A team of Duke researchers has identified a group of human DNA sequences that drive changes in brain development, digestion and immunity that appear to have evolved quickly after our family line split from that of chimpanzees but before we split with Neanderthals .
Our brains are bigger and our intestines are shorter than our ape companions.
Many of the traits that we think of as uniquely human and human-specific probably emerged during that time period in the 7.5 million years since the split with the common ancestor we share with the chimpanzee.”
Craig Lowe, Ph.D., assistant professor of molecular genetics and microbiology at Duke School of Medicine
Specifically, the DNA sequences in question, which the researchers have named Human Ancestor Quickly Evolved Regions (HAQERS), pronounced as hackers, regulate genes. They are switches that tell nearby genes when to turn on and off. The results appear from 23 November in the journal CELL.
The rapid evolution of these regions of the genome appears to have acted as a fine-tuning of regulatory control, Lowe said. More switches were added to the human operating system as sequences evolved into regulatory regions and they became more fine-tuned to adapt to environmental or developmental cues. By and large, these changes were beneficial to our species.
“They seem particularly specific in getting genes to turn on, we just think in certain cell types at certain times of development, or even genes that turn on when the environment changes in some way,” Lowe said.
Much of this genomic innovation was found in brain development and the gastrointestinal tract. “We see lots of regulatory elements that turn on in these tissues,” Lowe said. “These are the tissues where humans refine which genes are expressed and at what level.”
Today, our brains are larger than other apes and our intestines are shorter. “People have assumed that these two are even connected 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 hit the gut, it was probably a lot of these small changes over time.”
To produce the new findings, Lowe’s lab collaborated with Duke colleagues Tim Reddy, an associate professor of biostatistics and bioinformatics, and Debra Silver, an 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 sees switches in action in developing mouse brains.
“Our contribution was that if we could bring both of these 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 contacts that were completely new in humans,” Lowe said. Computationally, they were able to infer what the DNA of the human-chimpanzee ancestor would have been 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 from 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 genes on or not,” which they did dozens of times.
“And we showed that this is really a switch that turns genes on and off,” Lowe said. “It was really fun to see that new gene regulation came from completely new switches, rather than just some kind of toggle switch that already existed.”
Along with the positive properties that HAQERs gave humans, they may also be implicated in some diseases.
Most of us have remarkably similar HAQER sequences, but there are some variances, “and we were able to show that these variants tend to correlate with certain diseases,” said Lowe, namely hypertension, neuroblastoma, unipolar depression , bipolar depression and schizophrenia. The mechanisms of action are not yet known, and more research needs to be done in these areas, Lowe said.
“Perhaps human-specific diseases or human-specific susceptibilities to these diseases will be preferentially mapped back to these new genetic switches that exist only in humans,” Lowe said.
Mangan, RJ, et al. (2022) Adaptive Sequence Divergence Forged Novel Neurodevelopmental Enhancers in Humans. Cell. doi.org/10.1016/j.cell.2022.10.016.