What makes us human? Mostly gene regulation, according to an area of research launched by Katie Pollard, PhD

Katie Pollard poses at the Gladstone Institutes
Photo: Michael Short/Gladstone Institutes

Like many researchers, Katie Pollard, PhD, was drawn to human genetics because she wanted to understand how DNA accounts for the differences between humans and other animals. But unlike most, Pollard found a big piece of the puzzle while she was still a postdoc.

Pollard wrote a computer program to look for any stretches where chimpanzee DNA was similar to other mammals’ but distinct from humans’. To her surprise, her program identified areas where chimpanzee DNA is nearly identical to all other mammals, but dramatically different from human groups – suggesting something important changed during human evolution.

Pollard dubbed these areas “human accelerated regions” (HARs). “Accelerated” refers to what must have happened to account for what Pollard saw. Only a period of rapid evolution – starting with humans’ and chimpanzees’ common ancestor and completed before Neanderthals and the first modern humans emerged ­­– could explain it.

Much about HARs did not make immediate sense. “When HARs were discovered in 2006, their function was mysterious due to scant annotation of the noncoding genome,” Pollard and her lab’s lead computer scientist, Sean Whalen, PhD, wrote in a recent commissioned review of progress in the field in the Annual Review of Genetics.

That HARs turned up in noncoding regions – at that time called “junk DNA” – was a surprise. If one went looking for the DNA recipe to explain how humans are so different from other animals, one would expect to find it in the genes that encode the proteins that make up the body. But HARs don’t encode proteins; they help regulate the genes that do.

With the benefit of significantly more research into genomics since 2006, it now makes more sense that gene regulation is an important piece of what makes humans different from other mammals.

“During development, particularly, you’re turning on and off and on and off a lot of genes,” Pollard explained. “If you do that in a different order or with a different timing, you can get agile fingers or a bigger cortex, like humans have.”

Early on, the most discernable HARs were linked to gene expression related to neurodevelopment, but Pollard wondered if that wasn’t because it’s easier to make connections to unique aspects of the human brain – long the focus of evolutionary and developmental study – than to other systems.

“I always was worried that there must just be a knowledge bias,” she said. “HARs don’t all act on the brain, but the fact that there are a lot that do is holding up over time.”

Growing evidence of the close relationship of HARs with the brain is documented in Pollard and Whalen’s Annual Review article. The article also tracks the growing evidence base showing that most HARs control gene expression.

The article lists the HARs for which there is most evidence to suggest they changed gene expression relevant to human evolution. Pollard and Whalen contributed work to backstop this initial hypothesis. Pollard worked with UCSF collaborators Alex Pollen, Nadav Ahituv and Tomasz Nowakowski to take chimpanzee stem cells, turned them into various relevant types of cells and then engineered them to test whether HARs can facilitate chimp gene-regulating processes. They found that the chimp cells then behaved like human cells. Whalen has also used computer modeling to predict what effect HAR-influenced processes would have on primate cells.

“A computer model and a lab experiment – both are imperfect, but when they converged at the same conclusion that was an aha moment,” Pollard said.

The article also flags the big questions that remain about HARs, inviting researchers to explore what forces drove the rapid evolution of HARs and how HARs might pave the way for unique human behaviors, such as language, and uniquely human diseases, such as schizophrenia.

There are already some leads.

“Other researchers building on my work have looked at human-to-human genetic variants, and where someone does have a variant in a HAR, there’s a higher chance that the person has a psychiatric disease,” Pollard said. “There’s a theory out there that to make a human brain do all the things that it does also opens us up to some vulnerabilities – those evolutionary changes that make us able to do what we do are also an Achilles’ heel.”

Pollard’s work on HARs recently earned her a place in the National Academy of Medicine.