A team of Duke researchers has identified a group of human DNA sequences leading to changes in brain development, digestion and immunity that appear to have evolved rapidly after our family line split from that of chimpanzees but before we split with Neanderthals.
Our brains are bigger and our guts are shorter than our ape peers.
“Many of the traits that we think of as uniquely human and human-specific probably emerged during this time period,” the 7.5 million years after the split with the common ancestor we share with chimpanzees, said Dr. Craig Lowe.D ., assistant professor of molecular genetics and microbiology at the Duke School of Medicine.
Specifically, the DNA sequences in question, which the researchers have named human ancestral rapidly evolved regions (HAQERS), pronounced hackers, regulate genes. They are the switches that tell nearby genes when to turn on and off. The findings appear Nov. 23 in the journal cell.
The rapid evolution of these regions of the genome appears to have served to fine-tune regulatory control, Lowe said. More switches were added to the human OS as sequences evolved into regulatory regions and were fine-tuned to adapt to environmental or developmental cues. Overall, these changes were beneficial to our species.
“They seem particularly specific in causing genes to turn on, we think, only in certain types of cells at certain times in development, or even genes that turn on when the environment changes in some way,” Lowe said.
Much of this genomic innovation has been found in the development of the brain and gastrointestinal tract. “We’re seeing a lot of regulatory elements that come into play in these tissues,” Lowe said. “These are the tissues in which people refine which genes are expressed and at what level.”
Today, our brains are bigger than other apes and our intestines are shorter. “People have hypothesized that these two are even related because they are two really expensive metabolic tissues to have around,” Lowe said. “I think what we’re seeing is that there wasn’t really one mutation that gave you a big brain, and one mutation that really affected the gut, it was probably a lot of these little changes over time.”
To produce the new findings, Lowe’s lab collaborated with Duke colleagues Tim Reddy, associate professor of biostatistics and bioinformatics, and Debra Silver, associate professor of molecular genetics and microbiology, to leverage their expertise. Reddy’s lab is able to look at millions of genetic switches at once, and Silver observes switches in action in developing mouse brains.
“Our contribution was that if we could bring both technologies together, then we could look at hundreds of switches in this kind of complex developing tissue that you can’t really get from a cell line,” Lowe said.
“We wanted to identify switches that are completely new to people,” Lowe said. Through calculations, they were able to infer what the DNA of the human-chimpanzee ancestor would have been, as well as the extinct Neanderthal and Denisovan lineages. The researchers were able to compare the genome sequences of these other post-chimpanzee relatives thanks to databases created by the pioneering work of 2022 Nobel Laureate Svante Pääbo.
“So, we know the Neanderthal sequence, but let’s test this Neanderthal sequence and see if it can actually include genes or not,” which they did dozens of times.
“And we’ve shown that this is indeed a switch that turns genes on and off,” Lowe said. “It was really fun to see that the new gene regulation came from completely new switches, not just flipping switches that already existed.”
Along with the positive traits that HAQER have given humans, they can also be implicated in some diseases.
Most of us have remarkably similar HAQER sequences, but there are some variations, “and we’ve been able to show that these variants tend to correlate with certain diseases,” Lowe said, namely hypertension, neuroblastoma, unipolar depression, bipolar depression and schizophrenia. The mechanisms of action are not yet known, and more research will need to be done in these areas, Lowe said.
“Perhaps human-specific diseases, or human-specific susceptibility to those diseases, will be preferentially mapped back to these new genetic switches that only exist in humans,” Lowe said.
Support for the research came from the National Human Genome Research Institute – NIH (R35-HG011332), the North Carolina Biotechnology Center (2016-IDG-1013, 2020-IIG-2109), Sigma Xi, the Triangle Center for Evolutionary Medicine, and a Duke Fellowship Whitehead.