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Editorial: 鈥�We are the improbable ape鈥�

THE stage was set. Around 2.5 million years ago, the erroneous duplication of a single gene changed the course of our brains鈥� evolution forever. Suddenly, our ancestors鈥� neurons developed complex shapes that made them capable of exchanging information with a larger number of neighbouring cells. At the same time, infant skulls became more flexible, allowing them to accommodate larger brains.

Three new studies reveal this remarkable sequence of events. Crucially, they also show that the changes happened precisely at the same time as our own Homo genus split from the australopithecines (see evolutionary tree).

Gene duplications are rare in human history. Only about 30 genes have copied themselves since we split from chimps between 4 and 6 million years ago. The few that have been studied encode genes that are very exciting, says human geneticist of the University of Washington in Seattle. Many are involved in brain development.

Eichler and of the Scripps Institute in La Jolla, California, focused on SRGAP2. This gene helps drive development of the neocortex, which in humans controls higher-order brain functions such as language and conscious thought. Humans with mutations in SRGAP2 are prone to epileptic seizures, as are mice that have been engineered to lack it.

Eichler noted that the official sequence of the human genome featured unaccounted-for genetic material next to SRGAP2. His team found that this was because the gene had duplicated itself twice and the copies were so similar to the original that no one had distinguished between them.

Further analysis revealed that the first duplication happened 3.4 million years ago, producing SRGAP2b. Around 1 million years later, this 鈥渄aughter鈥� of the original gene underwent its own duplication, producing a 鈥済randdaughter鈥� copy: SRGAP2c. All three coexist in modern humans ().

But just like a photograph of a photograph, each new copy decreased in quality. The daughter and granddaughter genes were shorter than the original. And when Polleux replaced the original SRGAP2a gene in mice with either SRGAP2b or 2c, their brains didn鈥檛 mature normally.

When he inserted human versions of all three genes into mice, the proteins produced by the 2b and 2c genes bound to the original 2a proteins and hindered their ability to do their job. The net effect of this genetic sabotage was to give the mouse brains more time to develop.

Although the modified brains didn鈥檛 grow larger, the neurons in its neocortex changed to look like human brain cells. The spines that neurons use to exchange information with other cells grew thicker, longer and in greater numbers than in normal mouse neurons. This, say the researchers, would be likely to increase the brain鈥檚 processing power. Finally, the neurons migrated to their final positions more quickly than in unmodified mice, suggesting they could have travelled greater distances before maturity in a larger brain ().

鈥淚t all makes sense in an elegant way,鈥� says James Noonan of Yale University. To really pin down the effects of the gene, he says, the researchers have to show that a mouse with a full triplet of SRGAP2 genes has a more connected neocortex and that its behaviour changes.

Polleux鈥檚 lab are now testing whether this is the case. His team also plans to put the human genes into a marmoset 鈥� a much closer human relative. Eichler鈥檚 group is searching for people with mutations in the granddaughter copy of SRGAP2. They want to know if this causes cognitive disorders.

The timing of the duplications is significant. The first happened 3.4 million years ago, which corresponds with when Australopithecus afarensis first began using tools, says Dean Falk of Florida State University in Tallahassee. Better still, the second duplication was 2.5 million years ago 鈥� when our genus, Homo, began separating from the now-extinct Australopithecus.

鈥淭he accidental gene duplication coincided with the time when our genus, Homo, was born鈥�

鈥淚鈥檓 really excited about this,鈥� Falk says, in part because it suggests human intelligence has as much to do with brain connectivity as size. It is likely that the changes 2.5 million years ago were instrumental in allowing our brains to go through their unique growth spurt. Or as Falk puts it: 鈥淎s other mutations pile on, the machinery allows for further increases in brain size.鈥�

Falk herself has recently found evidence that while SRGAP2 was changing our brains, our ancestors鈥� skulls were shifting too. A 2.5-million-year-old A. africanus toddler had the same gaps in its skull as a modern baby, allowing the head to compress and fit through the birth canal. That suggests hominin brains 鈥� especially the frontal cortex 鈥� were already expanding by this time (see 鈥�The scars of size鈥�).

What鈥檚 interesting about the SRGAP2 duplication, Eichler says, is that it would have changed brain development immediately and dramatically. Human ancestors with two, three or even more copies of the gene 鈥� and consequently stark differences in their cognitive abilities 鈥� could have coexisted at one point. 鈥淭hat鈥檚 fun to think about,鈥� he says.

The researchers suspect other gene duplications will hold even more secrets about how our brains evolved. 鈥淲e still have a few hundred gaps in the human genome and that鈥檚 precisely where those duplicated genes are mapping,鈥� says Eichler. It may be that genes we share with our closest primate relatives are far more important than those that are different, and may explain why our cognitive abilities are so much greater.