Human evolution was not just the score, but how it was played

Human evolution was not just the score, but how it was played

A team of Duke researchers 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 our split from Neanderthals.

Our brains are bigger and our guts are shorter than our monkey peers.

“Many of the traits that we think of as uniquely human and specific to humans probably appear during this time,” in the 7.5 million years since the break with the common ancestor we share with the chimpanzee, said 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 dubbed Human Ancestor Quickly Evolved Regions (HAQERS), pronounced as hackers, regulate genes. These are the switches that tell nearby genes when to turn on and off. The results appear on November 23 in the newspaper Cell.

The rapid evolution of these regions of the genome appears to have served as a fine-tuning of regulatory control, Lowe said. More switches were added to the human OS as sequences developed into regulatory regions, and they were more finely tuned to accommodate environmental or developmental cues. Overall, these changes were beneficial to our species.

“They seem particularly specific for causing genes to turn on, we only think of certain cell types at certain times in development, or even genes that turn on when the environment changes in some way. “, said Lowe.

Much of this genomic innovation has been found in brain and gastrointestinal tract development. “We see a lot of regulatory elements that activate in these tissues,” Lowe said. “These are the tissues where humans refine which genes are expressed and at what level.”

Today, our brains are bigger than those of other monkeys and our guts are shorter. “People have speculated that these two are even related because they’re two very expensive metabolic tissues to have,” 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 hit the gut, it was probably a lot of these little ones. 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 tap into their expertise. Reddy’s lab is able to examine millions of genetic switches at once, and Silver observes the switches in action in developing mouse brains.

“Our contribution was that if we could bring these two technologies together, then we could look at hundreds of switches in this type of complex developing tissue, which you can’t really get from a cell line,” Lowe said.

“We wanted to identify switches that were totally new to humans,” Lowe said. By calculation, they were able to deduce what the human-chimpanzee ancestor DNA would have looked like, as well as the extinct Neanderthal and Denisovan lineages. The researchers were able to compare the genomic sequences of these other post-chimpanzee relatives using databases created from 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 really turn on genes or not,” which they’ve done dozens of times.

“And we showed that, whoa, it’s really a switch that turns genes on and off,” Lowe said. “It was really fun to see that the new gene regulation came from totally new switches, rather than some kind of rewiring switches that already existed.”

Apart from the positive traits that HAQERs have given to humans, they may also be implicated in certain diseases.

Most of us have remarkably similar HAQER sequences, but there are some discrepancies, “and we were able to show that these variants tend to be correlated 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 conducted in these areas, Lowe said.

“Perhaps human-specific diseases or human-specific susceptibilities to those diseases are going to be preferentially mapped to these new genetic switches that only exist 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, Triangle Center for Evolutionary Medicine and the Duke Whitehead Scholarship.

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