A newly discovered set of genes could help explain how humans diverged from other apes.
Three genes involved in nerve cell generation in the brain emerged roughly 3.5 million years ago and may have contributed to the rapid evolution of the large human brain, researchers report in the journal Cell. That work - and a paper from an independent research team published in the same issue - identifies genes that help build the neocortex, the wrinkly outer layer of the brain that gives humans our ability to think, plan, and reason.
Until now, the genes had been unexplored, masked by an error in the published version of the human genome. These genes, and others unique to humans, offer clues about what separates us from chimpanzees, says another author.
About 6.5 million years ago, humans and chimpanzees diverged from a common ancestor. A few million years after that, human brain size began to grow. "If you look at craniums from fossils of our ancestors, you can see this expansion," author says.
Today, the human neocortex is about three times larger than that of a chimp, but researchers haven't identified all the genetic factors responsible for the difference. Since humans and chimps split, the human genome has undergone roughly 15 million changes - tweaks to the DNA letters that make up our genetic instruction book.
About six years ago, study coauthor discovered a promising candidate - a gene called NOTCH2NL. It's a relative of NOTCH2, a gene that scientists knew was central to early brain development, author says. NOTCH2 controls vital decisions regarding when and how many neurons to make.
When the team looked in the official version of the human genome at that time - version 37 - NOTCH2NL appeared to be located in chromosome 1 near a region linked to abnormal brain size. Delete a hunk of the region, and brains tend to shrink. Duplicate part of it, and brains tend to overgrow.
"We thought, 'Oh, this is incredible,'" author says. NOTCH2NL seemed to check all the boxes for a key role in human brain development. But when the team mapped NOTCH2NL's precise location in the genome, they discovered the gene wasn't actually in the relevant chromosomal region after all; the once-promising candidate seemed to be a dud.
"We were downhearted," author says. That all changed with the next official version of the human genome - version 38. In this iteration, NOTCH2NL was located in the crucial region - "And there were three versions of it!" author says. Over the last three million years, the team calculated, NOTCH2NL was repeatedly copy-pasted into the genome, what thy call "a series of genetic accidents."
Genetic analysis of several primate species revealed that the three genes exist only in humans and their recent relatives, the Neanderthals and Denisovans, not in chimpanzees, gorillas, or orangutans. What's more, the timing of these genes' emergence matches up with the period in the fossil record when our ancestors' craniums began to enlarge, author says. Together, the results suggest that NOTCH2NL genes played a role in beefing up human brain size.
Experiments with lab-grown patches of brain tissue from mouse and human embryonic stem cells hinted that NOTCH2NL genes tell developing brains to make more neuron progenitors. The NOTCH2NL genes likely convey this brain-growing message via the well-studied Notch signaling pathway. Scientists already knew that cells rely on this pathway for proper neuronal function. Having three active NOTCH2NL genes cranks up the messaging, "adding an extra push to the pathway," another author says.
Deviations in these genes' copy numbers could be tied to neurological disorders other than abnormal brain size, the researchers found. An analysis of cells from six autism patients in the Simons Variation in Individuals project revealed that each patient had lost or gained parts of NOTCH2NL genes. Until now, scientists hadn't mapped the exact genomic regions duplicated or cropped out.
Precise mapping was difficult, because that area of the genome is so repetitive - assembling the correct sequence of DNA is like trying to put together a puzzle with nearly identical pieces.
But the team developed a sequencing technology to solve the problem, and pinpointed how the NOTCH2NL genes were improperly pieced together in the patients with autism. The results suggest a direct link between the disorder and reshuffled NOTCH2NL genes.
The second paper published in Cell designed a computational method to help detect genes active during human fetal brain development. The top gene on the list was the same one the other paper identified - NOTCH2NL. "It's very exciting that we picked up the same super-cool candidate," author of the second paper says.
Genes influencing brain size found!
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