The hidden Denisovan gene that helped humans conquer a new world

Now, a new study led by the University of Colorado Boulder suggests that these nomads carried something surprising with them -- a chunk of DNA inherited from a now-extinct species of hominin, which may have helped humans adapt to the challenges of their new home.

The researchers published their results in the journal Science.

"In terms of evolution, this is an incredible leap," said Fernando Villanea, one of two lead authors of the study and an assistant professor in the Department of Anthropology at CU Boulder. "It shows an amount of adaptation and resilience within a population that is simply amazing."

Denisovans were close relatives of modern humans who lived from Siberia and Russia through Oceania and as far west as the Tibetan Plateau before vanishing tens of thousands of years ago. Despite their wide range, little is known about them. Scientists first identified Denisovans only 15 years ago from DNA extracted from a bone fragment found in a Siberian cave. Like Neanderthals, they may have had heavy brow ridges and lacked chins.

"We know more about their genomes and how their body chemistry behaves than we do about what they looked like," Villanea said.

Research increasingly shows that Denisovans interbred with both humans and Neanderthals, leaving lasting traces of their DNA in modern people.

To further understand those genetic links, Villanea and co-lead author David Peede of Brown University analyzed genomes from populations around the world. Their focus was on a gene known as MUC19, which plays a vital role in the body's immune defense.

The team found that individuals with Indigenous American ancestry were more likely than others to carry a Denisovan-derived version of this gene. This suggests that a fragment of ancient DNA may have helped early humans survive and thrive in the unfamiliar ecosystems of North and South America.

A little-known gene

Villanea added that MUC19's function in the human body is about as mysterious as Denisovans themselves. It's one of 22 genes in mammals that produce mucins. These proteins make mucus, which, among other functions, can protect tissues from pathogens.

"It seems like MUC19 has a lot of functional consequences for health, but we're only starting to understand these genes," he said.

Previous research has shown that Denisovans carried their own variant of the MUC19 gene, with a unique series of mutations, which they passed onto some humans. That kind of admixture was common in the ancient world: Most humans alive today carry some Neanderthal DNA, whereas Denisovan DNA makes up as much as 5% of the genomes of people from Papua New Guinea.

In the current study, Villanea and colleagues wanted to learn more about how these genetic time capsules shape our evolution.

The group pored through already published data on the genomes of modern humans from Mexico, Peru, Puerto Rico and Colombia where Indigenous American ancestry and DNA is common.

They discovered that one in three modern people of Mexican ancestry carry a copy of the Denisovan variant of MUC19 -- and particularly in portions of their genome that come from Indigenous American heritage. That's in contrast to people of Central European ancestry, only 1% of whom carry this variant.

The researchers discovered something even more surprising: In humans, the Denisovan gene variant seems to be surrounded by DNA from Neanderthals.

"This DNA is like an Oreo, with a Denisovan center and Neanderthal cookies," Villanea said.

A new world

Villanea and his team believe the story of this ancient gene began long before humans ever set foot in the Americas. Their theory suggests that Denisovans first interbred with Neanderthals, passing along the Denisovan version of the MUC19 gene to their descendants. Later, Neanderthals mated with humans, transferring that same genetic fragment once again. This marks the first documented case of DNA moving from Denisovans to Neanderthals and then to humans.

As humans eventually made their way into the Americas, natural selection appears to have favored the spread of this inherited MUC19 variant.

Exactly why the Denisovan form of the gene became widespread in Indigenous populations of North and South America, but not elsewhere, remains uncertain. Villanea pointed out that the first peoples of the Americas faced completely unfamiliar environments filled with new plants, animals, and diseases. The Denisovan gene may have offered some biological advantage that helped them cope with these challenges.

"All of a sudden, people had to find new ways to hunt, new ways to farm, and they developed really cool technology in response to those challenges," he said. "But, over 20,000 years, their bodies were also adapting at a biological level."

To build that picture, the anthropologist is planning to study how different MUC19 gene variants affect the health of humans living today. For now, Villanea said the study is a testament to the power of human evolution.

"What Indigenous American populations did was really incredible," Villanea said. "They went from a common ancestor living around the Bering Strait to adapting biologically and culturally to this new continent that has every single type of biome in the world."

Other co-authors of the new study include researchers at Brown University; the University of Washington School of Medicine; Universidad Nacional Autónoma de México; University of Copenhagen; Clemson University; University of Padova; University of Turin; University of California, Berkeley; Université Paris- Saclay; and Trinity College Dublin.