Did this gene give the modern human brain its edge?

Over 500,000 years ago, the ancestors of Neanderthals and modern humans were migrating around the world when a fatal genetic mutation caused some of their brains to suddenly improve. This mutation, report researchers in Science¹dramatically increased the number of brain cells in hominins that preceded modern humans, likely giving them a cognitive advantage over their Neanderthal cousins.

“This is a surprisingly important gene,” says Arnold Kriegstein, a neurologist at the University of California, San Francisco. However, he expects it to be one of many genetic tweaks that gave humans an evolutionary advantage over other hominins. “I think it sheds a whole new light on human evolution.”

When researchers first fully sequenced a Neanderthal genome in 2014², they identified 96 amino acids – the building blocks of proteins – that differ between Neanderthals and modern humans in addition to a number of other genetic adjustments. Scientists studied this list to find out which of them helped modern humans surpass Neanderthals and other hominids.

Cognitive advantage

For neuroscientists Anneline Pinson and Wieland Huttner of the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden, Germany, one gene stood out. The gene, TKTL1, codes for a protein that is made when the fetal brain first develops. A single genetic mutation in the human version of TKTL1 changed an amino acid, resulting in a protein different from those found in hominin ancestors, Neanderthals and non-human primates.

The team suspected that this protein could drive neural progenitor cells – which develop into neurons – to proliferate as the brain develops, particularly in an area called the neocortex, which is involved in cognitive function. This, they reasoned, could contribute to the cognitive advantage of modern humans over human ancestors.

To test this, Pinson and his team inserted the human or ancestral version of TKTL1 into the brains of mouse and ferret embryos. Animals carrying the human gene developed many more neural progenitor cells. When the researchers engineered neocortex cells from a human fetus to produce the ancestral version, they found that the fetal tissue produced fewer progenitor cells and fewer neurons than it normally would. The same was true when they inserted the ancestral version of TKTL1 into brain organoids – mini-brain-like structures developed from human stem cells.

brain size

The fossil record suggests that human and Neanderthal brains were roughly the same size, meaning the neocortices of modern humans are either denser or take up more of the brain. Huttner and Pinson say they were surprised that such a small genetic change could affect neocortical development so drastically. “It was a chance mutation that had huge consequences,” says Huttner.

Neuroscientist Alysson Muotri of the University of California, San Diego is more skeptical. He points out that different cell lines behave differently when transformed into organoids and would like to see the ancestral version of TKTL1 tested in more human cells. Additionally, he says, the original Neanderthal genome has been compared to that of a modern European – human populations in other parts of the world may share some genetic variants with Neanderthals.

Pinson says the Neanderthal version of TKTL1 is very rare in modern humans, adding that it’s unclear whether it causes disease or cognitive differences. The only way to prove it has a role in cognitive function, Huttner says, would be to genetically modify mice or ferrets that still have the human form of the gene and test their behavior against animals that have the ancestral version. . Pinson says she now plans to dig deeper into the mechanisms by which TTKKL1 drives brain cell birth.