When modern humans left Africa for Europe tens of thousands of years ago, they met Neanderthals and had sex with them. The evidence of those encounters remains inside most of us today; 2 to 3 percent of the DNA of non-African humans comes from Neanderthals.
The bits of Neanderthal DNA that have persisted are not entirely random. Scientists have wondered whether they offered some advantage in the early days of humanity, as they cluster, curiously, around genes related to skin, hair, and the immune system. A new paper goes one step further, arguing that when humans first met Neanderthals, they got sick from unfamiliar Neanderthal viruses, against which they had no immunity—but then, through interbreeding, human populations ultimately acquired the genes granting resistance to those viruses, too. “We call it the poison-antidote model,” says David Enard, an evolutionary biologist now at the University of Arizona and an author of the paper.
“I think it’s very provocative,” says Kelley Harris, a computational biologist at the University of Washington who was not involved in the study. The case for the poison-antidote model is an indirect one, as these ancient viruses are long gone. Instead, Enard had to hunt for clues to their existence in stretches of Neanderthal DNA that are still found in modern humans today.
First, Enard systematically combed the scientific literature to compile a list of 4,534 human proteins that interact with modern viruses such as influenza, HIV, and hepatitis. Viruses evolve to have very specific interactions with the proteins of cells they infect. A flu virus might, for example, fit like a key into the “lock” of a cell-surface protein, tricking the human cell into letting it in. But modify that lock slightly and the virus will no longer fit; in other words, that cell is now resistant.
Enard reasoned that Neanderthals had evolved some resistance to the viruses that must have circulated among them in Europe. Modern humans, on the other hand, were likely encountering those viruses for the first time. So when they mated with Neanderthals, subsequent generations of offspring that inherited the genes for Neanderthal-virus–interacting proteins would be more likely to survive. Other scientists have identified segments of Neanderthal DNA in humans that likely served some evolutionary advantage, so Enard compared those with his list of 4,534 virus-interacting proteins. Indeed, he found that genes for virus-interacting proteins were enriched in the DNA of Neanderthal origin.
Of course, it should work the other way, too. Modern humans likely brought their own human viruses with them, and human-virus–interacting proteins would have had to be selected for in Neanderthals. There are no living Neanderthals, but scientists had previously sequenced the 50,000-plus-year-old genome of a Neanderthal man found in Siberia, who had stretches of modern-human DNA, suggesting a human ancestor. You can’t draw sweeping conclusions from just one individual, but Enard found that the longer remnants of human DNA in this Neanderthal man also matched up with human-virus–interacting proteins—proteins that may have protected his ancestors from human viruses.
The findings fit in nicely with previous research that found immune-related genes are common in stretches of Neanderthal DNA that persist in humans. “Pathogens have been a big driver in human adaptations,” says Emilia Huerta-Sanchez, a population geneticist at Brown University.
There were also unexplained patterns in the Neanderthal and human DNA. Viruses come in two big groups, ones whose genetic material is encoded in DNA (such as adenoviruses and smallpox) and ones whose genetic material is encoded in RNA (flu, yellow fever, HIV, etc.). Enard found that it was specifically Neanderthal genes that code for RNA-virus–interacting proteins that are most likely to remain in the human genome—but only among Europeans, not East Asians. Other research has suggested that the ancestors of Europeans and East Asians likely had separate histories of interbreeding with Neanderthals.
Enard tried to see if he could trace the pattern of virus-interacting proteins to specific RNA viruses. Viruses evolve very quickly, and the contemporary flu is likely very different from the flu of 50,000 years ago. But Enard did find that genes for proteins interacting with HIV-like and flu-like viruses were the most persistent in Europeans. Perhaps ancient HIV-like or flu-like epidemics broke out around the time Neanderthals met the ancestors of contemporary Europeans. It’s a very preliminary stab at understanding the ancient viral world.
The study of ancient viruses is hampered by the fact that viral RNA simply doesn’t last very long. Earlier this year, scientists analyzed a 7,000-year-old virus found inside the tooth of a Neolithic man—the oldest virus ever sequenced. But that was a DNA virus, whose double-stranded genetic material is much more stable than single-stranded RNA. “Finding the remains of RNA from very old viruses—it’s pretty hopeless,” says Enard. But looking at virus-interacting proteins could be an indirect way of studying those viruses. “Our approach is really basically filling a gap in the record of ancient epidemics,” he says.
Huerta-Sanchez adds that scientists are also sequencing more and more ancient DNA in humans that lived at different points in the past 100,000 years. By looking at when those Neanderthal-virus–interacting proteins swept through humans, they could start seeing not only whether these ancient epidemics happened, but maybe also when.