DNA study reveals how a mysterious, extinct human shaped our immune systems

In the summer of 2008, in a cave nestled within Siberia’s Altai Mountains, Russian scientists unearthed a sliver of a finger bone. At first, the scientists assumed the fossil was from a Neanderthal — the cave was a known treasure trove of stone artifacts left behind by our heavy-browed ancestors. But it wasn’t until a genetic analysis performed in 2010 that the scientific community realized they were dealing with an altogether different species of prehistoric human: the Denisovans.

Since then, we’ve learned more about our mysterious cousins — their namesake comes from the Denisova Cave the bony shard was found in — and that early humans definitely went past third base when the two hominins interacted tens of thousands of years ago. People across Asia carry Denisovan DNA, with the highest concentration among individuals living in the Pacific Island region of Melanesia (around four to six percent, by some estimates). While Neanderthal DNA is linked to a gamut of physical and personality traits, not to mention diseases like diabetes and Covid-19, what influence Denisovan DNA has in our modern age isn’t entirely clear.

But according to a study published Thursday in the journal PLOS Genetics, we may be closer to an answer, one that resides in the human immune system. A group of researchers led by the University of Melbourne in Australia found that for indigenous people of the New Guinea Island, Denisovan DNA appeared to be regulating immune genes and cells more consistently and with greater influence than Neanderthal DNA. The researchers suspect this function helped Papuans adapt to their local environment and fend off infectious diseases, and it could have implications for certain immune-related diseases affecting modern-day Papuans.

“It’s really nice to see a new study on the effects of Denisovan DNA in present-day Papuans,” Janet Kelso, a computational biologist at the Max Planck Institute for Evolutionary Anthropology in Germany, who was not involved in the study, told Inverse in an email. “There are still only rather few studies that have looked specifically at the effect of Denisovan DNA in present-day people in Oceania and Island Southeast Asia, so this is a nice addition.”

How they did it — The researchers took a large dataset that had sequenced genomes of over 300 individuals from Indonesia and Papa New Guinea, all of whom had Denisovan and Neanderthal DNA. This dataset, which was published in 2019, had sorted out which genes were associated with which archaic hominin but it hadn’t determined, for the Denisovan, exactly the DNA’s functional role.

Examining genomes of 56 Papuans from this dataset, Irene Gallego Romero, a human evolutionary biologist at the University of Melbourne who led the study, and her team compared the Denisovan DNA against another database from the National Institutes of Health called Roadmap Epigenomics, a public catalog of which genes are active in which cell types (basically, the genes that define a cell’s function and other characteristics).

What they found — Gallego Romero and her colleagues discovered that Denisovan DNA in Papuans, more so than Neanderthal DNA, tended to fall in regions of the genome that doesn’t actually make any proteins — called non-coding regions. Despite the name, that doesn’t mean these sequences aren’t important.

“Two percent of the genome is actually [involved] in protein coding,” Gallego Romero tells Inverse. “The rest is what used to be called junk DNA but it’s not junk. Its function is mostly controlling how much of a gene do you express, when do you express it, and what cell types response to what stimulus.”

And regularly, the researchers saw these non-coding Denisovan genetic sequences appeared most active in immune cells compared to Neanderthal DNA. Kelso from the Max Planck Institute for Evolutionary Anthropology says this finding is consistent with other studies that also linked Denisovan DNA to the immune system among Pacific Islanders.

So exactly which immune genes are Denisovan DNA turning off and on? That’s still a bit unknown, says Gallego Romero. That’s because a non-coding sequence isn’t necessarily next to the gene it regulates and there could be more than one gene involved, especially if they’re packed closely to each other. While there is a way to figure that out with advanced genomic tools, such data isn’t yet available for every cell type.

The closest the researchers could get to an answer was by looking at the activity of five specific Denisovan sequences within modified immune cell lines originating from a Papuan human donor. Within these cells, the sequences did different things, turning up or down activity of immune genes they were closest too in ways that may impact how an individual responds to an infection.

Why it matters — This study and others like it are fleshing out this murky picture of how some of our other long-dead prehistoric ancestors influenced our own evolution and health today. Gallego Romero says Denisovan DNA likely conferred a survival advantage, allowing indigenous peoples of the region to adapt and go up against new environmental pathogens as our ancestors were making they’re way out of Africa. According to some studies, this Denisovan DNA may still confer an immunological advantage today.

Aside from that, Gallego Romero says this study and similar research efforts are expanding the diversity of data, which is presently quite lacking.

“The human genetic datasets that have been used to understand Neanderthal DNA or to link it to phenotypes have mostly come from people of European ancestry… and not so much anyone else,” she says. “Denisovan DNA is missing from [genomic datasets], it’s missing from the UK Biobank, which is where you would go to work out what a [gene] does.”

What’s next — Gallego Romero and her team plan to uncover more about Denisovan DNA’s impact on our contemporary genomes and hope to work more closely with researchers in Indonesia and Papa New Guinea who would benefit tremendously from this information.

“This work connects the past and the present of our species in ways that are obvious to people, but I think, again, [makes] the past more knowable and tangible,” she says. “From looking at these genomes, we can understand a lot of what [were] the dynamics of these [ancient] people and what they were up to.”