The Origins of Human Accelerated Regions

Large parts of the human genome were changed over a million years ago due to a random event during egg or sperm formation that resulted in the deletion, duplication, or reversal of sections of DNA. Investigators have demonstrated that those structural variants likely set off a cascade of other fast alterations in human DNA that may underpin unique human traits, particularly the brain.

Kathleen Keough (left) and Katie Pollard (right) showed that large structural changes to the genomes of human ancestors could have spurred the smaller changes that set human brains apart from other primates. Image Credit: Gladstone Institutes.

The recent discovery, reported in Science by Gladstone Institutes researchers, stems from an investigation into how stretches of DNA known as human accelerated regions (HARs) differ between humans and chimpanzees. Human HARs are virtually identical, yet they differ between humans and all other mammals. Researchers have long puzzled over why these sequences, many of which affect brain development, altered so quickly during early human evolution.

What we found is that many HARs are in regions of DNA where structural variants caused the genome to fold differently in humans compared to other primates. This gave us an idea how HARs could have arisen in the first place.”

Katie Pollard PhD, Study Lead Author and Director, Gladstone Institute of Data Science and Biotechnology

Folding Like Origami

When comparing the genomes of humans and chimps nearly two decades ago, Pollard discovered regions of DNA—now known as HARs—that had been stable in mammals for millennia but abruptly changed in early humans. Her lab has recently shown that the majority of HARs are enhancers, which are short stretches of DNA that govern the activation of genes involved in brain development. However, scientists are still puzzled as to how HARs evolved and what role they play in distinguishing humans from other primates.

Pollard and her coworkers wondered if additional modifications in the DNA surrounding HARs could shed light on their origin. The researchers studied HARs and their surroundings in 241 mammalian genomes in partnership with The Zoonomia Project, a multinational effort to examine mammalian genomes. They concluded that HARs are more likely to be found in sections of the human genome that have significant structural differences from other animals.

The scientists then investigated if the structural alterations around HARs altered the way DNA folded.

The way the genome folds up in three-dimensional space like origami is particularly important for enhancers. That’s because enhancers can impact the activity of any gene that ends up close by, which can vary depending on how DNA is folded.”

Katie Pollard PhD, Study Lead Author and Director, Gladstone Institute of Data Science and Biotechnology

Pollard is also a professor at UC San Francisco and a Chan Zuckerberg Biohub Investigator.

Pollard’s team employed a machine learning model they initially created to predict DNA folding patterns to human and chimp DNA sequences to investigate the association between HARs and DNA folding. They then found the sections of the human genome that fold differently. The computer anticipated that roughly 30% of HARs were located in sections of the genome that folded differently in humans than in chimps.

“We realized that these human-specific structural changes may have created the right environment for HARs to evolve fast in the human ancestor, after remaining almost the same over millions of years of mammal evolution,” says Kathleen Keough, PhD, First Author of the Study and Former Postdoctoral Scholar in the Pollard Lab at Gladstone.

Piecing Together the Past

If DNA around HARs folded differently in humans, bringing various genes in close proximity to HARs, the repercussions for the ancestors could have been disastrous.

Imagine you’re an enhancer controlling blood hormone levels, and then the DNA folds in a new way and suddenly, you’re sitting next to a neurotransmitter gene and need to regulate chemical levels in the brain instead of in the blood. Your instructions are now out-of-date and need to be changed.”

Katie Pollard PhD, Study Lead Author and Director, Gladstone Institute of Data Science and Biotechnology

The machine learning model predicted that major structural changes had happened near HARs, but did not show which genes had come under their control. To answer that question, Pollard and her colleagues conducted laboratory studies that allowed them to detect which stretches of DNA were closest to hundreds of different HARs in human and chimp brain cells produced from stem cells.

Human HARs were shown to be close to genes known to have a role in brain development in many cases; in some cases, the neighboring genes were also related to neurodevelopmental or psychiatric diseases.

Pollard’s team recently showed that the changes that rapidly occurred in HARs throughout early human evolution frequently opposed one other, first increasing and then decreasing the activity of an enhancer or vice versa. She claims that the new findings are consistent with the concept established in that study.

Pollard states, “Something big happens like this massive change in genome folding, and our cells have to quickly fix it to avoid an evolutionary disadvantage. But the fix might kind of overdo it and need to be refined over time.”

While the new paper helps to explain how HARs may have emerged in the first place, Pollard’s team still has questions about why the massive structural changes survived the test of time and how HARs affect human brain development.