Three genes that appeared during our early evolution probably increased the number of neurons in our heads—but at a cost.
The Atlantic said:It started with some blobs of brain-like tissue, growing in a dish.
Frank Jacobs, then at the University of California at Santa Cruz, had taken stem cells from humans and monkeys, and coaxed them into forming small balls of neurons. These “organoids” mirror the early stages of brain development. By studying them, Jacobs could look for genes that are switched on more strongly in the growing brains of humans than in those of monkeys. And when he presented his data to his colleagues at a lab meeting, one gene grabbed everyone’s attention.
“There was a gene called NOTCH2NL that was screaming in humans and off in [the monkeys],” says Sofie Salama, who co-directs the Santa Cruz team with David Haussler. “What the hell is NOTCH2NL? None of us had ever heard of it.”
The team ultimately learned that NOTCH2NL appears to be inactive in monkeys because it doesn’t exist in monkeys. It’s unique to humans, and it likely 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 those of others apes.
These human-only genes are typically created when bits of DNA accidentally get duplicated. Duplication creates backup copies of 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.
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But between 3 and 4 million years ago, in the ancestors of humans, something special happened. The original NOTCH2 gene partly overwrote its broken duplicate. This process, known as gene conversion, revived NOTCH2NL, allowing it to play an active role in its owners’ biology. And having been resurrected, it duplicated twice more, creating the A, B, and C genes that we have today.
While Jacobs’s team was learning all of this, Ikuo Suzuki and colleagues from KU Leuven, a university in Belgium, were homing in on the NOTCH2NL genes through a different route. They started by identifying genes that have three characteristics: They arose from duplication events, are strongly active in the developing brain, and are unique to humans. Suzuki and his team came up with a shortlist of 35 genes, and introduced several of these into the brains of embryonic mice to see what would happen.
One gene—NOTCH2NLB—had a particularly interesting effect on the radial glia, the cells responsible for building a brain. The radial glia are like factories that manufacture two products: neurons and more factories. Both Suzuki and Jacobs found that NOTCH2NL genes nudge the glia toward the latter: They make more of themselves. As their numbers swell, they collectively churn out more neurons and build bigger brains. By influencing the radial glia, the NOTCH2NL genes might have contributed to the evolution of our large brains and vaunted intellects.
These changes could have come at a cost. The NOTCH2NL genes are so similar that even our cells can get them confused. As a result, the stretch of DNA where these genes reside is very unstable. Sometimes, it gets duplicated. Sometimes, it’s deleted. Sometimes, the A gene might overwrite the B one, or vice versa. These genetic upheavals can lead to developmental disorders.
In extreme cases, the duplication of the 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 heads. 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 enable a bigger brain might also make us susceptible to these disorders,” Salama says. “We’re paying the price for the gain we got in our evolution.”
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