Denisovan Genes May Have Boosted Modern Human Immunity

When modern humans first migrated from Africa to the tropical islands of the southwest Pacific, they encountered unfamiliar people and new pathogens. But their immune systems may have picked up some survival tricks when they mated with the locals—the mysterious Denisovans who gave them immune gene variants that might have protected the newcomers’ offspring from local diseases.

Some of these variants still persist in the genomes of people living in Papua New Guinea today, according to a new study.

Researchers have known for a decade that living people in Papua New Guinea and other parts of Melanesia, a subregion of the southwest Pacific Ocean, inherited up to 5% of their DNA from Denisovans, ancient humans closely related to Neanderthals who arrived in Asia about 200,000 years ago.

Scientists assume those variants benefited people in the past—perhaps by helping the modern humans better ward off local diseases—but they have wondered how that DNA might still be altering how people look, act, and feel today.

It’s been difficult to detect the function of Neanderthal and Denisovan DNA in Melanesians, however, because scientists have analyzed so little genetic data from living humans in Papua New Guinea and other parts of Melanesia.

The new study overcomes that problem by using genetic data from 56 individuals from Papua New Guinea that were recently analyzed for another paper, part of the Indonesian Genome Diversity Project.

The researchers, mostly from Australia and New Guinea, compared those genomes with those of Denisovans from Denisova Cave in Siberia, as well as Neanderthals.

They found the Papuans had inherited unusually high frequencies of 82,000 genetic variants known as single nucleotide polymorphisms, which arise from differences of a single base or letter in the genetic code—from Denisovans.

The team then looked for those variants in a database that links genes to various functions in different tissues in humans. They homed in on immune-related gene variants that might promote or enhance a nearby gene’s production of proteins, for example, or shut off or dampen its function. These tweaks can help optimize an immune system for the specific pathogens in its environment; too strong an immune response can be as deadly as the infection itself.

In Papuans, the scientists found many Denisovan variants that were located near genes known to impact human immune responses to viruses and other pathogens, such as the flu and chikungunya. Next, they tested the function of eight Denisovan gene variants associated with the expression of proteins produced by two genes, in particular, OAS2 and OAS3, “lymphoblastoid”—cell lines of B cells, a type of white blood cell that makes antibodies critical to the body’s immune response. Those cell lines were collected from Papuans by study co-author Christopher Kinipi, a Papuan physician and health services director at the University of Papua New Guinea.

Two of the Denisovan genetic variants found in those Papuan cell lines lowered the transcription or production of proteins that regulate cytokines, part of the immune system’s defense against infections, reducing inflammation. This subdued inflammatory response could have helped Papuans weather a rash of new infections they would have encountered in the region.

“One of the strengths of the study is that they tested the Denisovan variants in Papuan cell lines, which are essentially the cell environment in which they evolved,” says functional genomicist Francesca Luca of Wayne State University, who was not part of the study.

Taken together, these experiments suggest those Denisovan gene variants “might be fine-tuning the immune response” to optimize it to its environment, says human evolutionary geneticist Irene Gallego Romero of the University of Melbourne, lead author of the new study published in PLOS Genetics. “In the tropics where people have high loads of infectious disease, you might want to tone down the immune response a little and not go overboard.”

These findings dovetail with earlier work on the role of Neanderthal variants in living Europeans. Studies of both Neanderthal and Denisovan DNA in different populations are showing how mating with archaic humans—long-adapted to their regions—provided a rapid way for incoming modern humans to pick up beneficial genes, says computational biologist Janet Kelso of the Max Planck Institute for Evolutionary Anthropology.

The study shows this sort of gene swap was “an important mechanism for how humans adapted quickly [to new challenges], specifically pathogens,” says human geneticist Luis Barreiro of the University of Chicago.

But he would like to see future work test whether the Denisovan gene variants actually give Papuans a better shot at warding off or surviving specific diseases.

Overall, this study shows “matings which took place tens of thousands of years ago are still influencing the biology of contemporary individuals,” says population geneticist Joshua Akey of Princeton University.