Two teams have independently discovered what they call the holy grail of their field – the genes responsible for our brains being so much larger than our nearest relatives.
As important as walking upright and having opposable thumbs may be, it is our brains that really set us apart from other animals. Yet strangely, the genetic basis for this difference has been a mystery. Now two papers published in Cell give the credit to NOTCH2NL, a gene family so overlooked we previously mismapped its location in the genome.
The authors of both papers note NOTCH2L genes are limited to humans. They delay the process of cortical stem cells differentiating to become neurons, slowing brain development but ensuring we have more neurons in the end.
“Our brains got three times as big primarily through the expansion of certain functional areas of the cerebral cortex, and that has to be a fundamental substrate for us becoming human,” said senior author of one of the papers, Professor David Haussler of the University of California, Santa Cruz, in an emailed statement. “There’s really no more exciting scientific question that I can think of than discovering and decoding the mysterious genetic changes that made us who we are.”
Haussler’s team suspected something when comparing the genes expressed in the brains cells of humans and macaques, and found the monkeys NOTCH2NL-free. Further investigation revealed the great apes also lack an equivalent set of genes.
In attempting to trace the history of NOTCH2NL, Haussler concluded that the NOTCH2 gene, which is essential to brain development in all animals, became duplicated. Originally non-functional, the second version underwent gene conversion around 4 million years ago, coinciding with the great expansion of our brains. These now functional genes duplicated twice more before we diverged from the Neanderthals, further fueling our increased brain capacity.
When Haussler’s team deleted NOTCH2NL from human stem cells, they found the miniature brain cortex patches they were growing in vitro developed faster initially but ended up smaller, reflecting the way other animals’ brains grow compared to our own.
Meanwhile, at the Université Libre de Bruxelles, Dr Pierre Vanderhaeghen was looking for human-specific genes that influence brain development. Vanderhaeghen was able to find 35 such genes active in the cerebral cortex, and he concluded NOTCH2’s known role in brain cell development made NOTCH2NL a particularly likely candidate.
When Vanderhaeghen’s team transferred NOTCH2NL to mouse embryos, it created the conditions to increase the number of neurons in the mouse cortex, much like in the book Flowers for Algernon.
There is a price to pay for this extra capacity, however. The genome region in which NOTCH2NL resides is associated with many brain diseases when development goes wrong; errors in NOTCH2NL may be responsible for neuron over- and under-production.