What makes your brain different from a Neanderthal brain?

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

The mutation, which arose over the past hundreds of thousands of years, spurs the growth of more neurons in the part of the brain we use for the most complex forms of thought, according to a new study published in Science on Thursday.

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

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

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

Our brain also has distinctive anatomical features. The area of ​​the cortex just behind our eyes, known as the frontal lobe, is essential for some of our most complex thinking. According to a 2018 study, the human frontal lobe has far more neurons than the same region in chimpanzees.

But comparing humans to living apes has a serious drawback: our most recent common ancestor with chimpanzees lived about 7 million years ago. To piece together what happened since then, scientists had to turn to fossils of our most recent ancestors, known as hominins.

By inspecting hominid skulls, paleoanthropologists discovered that our ancestors’ brains increased dramatically in size starting about 2 million years ago. They reached the size of living humans about 600,000 years ago. Neanderthals, among our closest extinct relatives, had brains as big as ours.

But Neanderthal brains were elongated, while humans are more spherical in shape. Scientists can’t say what explains these differences. One possibility is that different areas of our ancestors’ brains changed in size.

In recent years, neuroscientists have begun to investigate ancient brains with a new source of information: bits of DNA preserved within fossil human fibers. Geneticists have reconstructed entire genomes of Neanderthals as well as their eastern cousins, the Denisovans.

Scientists have zeroed in on potentially critical differences between our genome and that of Neanderthals and Denisovans. Human DNA contains approximately 19,000 genes. The proteins encoded by these genes are mostly identical to those of Neanderthals and Denisovans. However, the researchers found 96 human-specific mutations that changed the structure of a protein.

In 2017, Anneline Pinson, a researcher in Huttner’s lab, was looking over this list of mutations and noticed one that changed 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,” Pinson said. “So that was a good indication that he could be an interesting candidate.”

Pinson and her colleagues first experimented with TKTL1 in mice and ferrets. After injecting the human version of the gene into the animals’ developing brains, they found that it made the mice and ferrets make more neurons.

The researchers then performed experiments on human cells, using pieces of fetal brain tissue obtained through consenting women who had abortions at a Dresden hospital. Pinson used molecular scissors to cut out the TKTL1 gene from the cells in the tissue samples. Without it, human brain tissue produced fewer so-called progenitor cells that make neurons.

For their latest experiment, the researchers set out to create a tiny Neanderthal-like brain. They started with a human embryonic stem cell, editing the 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.

They then put the stem cell in a bath of chemicals that prompted it to turn into a cluster of developing brain tissue, called a brain organoid. It created progenitor brain cells, which then produced a tiny cortex made of layers of neurons.

The Neanderthal-like brain organoid produced fewer neurons than organoids with the human version of TKTL1. This suggests that when the TKTL1 gene mutated, our ancestors could produce extra neurons in the frontal lobe. Although this change did not increase the overall size of our brains, it may have rearranged its wiring.

“It’s really a tour de force,” said Laurent Nguyen, a neuroscientist at the University of Liege in Belgium, who was not involved in the study.

The new finding does not mean that TKTL1, by itself, offers the secret to what makes us human. Other researchers are also looking at the list of 96 protein-altering mutations and conducting their own organelle experiments.

Other members of Huttner’s lab reported in July that two other mutations change 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 that human neurons make with each other.

Other mutations may also prove important for our brains. For example, as the cortex develops, individual neurons must migrate to find their proper location. Nguyen noticed that some of the 96 mutations that are unique to humans changed genes possibly involved in cell migration. He speculates that our mutations may cause our neurons to fire differently than neurons in a Neanderthal’s brain.

“I don’t think it’s the end of the story,” he said. “I think more work is needed to understand what makes us human in terms of brain development.”

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