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Why is the human brain so big?



It started with some blobs of brain-like tissue growing in a bowl.

Frank Jacobs, then at the University of California, Santa Cruz, had taken stem cells from humans and monkeys and made them become small balls of neurons. These "organoids" reflect the early stages of brain development. Through her research, Jacobs could search for genes that are more activated in growing brains of humans than in monkeys. And when he presented his data during a lab visit to his colleagues, a gene caught everyone's attention.

"There was a gene called NOTCH2NL that shouted and shushed people in [the monkeys]," says Sofie Salama. leads the Santa Cruz team with David Haussler. "What the hell is NOTCH2NL? None of us had ever heard of it."

The team finally learned that NOTCH2NL appears to be inactive in monkeys because it does not exist in monkeys . It's unique to humans, and it probably controls the number of neurons we make as embryos. It's one of a growing list of human-only genes that could help explain why our brains are so much bigger than other apes.

These human-only genes are typically generated when DNA parts are randomly duplicated. Duplication backs up existing genes, which are then free to mutate with impunity and take on new roles. In this way, duplication events provide fresh fuel for evolution.

They also cause headaches for researchers trying to understand our genome. Scientists sequencing genomes by breaking long sections of DNA into more manageable fragments. Then decipher each piece individually before joining the pieces together to form a whole. But when genes are duplicated, fragments of the copies are almost indistinguishable from fragments of the originals, causing confusion. It's like trying to put together several puzzles that differ only slightly: if their parts are messed up, it looks like they all come from a single puzzle.

That was the case with NOTCH2NL. In earlier designs of the human genome, it looked like a gene. But when the last (and the twentieth) draft was published in December 201

3, Jacobs and his colleagues determined that this mysterious gene was indeed three genes. They are known as NOTCH2NLA, NOTCH2NLB and NOTCH2NLC. They are 99.7 percent identical. And they have a kinky story.

In the common ancestor of all apes there was only one gene: NOTCH2. At some point it was duplicated, but only partially. His doppelganger, the first NOTCH2NL gene, lacked important sections and did not work properly. It was useless, a manual with random chapters. At this time, chimpanzees and gorillas still have these dead versions of NOTCH2NL.

But 3 to 4 million years ago something special happened in people's ancestors. The original NOTCH2 gene has partially overwritten its broken duplicate. This process, known as gene conversion, has revived NOTCH2NL and allowed it to play an active role in its owner's biology. And after being revived, he duplicated twice more and created the A, B, and C genes that we have today.

While Jacobs & # 39; team learned all this, Ikuo Suzuki and colleagues from KU Leuven, a university in Belgium, took the NOTCH2NL genes a different route. They began by identifying genes that have three characteristics: they originated from duplication events, are highly active in the developing brain, and are unique to humans. Suzuki and his team developed a list of 35 genes and introduced several of them into the brains of embryonic mice to see what would happen.

One gene – NOTCH2NLB – had a particularly interesting effect on the radial glial cells responsible for building a brain. The Radialglia are like factories that make two products: neurons and more factories. Both Suzuki and Jacobs found that NOTCH2NL genes nudge the glia towards the latter: they do more of themselves. As their numbers swell, they together grow more neurons and build bigger brains. By influencing the radial glia, the NOTCH2NL genes may have contributed to the evolution of our great brains and famous intellect.

These changes could have been costly. The NOTCH2NL genes are so similar that even our cells can confuse them. As a result, the DNA segment in which these genes are located is very unstable. Sometimes it is duplicated. Sometimes it is deleted. Sometimes the A gene can overwrite the B gene or vice versa. These genetic upheavals can lead to developmental disorders.

In extreme cases, the doubling of NOTCH2NL genes can lead to macrocephaly, where people grow up with unusually large brains and heads. Conversely, the wholesale loss of these genes can lead to microcephaly – a condition of small brains and minds. Other changes in this region have been linked to autism, schizophrenia and intellectual disorders. "It's fascinating to think that the same mechanism that helped create a larger brain could also make us susceptible to these disorders," says Salama. "We pay the price for the profit we got in our evolution."

Right now, it's hard to say how much NOTCH2NL genes vary between people and how specific variations affect either the size of the brain or the disease risk. This is likely to change as new "long read" technology allows scientists to sequence large contiguous DNA segments without first breaking them to pieces. "Sequencing more human genomes with long-read methods gives us a more complete picture of NOTCH2NL's role in disease and human traits," says Megan Dennis of UC Davis, who was not involved in either study.

The NOTCH2NL genes are by far not the only ones related to the size of the brain. Others like them have recently been identified, with names as sinuous as SRGAP2C and ARHGAP11B. And do not forget that Suzuki was focusing on NOTCH2NLB after first finding a shortlist of 35.

"We hit the jackpot here, but there could be a lot more jackpots," says Pierre Vanderhaeghen, who led Suzuki's study.


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