Credit: Silver lab, Duke University
Credit: Silver lab, Duke University

Fast-Evolving Human DNA Leads to Bigger-Brained Mice

Between 5 and 7 million years of evolution separate us humans from our closest relatives—chimpanzees. During that time, our bodies have diverged to an obvious degree, as have our mental skills. We have created spoken language, writing, mathematics, and advanced technology—including machines that can sequence our genomes. Those machines reveal that the genetic differences that separate us and chimps are subtler: we share between 96 and 99 percent of our DNA.

Some parts of our genome have evolved at particularly high speed, quickly accumulating mutations that distinguish them from their counterparts in chimps. You can find these regions by comparing different mammals and searching for stretches of DNA that are always the same, except in humans. Scientists started identifying these “human-accelerated regions” or HARs about a decade ago. Many turned out to be enhancers—sequences that are not part of genes but that control the activity of genes, telling them when and where to deploy. They’re more like coaches than players.

It’s tempting to think these fast-evolving enhancers, by deploying our genes in new formations, drove the evolution of our most distinguishing traits, like our opposable thumbs or our exceptionally large brains. There’s some evidence for this. One HAR controls the activity of genes in the part of the hand that gives rise to the thumb. Many others are found near genes involved in brain development, and at least two are active in the growing brain. So far, so compelling—but what are these sequences actually doing?

To find out, J. Lomax Boyd from Duke University searched a list of HARs for those that are probably enhancers. One jumped out—HARE5. It had been identified but never properly studied, and it seemed to control the activity of genes involved in brain development. The human version differs from the chimp version by just 16 DNA ‘letters’. But those 16 changes, it turned out, make a lot of difference.

Boyd’s team introduced the human and chimp versions of HARE5 into two separate groups of mice. They also put these enhancers in charge of a gene that makes a blue chemical. As the team watched the embryos of their mice, they would see different body parts turning blue. Those were the bits where HARE5 was active—the areas where the enhancer was enhancing.

Embryonic mice start building their brains on their ninth day of life, and HARE5 becomes active shortly after. The team saw that the human version is more strongly active than the chimp one, over a larger swath of the brain, and from a slightly earlier start.

HARE5 seems to be particularly active in stem cells that produce neurons in the brain. The human version of the enhancer makes these stem cells divide faster—they take just 9 hours to split in two, compared to the usual 12. So in a given amount of time, the mice with human HARE5 developed more neural stem cells than those with the chimp version. As such, they accumulated more neurons.

And they developed bigger brains. On average, their brains were 12 percent bigger than those of their counterparts. “We weren’t expecting to get anything that dramatic,” says Debra Silver, who led the study.

“Ours stands as among the first studies to demonstrate any functional impact of one of these HARs,” she adds. “It shows that just having a few changes to our DNA can have a big impact on how the brain is built. We’ve only tested this in a mouse so we can’t say if it’s relevant to humans, but there’s strong evidence for a connection.”

“I’m really excited that people are following up [on these HARs] and finding out what they do,” says Katherine Pollard from the Gladstones Institutes, who was one of the scientists who first identified these sequences. “It’s been really daunting to figure out what the heck these things do. Each one takes years. These guys went the extra mile beyond what everyone else has been doing, by showing changes in the cell cycle and in brain size.”

“It’s a very clever use of mice as readouts for human-chimp differences,” says Arnold Kriegstein from the University of California, San Francisco. “The [brain] size difference isn’t terribly big, but it’s certainly in the correct direction.”

Eddy Rubin from the Joint Genome Institute is less convinced. His concern is that the team’s methods could have saddled the mice with multiple copies of HARE5 in various parts of their genome. As such, it’s not clear if the differences between the two groups are due to these factors, rather than to the 16 sequence differences between the human and chimp enhancers. “[That] casts major shadow on the conclusions,” says Rubin. “This is an interesting study pursuing an important issue, but the results should be taken with a grain of salt.”

Regardless, Silver’s team are now continuing to study HARE5. Now that their mice have grown up, they are designing tests to see if the adults behave differently thanks to their larger brains. This is important—bigger brains don’t necessarily mean smarter animals. They’re also looking into a few other enhancers. One of them, for example, seems to a control a gene that affects the growth of neurons.

“I think HARE5 is just the tip of the iceberg,” says Silver. “It is probably one of many regions that explain why our brains are bigger than those of chimps. Now that we have an experimental paradigm in place, we can start asking about these other enhancers.”

Reference: Boyd, Skove, Rouanet, Pilaz, Bepler, Gordan, Wray & Silver. 2015. Human-Chimpanzee Differences in a FZD8 Enhancer Alter Cell-Cycle Dynamics in the Developing Neocortex. Current Biology

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