UCSD research finds ‘volume control’ that genetically separates humans from chimps

One percent might not seem like a lot, but in human evolution, it’s all that genetically separates humans from chimpanzees.

Scientists have long pondered how a 1% genetic difference could be so pivotal, but researchers at UC San Diego in La Jolla think they’ve found the answer.

A study led by Miles Wilkinson and Kun Tan of human-accelerated regions, or HARs — sections of the human genome that have accumulated an unusually high level of mutations as humans have evolved — identified one particular HAR — called HAR123 — that appears to be instrumental in shaping the human brain.

According to the study, HAR123 promotes a particularly advanced human trait called cognitive flexibility, or the ability to unlearn and replace previous knowledge.

Wilkinson and Tan are professors in the Department of Obstetrics, Gynecology & Reproductive Sciences at the UCSD School of Medicine. Wilkinson also is an affiliate faculty member of the UCSD Institute for Genomic Medicine. The study was published online by Science Advances.

For Wilkinson, the work represents decades of interest.

Starting when he was an undergraduate at UC Santa Barbara, Wilkinson was inspired by an anthropology class that discussed human evolution, including the evolution of human brains.

“At that time in the 1970s, they were really only beginning to understand,” he said. “But I … have been interested in that topic ever since. But there wasn’t any direction or project that my lab was doing that would lead me there.”

However, he kept thinking about it.

Though he noted that evolution is still a theory, Wilkinson said there is “overwhelming evidence that we have a common ancestor that we share with chimps,” but when it came to brain development, “chimps went one way and humans went another way.”

The challenge with studying the brains of early humans is, unlike bones or other fossils, the cells don’t last once the subject is deceased.

So the question became, what happened genetically to make humans evolve differently from chimpanzees some 5 million years ago?

“Finally, there was a project that could go that direction that was connected to a molecular pathway [my] lab had been studying,” Wilkinson said. “We knew the pathway was important for brain development and function, so my thought was simple: If this pathway is important in the brain in the present, maybe changes in the pathway shaped the development of the human brain in the past.”

HAR123 is a type of molecular “volume control” known as a transcriptional enhancer, which can control which genes are activated, how much they are activated and at what times they are activated during an organism’s development.

“Now we have lines of evidence that the change in volume control led to differences responsible for the human brain vs. the chimpanzee brain,” Wilkinson said.

But the unique cognitive flexibility in humans comes with another unique trait — neural disorders.

“Other primates don’t get neural disorders such as autism or schizophrenia,” Wilkinson said. “The idea is, during brain development, it takes more time for our neural circuits to form so we can develop things like language. During that time, there is more time for things to not develop properly. So yes, we are unique, but we are unique in getting these disorders.”

With this discovery, “we’d like to know if mutations in HAR123 have a causal role in neural disease. Since HAR123 is a critical volume control, if it doesn’t work, you could have diseases. So it justifies future studies.”