Fascinating article by Jon Cohen at sciencemag.org:

Alysson Muotri, a geneticist at the University of California, San Diego (UCSD) School of Medicine, described his group’s Neanderthal organoids for the first time this month at a UCSD conference called Imagination and Human Evolution. His team has coaxed stem cells endowed with Neanderthal DNA into pea-size masses that mimic the cortex, the outer layer of real brains. Compared with cortical minibrains made with typical human cells, the Neanderthal organoids have a different shape and differences in their neuronal networks, including some that may have influenced the species’s ability to socialize. “We’re trying to recreate Neanderthal minds,” Muotri says….

Muotri focused on one of approximately 200 protein-coding genes that differ between Neanderthals and modern humans. Known as NOVA1, it plays a role in early brain development in modern humans and also is linked to autism and schizophrenia. Because it controls splicing of RNA from other genes, it likely helped produce more than 100 novel brain proteins in Neanderthals. Conveniently, just one DNA base pair differs between the Neanderthal gene and the modern human one

Muotri and his co-workers start with skin cells from a “neurotypical person”—someone without any known genetic defects linked to neurological disorders—and manipulate their genomes to turn them into pluripotent stem cells. Using CRISPR, the team then targets NOVA1 and swaps in the Neanderthal base pair to replace the modern human one. To avoid being misled by the “off-target” DNA changes made by CRISPR as well as genetic errors that can occur from producing the stem cells, they sequence the resulting cells and discard any that have unintended mutations.

It takes several months to grow the Neanderthal DNA–containing stem cells into organoids—”We call them Neanderoids,” Muotri says. Comparing them with modern human brain organoids made under identical conditions, his team found that the neuronal cells with the Neanderthalized NOVA1 migrate more quickly within an organoid as they form structures. “We think it’s related to the shape of the organoid, but we have no idea what it means,” says Muotri, noting that the Neanderoids have a “popcorn” shape, whereas modern human cortical organoids are spherical. The Neanderoid neurons also make fewer synaptic connections, creating what resembles an abnormal neuronal network.

Several of these differences mirror what Muotri has found studying neuronal development in the brains of children with autism. “I don’t want families to conclude that I’m comparing autistic kids to Neanderthals, but it’s an important observation,” says Muotri, who has a stepson with autism. “In modern humans, these types of changes are linked to defects in brain development that are needed for socialization. If we believe that’s one of our advantages over Neanderthals, it’s relevant.”

Muotri has developed the modern human brain organoids to the stage where his team can detect oscillating electrical signals within the balls of tissue. They are now wiring the organoids to robots that resemble crabs, hoping the organoids will learn to control the robots’ movements. Ultimately, Muotri wants to pit them against robots run by brain Neanderoids.

So it seems like a single base-pair change in the NOVA1 gene means the difference between popcorn brain and sphere brain.

Could this be the single mutation Richard Klein claimed caused behavioral modernity to fully blossom some 50,000 years ago?  Perhaps before 50,000 years ago, both modern humans and Neanderthals had popcorn brain but after 50,000 years ago, modern humans suddenly mutated sphere brain, which allowed them to conquer Neanderthals and create representational art?  Seems too simple to be true.

I guess the way to test this would be to see how long ago the mutation occurred and whether there was a selective sweep for the human variant around 50,000 years ago.

However since the NOVA1 gene seems related to both autism and schizophrenia, my guess is that it has something to do with executive functioning,  the most elusive of cognitive abilities, and the impairment shared by both autistics and schizophrenics.

Richard Klein noted that before 50,000 years ago, humans were incapable of organizing their camp sites,  They would eat, sleep, cook and defecate everywhere.  After 50,000 years ago they suddenly started organizing campsites into cooking areas, eating areas, sleeping areas etc.    Perhaps this was the dawn of executive functioning?

Btw, this is not the first time Neanderthal DNA has been linked to autism.   Steve Hsu quoted scientists making the following claim:

Of particular interest is the modern human-specific duplication on 16p11.2 which encompasses the BOLA2 gene. This locus is the breakpoint of the 16p11.2 micro-deletion, which results in developmental delay, intellectual disability, and autism5,6. We genotyped the BOLA2 gene in 675 diverse human individuals sequenced to low coverage as part of the 1000 Genome Project Phase I7 to assess the population distribution of copy numbers in homo-sapiens (Figure S8.3). While both the Altai Neandertal and Denisova individual exhibit the ancestral diploid copy number as seen in all the non-human great apes, only a single human individual exhibits this diploid copy number state.