The blue stains in these developing mice embryos show that the human DNA inserted into the rodents turns on sooner and is more widespread (right) than the chimp version of the same DNA, promoting a bigger brain.

Researchers have increased the size of mouse brains by giving the rodents a piece of human DNA that controls gene activity. The work provides some of the strongest genetic evidence yet for how the human intellect surpassed those of all other apes.

«[The DNA] could easily be a huge component in how the human brain expanded,» says Mary Ann Raghanti, a biological anthropologist at Kent State University in Ohio, who was not involved with the work. «It opens up a whole world of possibilities about brain evolution.»

For centuries, biologists have wondered what made humans human. Once the human and chimp genomes were deciphered about a decade ago, they realized they could now begin to pinpoint the molecular underpinnings of our big brain, bipedalism, varied diet, and other traits that have made our species so successful. By 2008, almost two dozen computerized comparisons of human and ape genomes had come up with hundreds of pieces of DNA that might be important. But rarely have researchers taken the next steps to try to prove that a piece of DNA really made a difference in human evolution. «You could imagine [their roles], but they were just sort of ‘just so’ stories,” says Greg Wray, an evolutionary biologist at Duke University in Durham, North Carolina.

Wray is particularly interested in DNA segments called enhancers, which control the activity of genes nearby. He and Duke graduate student Lomax Boyd scanned the genomic databases and combed the scientific literature for enhancers that were different between humans and chimps and that were near genes that play a role in the brain. Out of more than 100 candidates, they and Duke developmental neurobiologist Debra Silver tested a half-dozen. They first inserted each enhancer into embryonic mice to learn whether it really did turn genes on. Then for HARE5, the most active enhancer in an area of the brain called the cortex, they made minigenes containing either the chimp or human version of the enhancer linked to a “reporter” gene that caused the developing mouse embryo to turn blue wherever the enhancer turned the gene on. Embryos’ developing brains turned blue sooner and over a broader expanse if they carried the human version of the enhancer, Silver, Wray, and their colleagues report online today in Current Biology.

The researchers determined that HARE5 likely controls a gene called Frizzled 8, which is part of a molecular pathway important in brain development. Their further studies showed that the human version of the enhancer causes cells that are destined to become nerve cells to divide more frequently, thereby providing a larger of pool of cells that become part of the cortex. As a result, the embryos carrying human HARE5 have brains that are 12% largerthan the brains of mice carrying the chimp version of the enhancer. Silver and Wray plan to test these mice to see if the bigger brains made them any smarter.

«They have found a smoking gun in the human genome that connects a regulatory element with a proposed pathway for increasing brain size,» says Todd Preuss, a neuroanatomist at the Yerkes National Primate Research Center in Atlanta, who was not involved with the work.

But he; geneticist Evan Eichler of the University of Washington, Seattle; and others point out that there’s more to be done. Several researchers worry that more extensive studies are needed to nail down that the HARE5 effects are not by chance. They’d like to see Silver and her colleagues replace the mouse HARE5 with the human and chimp HARE5—a feat the Duke group has yet to succeed in doing.

Even so, Eichler is pleased with just how much the Duke team has learned so far. And, Wray says, given the growing ability of researchers to study enhancers and other DNA in mice, “my guess is there are probably other stories like this in the works.”

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