Around two percent of the genome of modern Europeans comes from Neanderthals. The archaic gene variants influence, among other things, our immune system and help us fight off RNA viruses. But with DNA viruses such as the Epstein-Barr virus (EBV), they apparently have the opposite effect: a study shows that the Neanderthal variants are associated with an increased viral load in modern humans. At the same time, the results suggest that the same variants could have been useful in earlier times.
When humans and Neanderthals lived side by side more than 40,000 years ago, crossbreeding between the sister species occurred repeatedly. This is how Neanderthal genes entered our genome. Most did not succeed in evolution, but some offered advantages to our ancestors and were passed down from generation to generation. To this day, an average European carries around two percent Neanderthal DNA in their genome. Similarly, people in Oceania inherited about two to four percent of their genetic variants from another early human species, Denisovans.
Previous studies have already shown that some of the archaic gene variants are still active today and influence, among other things, our metabolism and immune system. For example, those who carry Neanderthal variants in important immune genes are better armed against RNA viruses and can therefore better ward off diseases such as influenza and hepatitis. How the archaic variants affect the immune response to DNA viruses was previously unclear.
Weaker protection instead of stronger defense
To answer this question, a team led by Rutvi Rajpara from the University of Tartu in Estonia has now examined the extent to which archaic gene variants influence the DNA viral load. Many DNA viruses, including herpes viruses, remain in the body for life after an infection – usually without causing symptoms. The viral load provides information about how well the immune system keeps these viruses in check. For their genome-wide association study, the researchers used data from the UK Biobank, one of the world’s largest biomedical research databases, which includes health and genomic data from around half a million volunteers.
In fact, Rajpara and her team found 18 significant associations between archaic gene variants and exposure to various DNA viruses, including Epstein-Barr virus (EBV) and human herpesvirus 7 (HHV-7). But contrary to expectations, the Neanderthal and Denisovan variants had no protective effect, but were instead even associated with an increased viral load. “Our results suggest that Neanderthal-derived variants may not provide effective protection against various DNA viruses in modern humans,” says Rajpara’s colleague Michael Dannemann. “This is in stark contrast to the previously reported positive effects on immunity against RNA viruses.”
Evolutionary change
But why have these archaic gene variants been able to prevail to this day despite their detrimental effects? From the researchers’ point of view, the explanation is probably that viruses have changed significantly since the time of the Neanderthals. “The pathogenic landscape that Neanderthals faced tens of thousands of years ago may have been very different from the one we face today,” explains Dannemann. “A variant that reduced viral load in the past may increase it today.”
The researchers found evidence of such a change during a closer analysis of one of the affected regions in the genome. One of the archaic variants identified was twice as common around 10,000 years ago as it is today. “The high distribution around 10,000 years ago suggests that this haplotype was originally subject to positive selection,” explain Rajpara and her colleagues. “Over the last 10,000 years, the cultural transition to agriculture may have altered exposure to pathogens.” As a result, the originally useful gene variant became more of a hindrance, leading to strong negative selection.
“Our results open up a new perspective on the role of archaic DNA in shaping antiviral immunity,” summarizes the research team. “They suggest that the characteristics of the immune response may differ depending on the virus type and that certain immune components in archaic humans may have been better or worse equipped to deal with specific viral challenges.”
Source: Rutvi Rajpara (University of Tartu, Estonia) et al., Genome Biology and Evolution, doi: 10.1093/gbe/evag110