What makes your brain different from that of a Neanderthal?

Scientists have discovered a flaw in our DNA that may have helped differentiate the minds of our ancestors from those of Neanderthals and other extinct human relatives.

According to a new study published Thursday in the journal Science, the mutation, which emerged over the last few hundred thousand years, promotes the development of more neurons in the part of the brain we use for our most complex ways of thinking.

“What we found is a gene that undoubtedly contributes to making us human,” said one of the study’s authors, neuroscientist Wieland Huttner, from the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden, Germany.

The human brain allows us to do things that other living species cannot, such as use complex language and make complicated plans for the future. Scientists have for decades compared the anatomy of the human brain to that of other mammals to understand how these sophisticated faculties evolved.

The most obvious feature of the human brain is its size: four times the size of chimpanzees, our closest living relatives.

The human brain also has anatomical features that distinguish it. The region of cortex just behind the eyes, known as the frontal lobe, is essential for some of the most complex thinking. According to a 2018 study, the human frontal lobe has many more neurons than the same region in chimpanzees.

But there is a serious problem when drawing comparisons between humans and apes alive today: the most recent common ancestor we share with chimpanzees lived approximately 7 million years ago. To fill in the unknowns as to what has happened since then, scientists have turned to fossils of our most recent ancestors, known as hominins.

Examining hominin skulls, paleoanthropologists have found that the brains of our ancestors began to grow sharply from about 2 million years ago. They reached the brain size of today’s humans about 600,000 years ago. Neanderthals, who are among our closest extinct hominin relatives, had brains as big as ours.

But Neanderthals’ brains were elongated, while humans’ brains were more spherical. Scientists cannot explain the cause of these differences. One possibility is that several regions of our ancestors’ brains changed in size.

In recent years, neuroscientists have begun to probe ancient brains with a new source of information: pieces of DNA preserved within hominin fossils. Geneticists reconstructed entire genomes of Neanderthals and also of their early Orientals, the Denisovans.

Scientists have identified potentially crucial differences between our genome and the genomes of Neanderthals and Denisovans. Human DNA contains about 19,000 genes. The proteins encoded by these genes are, for the most part, identical to those of Neanderthals and Denisovans. But researchers found 96 human-specific mutations that altered the structure of a protein.

In 2017 a researcher in Huttner’s lab, Anneline Pinson, was looking at that list of mutations and noticed that one of them altered a gene called TKTL1. Scientists know that TKTL1 becomes active in the developing human cortex, especially the frontal lobe.

“We know that the frontal lobe is important for cognitive functions,” said Pinson. “So that was a good indication that he could be an interesting candidate.”

Pinson and his colleagues conducted initial experiments with TKTL1 in mice and ferrets. After injecting the human version of the gene into the animals’ developing brains, they found that this caused the mice and ferrets to produce more neurons.

Then the scientists experimented with human cells, using pieces of fetal brain tissue obtained with the consent of women who had had abortions at a hospital in Dresden. Pinson used molecular scissors to cut out the TKTL1 gene from the tissue sample cells. Without the gene, human brain tissue produced fewer of the so-called progenitor cells that give rise to neurons.

In their final experiment, the researchers set out to create a miniature Neanderthal-like brain. They started with a human embryonic stem cell, editing its TKTL1 gene so that it no longer had the human mutation. Instead, it carried the mutation found in our relatives, including Neanderthals, chimpanzees and other mammals.

Then they immersed the stem cell in a bath of chemicals that induced it to convert into a mass of developing brain tissue called a brain organoid. It spawned progenitor brain cells, which then produced a miniature cortex composed of layers of neurons.

The Neanderthal-like brain organoid produced fewer neurons than organoids that contained the human version of TKTL1. This fact suggests that when the TKTL1 gene mutated, our ancestors were able to produce additional neurons in the frontal lobe. While this change did not increase the overall size of our brain, it may have rearranged its “wiring.”

“This is really a tour de force,” commented Laurent Nguyen, a neuroscientist at the University of Liège in Belgium and not involved with the study.

The new discovery does not mean that TKTL1 alone is the secret to what makes us human. Other researchers are also studying the list of 96 mutations that altered proteins and are conducting their own experiments with organoids.

Other members of Huttner’s lab reported in July that two other mutations alter the rate at which developing brain cells divide. Last year a team of researchers at the University of California San Diego found that another mutation appears to change the number of connections between human neurons.

Other mutations may also turn out to be important for our brains. For example, as the cortex develops, individual neurons must migrate to find their own place. Nguyen noted that some of the 96 mutations that occur only in humans altered genes that are likely involved in cell migration. He speculates that our mutations might make our neurons move differently than neurons in a Neanderthal brain.

“I don’t believe the story is limited to this,” he said. “I think more studies are needed to understand what makes us human in terms of brain development.”

^{Translation by Clara Allain}