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The Gene that Makes Us Human?

Scientists have identified a gene that just might be the key to the unique evolution of the human brain.

A small section of DNA that has rapidly evolved in humans could play a key role in the development and evolution of the human brain, according to research published online yesterday in the journal Nature. Although scientists don’t yet know exactly how the gene functions in the brain, they do know that the sequence is entirely unique to humans and is expressed in the cortex – which is responsible for complex thought – during a key stage of brain development.

“This is a very exciting finding,” says Bruce Lahn, a geneticist who studies brain evolution at the University of Chicago. “It brings us one step closer to the overall goal of understanding human brain evolution at the level of genes.”

Sometime in the last five to seven million years, when humans and chimpanzees split from each other on the evolutionary tree, our brains became three times bigger than those of our closest primate relatives. That impressive growth was largely due to expansion in the cerebral cortex, the outer layer of the brain responsible for reasoning and other types of complex thought. Since the sequences of the human and other animal genomes have become available for study, scientists have been scouring reams of DNA for genetic clues to our brains’ unique growth spurt – and to the biological changes that make us uniquely human.

In the new paper, researchers at the University of California, Santa Cruz compared the human genome to the genomes of chimps, dogs, rats, mice, and chickens, searching for genetic sequences that were highly conserved during evolution and therefore functionally important. They then looked for sequences within those conserved regions that had changed rapidly in humans, indicating that those changes were important for human’s unique evolution.

The researchers identified several rapidly evolving chunks of DNA, but the fastest piece by far was a small chain of DNA that’s part of a gene expressed in the hippocampus, which is involved in learning and memory. According to the findings, the sequence was very similar in chickens and chimps, with only two changes to the genetic code; but it had changed remarkably in human DNA, showing 18 genetic differences from the version in chimps.

“That really confirmed that this [sequence] is specific to the human lineage,” says David Haussler, a genomics expert at UCSC who led the work. “We also sequenced human DNA from different people around the world – everyone seems to have these same 18 variations.”

The researchers then discovered that the gene, known as HAR1F, has some even more enticing properties: it is expressed in a particular set of cells in the human brain between 9 and 19 weeks of gestation – when the cortex is undergoing a rapid period of development. “It’s essentially the initial phase of the development of the cortex, the thinking part of the brain,” says Haussler. “That’s the part of our brain that’s gotten so much bigger during the last few million years of evolution.”

Since scientists don’t yet know the function of the gene, it’s difficult to predict its role in brain development or human evolution. “Finding these rapidly evolving genes is a starting point to understanding human genetic evolution,” says Lahn, “but it doesn’t tell us how changes in the genetic sequence lead to changes in human biology.”

Indeed, HAR1F is rather mysterious. It codes only for an RNA, while most genes ultimately code for a protein. While other RNA coding genes have been identified – RNA genes sometimes have a regulatory function, altering production of a protein – this sequence resembles none of the known RNA genes. “The gene seems to be a gene in its own universe,” says Lahn.

The gene is also distinct from previously identified genes that might play a role in brain evolution. Last year, Lahn’s group identified two brain genes as being under recent evolutionary pressure. Unlike HAR1F, these genes have a known function – they’re both involved in control of brain size. In addition, different variations of these genes are found in different regions of the world, while everyone tested so far seems to carry the same 18 variations in the rapidly evolving chunk of HAR1F.

Haussler’s group was able to identify the novel piece of DNA because of their unique approach to genome analysis. Previous studies focused on the coding regions of the genome: the section of DNA that directs the production of proteins. Haussler’s group, on the other hand, did a genome-wide search for rapidly evolving sequences within the conserved regions of DNA. “Their method seems to be a very elegant way of picking up the potential regulatory elements that acquired unique functions in the human lineage,” says Ganeshwaran Mochida, a neuroscientist and geneticist at Harvard Medical School in Boston.

However, some scientists are skeptical that the piece of DNA will turn out to be the key to human brain evolution. “It is a bit hard to fathom how a 118 base pair piece of RNA could have been so stone-cold evolutionarily, with two changes in the last 318 million years, then undergo 18 successive independent substitutions in the human lineage since the split with chimpanzee,” says Andrew Clark, a population geneticist at Cornell University in Ithaca, NY. He suggests the recent changes may be the product of an unusual and not-yet-understood mutational process, rather than of evolutionary pressure. And he adds that no proof yet exists for either possibility. “In any event, the work serves as strong motivation to understand the biological function of this gene, and that has always been the excitement of this kind of work,” he says.

Haussler and collaborators are now trying to figure out what role HAR1F plays during brain development. Among other experiments, they plan to create a mouse that expresses the human form of the gene. “We don’t know if the mouse will start writing Shakespeare,” says Haussler. “It’s unlikely to function like a human gene because it’s being expressed in the mouse cortex with other mouse genes, but it’s something to try.”

Haussler predicts the findings will spark a wave of research into the role of HAR1F. For example, he hopes that scientists who study the genetics of schizophrenia and other disorders will search their patient populations for mutations in the gene, which might shed light on its role in brain development and cognitive function.

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