A gene for our big brains was rescued from the DNA garbage bin

Researchers have identified a unique human gene that may help explain why our brains are three times the size of chimpanzee brains.

It delays brain development and gives more time for neurons to grow

Skulls of various primates and their relative brain sizes. (Christopher Walsh, Harvard Medical School, cc-by-sa-2.5)
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Building the big human brain

Researchers in the U.S. and Europe have identified a unique human gene that seems to be an important factor in our oversized human brains, which are three times the size of our closest relatives, the chimpanzees.

The teams found that the gene works during brain development by creating a large population of neural stem cells — factories for producing neurons. When these stem cells are unleashed, they then explosively produce the 100 billion neurons found in the human brain.

They were also able to reconstruct the evolution of of this gene, which tells a fascinating tale of lucky accidents in our genetic history.

David Haussler, the director of the University of California Santa Cruz Genomics Institute, led the American team. The discovery had roots in work being done in his lab in 2012. They were culturing small patches of brain cells from humans and rhesus macaques, one of the best-known species of Old World monkeys, to look at the differences in how human and monkey genes operated as the tissue grew. What they saw was a big difference in the way the tissue was developing.

"That's when we knew we had something very exciting," says Haussler. The team was "shocked" to find out that there was one gene that was expressed very strongly in humans, and not expressed at all in macaque cerebral development. What they had discovered was a gene uniquely responsible for human brain size. They called it NOTCH2NL.

Making more cells to make more brain cells

This diagram shows the evolutionary events that led to the NOTCH2NL gene in modern humans (Sofie Salama)
Further work showed exactly how the gene worked. During the early period of brain development in the embryo, the gene activates. It delays the point when neural stem cells start maturing to produce all the various types of neurons that make up the brain. It also lengthens the period when neural stem cells themselves are being grown, and as a result, a much larger pool of these cells are created. "This all happens in the period of about five to 16 weeks in embryonic development," says Haussler. "This is the period of exponential growth in the number of neurons."

Understanding what NOTCH2NL did to build brains was only part of the story. The other part was understanding where it came from. It clearly had similarities to a very ancient gene we share with animals called NOTCH2. This gene is important to neural development, but of course, builds much smaller brains in other creatures.

Reconstructing the evolution of a gene

By comparing genomes between humans and our relatives — apes and other primates, Haussler and his team were able to reconstruct a fascinating series of evolutionary accidents that seem to have been critical for building our big brains.

The first step occurred about 10 million years ago when an ancestral ape acquired a mutation that led to an incomplete copy of NOTCH2 appearing in its genome. This broken "pseudogene" was inactive but was passed on to the ape's descendents. In fact this inactive pseudogene is still present in modern chimps and gorillas.

But in the human lineage, things went differently with this pseudogene, according to Haussler. "It sat around as a worthless copy for millions of years, and then sometime, we estimate between three and four million years ago, an ancestral child had another unusual event."

In another genetic fluke, the broken NOTCH2 copy seems to have been fixed by a genetic repair mechanism, reactivating it - but with some critical changes. These changes meant that the new gene - NOTCH2NL, operated differently from its progenitor gene, says Haussler. "At that point we had a new form of NOTCH activity." That new activity was key to building a bigger human brain.

Homo erectus appeared after the NOTCH2NL gene was reactivated in our lineage, and has a considerably larger brain than ancestral species who predate it (David Mdzinarishvili/Reuters)

Reconciling the DNA and the fossils

What Haussler finds intriguing is the way this matches up with other evidence about human brain evolution. "It was a human ancestor in which this occurred, and what's exciting is that when you look at the record of fossils now, this is about the time when you start to see larger and large skulls for our human ancestors." This is the period of transition from more ape-like and smaller-brained Australopithecines to very large brained species like Homo habilis and Homo erectus. "This is a great opportunity to make a connection between what we see in the bones and what we see in the DNA."  

This is certainly only part of the story of our big brains. Many more changes would have to occur to accommodate this new neural tissue within the brain, as well as external changes like a larger skull and body to support it. According to Haussler, the appearance of NOTCH2NL could be close to the start of that story.

"There are a few events that get the ball rolling and then there are many, many other accommodations that have to happen to enhance and allow for those new changes," he says. "There will literally be thousands of new discoveries that will be made as we learn a little bit more about how brains work, over the next several years."