment. These differences translated into varying levels of synapse proteins and, ultimately, differences in firing patterns. In addition to firing more quickly, the neurons with the archaic variant of NOVA1 had less-orderly patterns of action potentials.
Wolfgang Enard, an evolutionary geneticist at Ludwig Maximilian University of Munich who was not involved in the study, tells Nature that the changes observed were impressive, but he adds that that the appearance and behavior of organoids may not mean much about what Neanderthal brains looked like.
Camp agrees, telling Nature that Neanderthal brains would have contained many other differences, and that the results identified in this study may be the result of dropping a single Neanderthal variant into the background of a modern human genome.
Moreover, the organoids represent only the very early stages of brain development, notes Arnold Kriegstein, a developmental neurobiologist at the UC San Francisco School of Medicine who was not involved in the research, in speaking with Science. “It’s difficult to know how [the changes] would manifest in a more mature brain.”
Nevertheless, experts agree that this approach holds value for better understanding the human brain, and how it differs from our ancient cousins. “It’s a very useful model to move science forward and to get a better understanding of how the brain develops and how our genetic background affects that,” the National Institute of Mental Health’s Michael Gregory, who was not involved in the study, tells STAT. “The opportunity to use technology similar to this with other genetic changes opens up a world of scientific possibilities.”