HomeScienceGeneticsHuman evolution wasn't just the sheet music, but how it was played

Human evolution wasn’t just the sheet music, but how it was played

A team from Duke researchers has identified a group of human DNA sequences that cause changes in brain development, digestion, and immunity that appear to have evolved rapidly after our family line split from that of the chimpanzees, but before we parted ways with the Neanderthals.

Our brains are bigger and our guts are shorter than those of our ape companions.

“Many of the traits that we think are unique and human-specific probably appear during that time period,” said Craig Lowe, Ph. .D., assistant professor of molecular genetics and microbiology at Duke School of Medicine.

In particular, the DNA sequences in question, which the researchers have dubbed Human Ancestor Quickly Evolved Regions (HAQERS), pronounced hackers, regulate genes. It’s 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 refinement of regulatory control, Lowe said. More switches were added to the human operating system as sequences evolved into regulatory regions, and they became more finely tuned to adapt to environmental or developmental cues. Overall, those changes have been beneficial to our species.

“They seem especially specific in causing genes to turn on. We think only in certain cell types at certain developmental times, or even genes to turn on when the environment changes in some way,” Lowe said.

Much of this genomic innovation was found in the development of the brain and gastrointestinal tract. “We see a lot of regulatory elements kicking in in these tissues,” Lowe said. “These are the tissues where people fine-tune which genes are expressed and at what level.”

Today, our brains are larger than those of other apes, and our intestines are shorter. “People have hypothesized that those two are even linked because they’re two very expensive metabolic tissues to have around,” Lowe said. “I think what we’re seeing is 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 produce the new findings, Lowe’s lab teamed up with Duke colleagues Tim Reddy, an associate professor of biostatistics and bioinformatics, and Debra Silver, an associate professor of molecular genetics and microbiology to tap into their expertise. Reddy’s lab is able to watch millions of genetic switches at once and Silver looks at switches in action in developing mouse brains.

“Our contribution was that if we could bring both technologies together, we could look at hundreds of switches in these kinds of complex developing tissues, which you can’t really get out of a cell line,” Lowe said.

“We wanted to identify switches that were totally new in humans,” Lowe said. Computationally, they were able to deduce what the DNA of the human-chimpanzee ancestor would have looked like, as well as the extinct lineages of Neanderthals and Denisovans. 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 actually 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 nice to see new gene regulation come out of totally new switches, rather than just some kind of rewiring of switches that already existed.”

In addition to the positive properties that HAQERs have given people, they may also be involved in some diseases.

Most of us have remarkably similar HAQER sequences, but there are some anomalies, “and we were 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 preferentially be traced back to these new genetic switches that only exist in humans,” Lowe said.

Support for the study came from 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.

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