Genome studies are turning up exciting hints about what makes human brains unique. But scientists must now tackle a difficult question: how can they tell which leads point in the right direction and which are red herrings?

Researchers are comparing human and chimp genomes to find out what makes our brains so different. Credit: K. HUNTT/CORBIS

The new studies rely on genome sequence data from humans' closest relatives: other primates. A draft of the chimpanzee genome was released last year1 and a draft sequence of the macaque genome is also publicly available. The data are enabling scientists to compare chimp, human and monkey DNA to search out signals that seem unique to people.

This approach is yielding pointers to the mechanisms that may have driven human evolution. Last week, researchers led by James Sikela of the University of Colorado Health Sciences Center in Aurora, announced the latest2. They looked for genes repeated more often in human DNA than in chimp genomes. They found that one gene contains a protein-coding domain that is repeated 212 times in people, compared with 37 repeats in chimps, 30 in macaques and one in mice and rats. And, significantly, this protein domain is present in human brain cells. It is also present in other tissues, but Sikela's team is excited because the domain is found in the neocortex, which is much larger in humans than in other primates.

“The fact that a huge explosion of this domain occurred in the primate lineages, and the fact that it is found in the brain, seems to make it a good candidate for cognitive function,” says Sikela.

One take-home message here is that duplications rock.

Investigating such 'copy-number polymorphisms' — gene repeats, deletions and other large-scale rearrangements — is one of the hottest areas of genomic research, says geneticist Evan Eichler of the University of Washington in Seattle. These sorts of structural variants have only recently been discovered, and it's possible that they could be a major driver of human evolution3. “One take-home message here is that duplications rock, and structural variation is very important,” Eichler says.

A broader question raised by Sikela's work and other recent studies is how to find out what, exactly, the newly discovered genes are doing. The easiest way to pin down an unknown gene's function — mutating it in an individual — isn't ethically acceptable in chimps or, of course, people.

One solution, says Sikela would be to mutate the relevant genes in mice, to see what happens to the rodents' brains. In a 2002 study, researchers at the Beth Israel Deaconess Medical Center in Boston, Massachusetts, found that they could enlarge mouse brains by inducing fetal mice to over-express the regulatory chemical β-catenin4. That suggested the chemical might regulate pathways that control human brain size.

Researchers can also scan tissue banks to find out when in human development genes are expressed. In a paper published on 16 August5, a team led by David Haussler at the University of California, Santa Cruz, did just that. By comparing the human and chimp genomes, they found one gene that has evolved rapidly during the transition from chimps to people. They looked at embryonic tissue collected by collaborators in Belgium, and found that this gene is expressed at 7–19 weeks of human development, when neurons are known to be forming and moving throughout the brain.

Another way to work out what brain genes do is to look for effects on human health, and to study patients with brain dysfunctions. In a study published on 13 August in Nature Genetics6, Eichler's lab looked at duplications in the genomes of 290 patients with unexplained mental retardation. One patient had a deletion in the same region of the genome where Sikela's group found its new gene. “It doesn't prove anything, but it's interesting,” Eichler says.

Finding the function of highly repetitive genes is especially challenging, he adds, because such genes are tricky to analyse correctly, and genome assemblers often miss them. So there are large gaps in our understanding of where duplications occur. Eichler is trying to remedy this with a project to sequence all the structural variations in a small group of people.

Other investigators say that it will be hard to make better sense of the new genome studies without more studies on apes. Because chimps are difficult to work with, and scarce, researchers don't really know much about how the structure and function of chimp brains compare with those of human brains, says Todd Preuss, a neuroscientist at the Yerkes National Primate Research Center in Atlanta, Georgia. That makes it hard to decipher the meaning of genetic disparities in the two species' brains, and that must change, he says. “We're all dressed up with no place to go — we've got all this wonderful information and we can't do much with it. The way to get around this is to study apes, and to start looking at the differences between human and chimp brain organization.”