A team of Duke researchers have identified a group of human DNA sequences that drive 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 separated from the separated Neanderthals.
Our brains are larger and our guts are shorter than our fellow monkeys.
“Many of the traits that we believe to be uniquely human and human-specific likely emerge during this period,” said Craig Lowe, Ph.D., an assistant professor of molecular genetics and microbiology at the Duke School of Medicine.
Specifically, the DNA sequences in question, which the researchers have dubbed Human Ancestor Quickly Evolved Regions (HAQERS), regulate, pronounced like hackers, genes. They are the switches that tell nearby genes when to turn on and off. The results appear in the journal on November 23 CELL.
The rapid evolution of these regions of the genome appears to have served as fine-tuning of regulatory control, Lowe said. More switches were added to the human operating system as sequences evolved into regulatory regions, and they were fine-tuned to adapt to environmental or developmental cues. Overall, these changes have been beneficial to our species.
“They seem particularly specific for turning on genes, we think only in certain cell types at certain times of development, or even genes that turn on when the environment changes in some way,” Lowe said.
Many of these genomic innovations have been found in brain development and the gastrointestinal tract. “We see many regulatory elements turning 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 those of other great apes and our intestines are shorter. “People have hypothesized that these two are actually related because they’re two really expensive metabolic tissues,” 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 little changes over time.”
To achieve the new results, Lowe’s lab worked 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 study millions of genetic switches simultaneously, and Silver observes switches in action as mouse brains evolve.
“Our contribution was, if we could bring these two technologies together, we could study hundreds of switches in this type of complex, developing tissue that you can’t really get from one cell line,” Lowe said.
“We wanted to identify switches that were completely new in humans,” Lowe said. Computationally, they were able to deduce what the DNA of the human chimpanzee ancestor, as well as the extinct Neanderthal and Denisovan lines, might have been like. 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 Prize winner Svante Pääbo.
“So we know the Neanderthal sequence, but let’s test this Neanderthal sequence and see if it can actually turn on genes or not,” which they did dozens of times.
“And we showed that this really is a switch that turns genes on and off,” Lowe said. “It was really fun to see that new gene regulation comes from entirely new switches and not just some kind of rewiring of already existing switches.”
In addition to the positive properties that HAQER gave to people, they can also be associated with some diseases.
Most of us have remarkably similar HAQER sequences, but there are some variations, “and we were able to show that these variants tend to correlate with certain diseases,” Lowe said, namely hypertension, neuroblastoma, unipolar depression, and bipolar depression 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 those diseases are preferentially attributed to these new genetic switches that only exist in humans,” Lowe said.
Relation: Manganese RJ, Alsina FC, Mosti F, et al. Adaptive sequence divergence has generated new neurodevelopmental enhancers in humans. cell. 2022;185(24):4587-4603.e23. got to: 10.1016/j.cell.2022.10.016
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