May. 31, 2018
By Elizabeth Pennisi

Three nearly identical genes could help explain how 0.5 liters of gray matter in early human ancestors became the 1.4-liter organ that has made our species so successful and distinctive. The newly identified genes could also help explain how brain development sometimes goes wrong, leading to neurological disorders.

The genes, descendants of an ancient developmental gene that multiplied and changed in the course of evolution, add to a growing list of DNA implicated in human brain expansion. But they stand out because so much has been learned about how they work their magic, says James Noonan, an evolutionary genomicist at Yale University. Researchers have shown that this trio boosts the number of potential nerve cells in brain tissue, and one team even pinned down the protein interactions likely responsible. “These are new proteins that are potentially modifying a very important pathway in brain development in a very powerful way,” Noonan adds.

Until now, the four genes were thought to be one, NOTCH2NL, itself a spinoff of the NOTCH gene family, which controls the timing of development in everything from fruit flies to whales. But two studies in the 31 May issue of Cell trace a series of genetic accidents in recent evolutionary history that have yielded four very closely related NOTCH2NL genes in humans (see graphic, below).

David Haussler, a bioinformatician at the University of California, Santa Cruz, and his colleagues got on the trail of the genes after they discovered that the NOTCH pathway works differently in human and macaque brain organoids—test tube models of the developing brain. NOTCH2NL was missing in the macaque organoid and, later analyses showed, in other nonhuman apes as well. That suggested NOTCH2NL might have played a unique role in human evolution.

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