Side views of Homo sapiens and Homo neanderthalensis skulls facing each other.

Human and Neanderthal brains were roughly the same size.Credit: Adapted from Alamy

More than 500,000 years ago, the ancestors of Neanderthals and modern humans were migrating around the world when a pivotal genetic mutation caused some of their brains to improve suddenly. This mutation, researchers report in Science1, drastically increased the number of brain cells in the hominins that preceded modern humans, probably 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 that it will turn out 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 reported the sequence of a complete Neanderthal genome in 20142, they identified 96 amino acids — the building blocks that make up proteins — that differ between Neanderthals and modern humans, as well as some other genetic tweaks. Scientists have been studying this list to learn which of these changes helped modern humans to outcompete Neanderthals and other hominins.

Cognitive advantage

To neuroscientists Anneline Pinson and Wieland Huttner at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, one gene stood out. TKTL1 encodes a protein that is made when a fetus’s brain is first developing. A mutation in the human version changed one amino acid, resulting in a protein that is different from those found in hominin ancestors, Neanderthals and non-human primates.

The researchers suspected that this protein could increase the proliferation of neural progenitor cells, which become neurons, as the brain develops, specifically in an area called the neocortex — a region involved in cognitive function. This, they reasoned, could contribute to modern humans’ cognitive advantage.

To test their theory, Pinson and her team inserted either the human or the ancestral version of TKTL1 into the brains of mouse and ferret embryos1. The animals with the human gene had significantly 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 grown from human stem cells.

Brain size

Fossil records suggest that human and Neanderthal brains were roughly the same size, meaning that the neocortices of modern humans are either denser or take up a larger portion of the brain. Huttner and Pinson were surprised that such a small genetic change could affect neocortical development so drastically. “It was a coincidental mutation that had enormous consequences,” Huttner says.

Neuroscientist Alysson Muotri at the University of California, San Diego, is more sceptical. He points out that various cell lines behave differently when made into organoids, and he would like to see the ancestral version of TKTL1 tested in more human cell lines. Furthermore, he says, the original Neanderthal genome was compared with that of a modern European — human populations in other parts of the world might share some genetic variants with Neanderthals.

Pinson says that the Neanderthal version of TKTL1 is rare among humans today, but adds that it’s unknown whether the mutation causes any disease or cognitive differences. The only way to prove that it has a role in cognitive function, Huttner says, would be to genetically engineer mice or ferrets that have the human form of the gene and compare their behaviour to that of animals that express the ancestral version. Pinson is now planning to look further into the mechanisms through which TKTL1 drives the birth of brain cells.