A team of Dukes researchers identified a group of human DNA sequences driving changes in brain development, digestion and immunity that appear to have evolved rapidly after our family line split from chimpanzees but before we split from Neanderthals .
Our brains are bigger and guts are shorter than our ape peers.
“Many of the traits that we think are uniquely human and specific to humans probably appear during that time period,” in the 7.5 million years since the split with the common ancestor we share with the chimpanzee, Craig Lowe said. , Ph. .D., assistant professor of molecular genetics and microbiology at the Duke School of Medicine.
Specifically, the DNA sequences in question, which the researchers dubbed Human Ancestor Quickly Evolved Regions (pronounced HAQERS), like 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 as a fine-tuning of regulatory scrutiny, Lowe said. More switches were added to the human operating system as sequences developed into regulatory regions, and were more finely tuned to match developmental or environmental cues. Overall, those changes have been beneficial to our species.
“They seem particularly specific in causing genes to turn on, just think of in certain cell types at certain points 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 developing brain and gastrointestinal tract. “We see a lot of regulatory elements flaring up in these fabrics,” Lowe said. “These are the tissues where humans are fine-tuning which genes are expressed and at what level.”
Today our brains are bigger than other apes and our guts are shorter. “People have speculated that those two are even related, because they’re two very expensive metabolic tissues to have around,” Lowe said. “I think what we’re seeing is there wasn’t really a mutation that gave you a big brain and a 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 teamed up with Duke colleagues Tim Reddy, associate professor of biostatistics and bioinformatics, and Debra Silver, associate professor of molecular genetics and microbiology to draw on their expertise. Reddy’s lab is capable of examining millions of genetic switches at once, and Silver is observing the switches at work in developing mouse brains.
“Our input was, if we could bring both of these technologies together, then we could look at hundreds of switches in this kind of complex developing fabric, which you can’t really get from a cell line,” Lowe said.
“We wanted to identify totally new switches in humans,” Lowe said. Computationally, they were able to infer what human-chimpanzee ancestor DNA would have looked like, 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 that Neanderthal sequence and see if it can really turn on genes or not,” which they’ve done dozens of times.
“And we showed that, whoa, this really is a switch that turns genes on and off,” Lowe said. “It was really fun to see that the new genetic regulation came from completely new switches, rather than sort of rewiring switches that already exist.”
Along with the positive traits HAQERs have given to humans, they may 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 those 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 susceptibilities to these diseases will be preferentially traced to these new genetic switches that exist only in humans,” Lowe said.
Research support came from the National Human Genome Research Institute — NIH (R35-HG011332), North Carolina Biotechnology Center (2016-IDG-1013, 2020-IIG-2109), Sigma Xi, The Triangle Center for Evolutionary Medicine and the Duke Whitehead Scholarship.