How Interbreeding With Denisovans Affected Human Health

Oceanians with most Denisovan DNA have several medically significant genetic variants; Wellcome team finds Denisovan variant in Native Americans as well

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Goroka Tribal Festival. Papua New Guinea
Goroka Tribal Festival. Papua New Guinea Credit: isaxar / Shutterstock.com

Interbreeding with Denisovans tens of thousands of years ago affected the health of humans today, mainly Melanesians but also Native Americans, according to a breakthrough study by scientists at the Wellcome Sanger Institute in Britain.

For all our pretensions to have been made in the image of God, we all contain genes from other species of hominins – including, but not confined to, Neanderthals and Denisovans. About 1 to 2 percent of the DNA in non-Africans seem to originate in Neanderthals; Africans too have a faint Neanderthal whisper in their genomes. Also, some modern populations have a Denisovan signal in their genes.

Now the research done at the Wellcome Sanger Institute, a nonprofit genomics and genetics research institute, and reported in Cell, reveals that Denisovan heritage has a “medically important” influence on the response to viral infection among a majority of Papua New Guineans.

We had known that Neanderthal remnants in our DNA may affect some people’s physical health and possibly mental wellbeing as well. Now we learn more about how Denisovans had “medically important” consequences for us, at least if we are Melanesian.

Melanesians have the strongest Denisovan signal found so far: about 2.8 percent of their genes originate in that mysterious hominin, which thronged Eurasia tens of thousands of years ago. Previous research indicated a higher percentage of Denisovan ancestry in Oceanians, but the work has been refined, lead author Mohamed Almarri explains to Haaretz.

Meeting the Denisovans

People vary genetically in a host of ways; some mutations are neutral and may spread by random genetic drift. Some affect our survivability in a given environment: on the upside (good; you will thrive and pass on the mutation) or downside (you will not thrive).

Up to now, most large-scale genetic studies generally focused on point mutations affecting single base pairs of DNA. At the Sanger Institute, they set out to find structural variations in whole sequences (not isolated points), compared to the human reference genome, based on previous work to sequence over 900 genomes from 54 diverse populations around the world. (Note ye with regard to the reference genome: It was the sequence consisting mostly of one New Yorker of African and European origin, which, as Almarri points out, is inadequate to demonstrate the range of the human condition.)

The Denisova Cave in Siberia, where the Denisovans were discoveredCredit: Igor Boshin / Shutterstock.com

The team found over 126,000 such structural variations in stretches of DNA. The team then checked how common these structural variations are in each of the 54 populations, and which of them were inherited from Neanderthal or Denisovan ancestors. If a given population of humans has a stretch of DNA that doesn’t exist in other modern humans but does exist in the Denisovan or the Neanderthal, that’s pretty indicative.

They identified about 10 variations in Melanesians that originated in Denisovans and seem to have persisted thanks to natural selection – they conferred an advantage.

Among the 10 was a gene known as AQR. Papuans have a variant of this gene inherited from the Denisovans, which affects how their immune systems react to viruses. That is what the experts call a “medically important variant.”

Love at first sight

By the way, it seems that as we moved into Europe, it was love at first sight. Or something at first sight.

“It is thought that the population that gave rise to all modern humans today interbred with Neanderthals as soon as they expanded out of Africa about 60,000 years ago. A consequence of this is we see a similar amount of Neanderthal ancestry in both Eurasians and Papuans,” Almarri tells Haaretz.

The introgression from Denisovans happened later. We still have no idea of the Denisovans’ range, but they seem to have lived farther from Africa than the Neanderthals. The admixture event with Denisovans is estimated to have occurred some 50,000 years ago, he says.

Neanderthals and Denisovans admixed too; theoretically, we could have picked up our Denisovan component from mixing with Neanderthals. Or not. “It is not believed to have occurred through a hybrid Neanderthal-Denisovan,” Almarri says. “The modern human population that gave rise to modern-day Papuans subsequently interbred with a Denisovan population, resulting in the large proportion of their genome that is of Denisovan ancestry which is not found in Eurasia,” he adds.

In eastern Asia, about 0.2 percent of our DNA is of Denisovan origin; in Europeans it's even less; and in the Papuans and aboriginal Australians, it’s about 2.8 to 3 percent. Almarri points out that the Papuans and aboriginal Australians were one population that separated about 37,000 years ago, well before the sea level rose and cut off Australia (which was about 10,000 years ago).

They didn’t find Denisovan variants in Europeans and Asians because we have very little Denisovan DNA, Almarri explains.

They also found that Native Americans, who originally hailed from Asia, crossing to the Americas perhaps 20,000 years ago when sea levels were low, have deletions in their MS4A1 gene, which they inherited from Neanderthals, and could affect how leukemia is treated in the population.

Denisovan signals in New Guinea

The AQR gene, which is special in Papuans, plays a role in detection of viruses and regulation of antiviral immune response. “In this case, 63 percent of Papuan individuals carry this deletion,” Almarri says. “The deletion is only found in Papuans, and not in any of the other 53 global populations we studied.”

Separate research has indicated that AQR recognizes and regulates the responses to viruses such as HIV. However, since the geneticists detected strong signatures consistent with positive selection of this mutation in Papuans thousands of years ago, the selection was not related to HIV itself, he explains. Likely the deletion variant spread in the population because it was adaptive to the Oceanian environment.

Papuans are also unique in their variant of a gene called JAK1, which codes for a protein that is important in cytokine signaling – a process where immune cells communicate with each other. That also came from Denisovans.

Aboriginal Australians probably also commonly have AQR deletion variants: “The Denisovan admixture event occurred before the two populations separated from each other,” Almarri says. Sadly, that couldn’t be checked because the Human Genome Diversity Project on which the work was based does not contain Aboriginal Australian populations.

Another Denisovan attribute we know of today is found in Tibetans, who famously inherited their tolerance for extreme altitude from our long-dead cousins. But the Tibetan proportion of Denisovan inheritance is not exceptional, Almarri adds.

It doesn’t take admixture with other species to cause unusual divergences in specific populations, of course. The team mentions the Karitiana people in modern-day Brazil, who differ in their MGAM gene, impairing starch digestion.

That isn’t actually advantageous: “The Karitiana diet is derived from fishing, hunting and farming, so a decrease in starch digestion is probably disadvantageous and therefore surprising,” the team says, and suggests that maybe “bad luck may have concentrated this variation in the small population that survived a population crash within the last 5,000 years.”

Another example: All African populations included in the study carried multiple copies of the HPR gene, which confers resistance to sleeping sickness. That is good. The highest number of copies of HPR are carried by Central and West African populations where the fly-borne disease is most prevalent.

Yet another discovery is that the Mbuti hunter-gatherers of the Central African rainforest have a “private mutation” (not found in any other group): 54 percent of them have it, Almarri tells Haaretz. “This mutation is interesting, because it deletes a whole gene called SIGLEC5. This gene encodes a receptor on immune cells that allows it to recognize ‘self’ from ‘foreign’ cells. As the immune cell circulates the body, it searches for foreign cells to attack, and the receptor allows it to prevent attacking the host cells. The deletion we find is surprising, as the immune cell is now possibly not able to distinguish ‘self’ from ‘foreign,’ possibly resulting in immune hyperactivity and autoimmune disease.”

The discovery of the previously unknown variations in medically important genes could affect the efficacy of medical treatments in certain populations, the team sums up. What works in one population might not work in another.

One bottom line of all this is that we clearly need more reference genomes from diverse populations, Almarri sums up. The genes of that one American dude of European origin do not tell the whole story of humanity.

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