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Scientists pinpoint a gene regulator that makes human brains bigger

The human version of a DNA sequence called HARE5 turns on a gene important for brain development (gene activity is stained blue), and causes a mouse embryo to grow a 12 percent larger brain by the end of pregnancy than an embryo injected with the chimpanzee version of HARE5. (Silver Lab, Duke University)

By inserting bits of human DNA into mice, scientists were able to make their brains develop more rapidly -- and ultimately grow bigger -- in the womb. The study, published Thursday in Current Biology, suggests that the evolution of this gene may be one of the things that sets us apart from our close relatives in the primate world.

Human brains are unique, even when compared with our close genetic relatives, such as chimpanzees. Our brains are about three times heavier than those of our cousins, and are more complex and interconnected as well. It's generally accepted that these neurological differences are what allowed us to evolve the higher brain function that other primates lack. But just what genetic changes allowed humans to surpass chimps in the brain arena is one that's still being answered.

There are a lot of physical differences to examine more closely, but size is such a dramatic one that the authors of the new study chose to start there.

Using databases created by other labs, the Duke University scientists cross-checked areas of human DNA that had developed differences from chimp DNA with areas of DNA they expected to be important for gene regulation. Regulator genes help determine how other genes will express themselves, and the researchers suspected that some of these regulators might be making brain development more active in human embryos than in chimps.

They ended up focusing on a region called HARE5 (short for human-accelerated regulatory enhancer), which testing indicated had something to do with brain development. They suspected that the enhancer, which is found close to a molecular pathway important in brain development, might have changed in a way that influenced brain size in humans.

"We discovered that the human DNA sequence, which only had 16 changes in it compared to the chimp sequence, was being expressed differently in mice," said study author Debra Silver, an assistant professor of molecular genetics and microbiology in the Duke University Medical School.

In fact, HARE5 was regulating how many neural stem cells -- the precursors of brain cells -- a mouse embryo could produce.

"The human DNA was really able to accelerate the way the stem cells divide," Silver said. "And as a result, the mice were able to produce more neurons."

The brains of these genetically modified mice grew 12 percent bigger than ones given the chimpanzee version of HARE5.

For humans, Silver said, this difference could be crucial. Humans and chimps have similar gestation periods, which are fairly long when compared with other species.

"HARE5 seems to promote the ability to create more neurons and increase brain size, which allows human brain development to take advantage of that," Silver said.

Indeed, previous studies have shown that human and chimp brains start off at the same developmental pace in the womb. But after 22 weeks, chimp brain growth levels off while human development continues.

Humans may be unusually wimpy and helpless when they emerge from the womb, but our brains are already prepped for a lifetime of speech, complex social interaction, and deep critical thought that would be unheard of in any other species.

But the study raises a question nearly as gripping as the origin of our own species's ability to think: Did Silver and her team develop a team of super genius mice?

(We're kidding -- a little.)

"We're seeing differences in brain development, particularly in the structure of the brain that becomes the cerebral cortex," Silver said. The cerebral cortex has an important function in decision making and thought in humans. "We're definitely interested in testing whether it might affect memory or socialization in mice," she said.

They'll need to figure out how the genes will change adult mouse brains, since this study focused on fetal development, but she hopes they can do behavioral tests on mice with human HARE5 soon.

To Silver, the biggest takeaway is that her team has barely scratched the surface.

"It really highlights that just a small difference in the regulatory regions of human DNA -- even ones that don't really make a gene, per se, but help to control genes -- can have a big impact on how the brain is built, and ultimately how it functions," she said.

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