Science’s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.
If you become infected with the coronavirus SARS-CoV-2, you might wish there was a fast way to check your Neanderthal ancestry. A small but significant number of people have an ancient gene variant from the extinct hominin that may double, or even quadruple, their risk of serious complications from COVID-19.
The finding, posted last week as a preprint on bioRxiv, shines a light on an enzyme called dipeptidyl peptidase-4 (DPP4). Scientists already know the protein allows another coronavirus, which causes Middle Eastern respiratory syndrome (MERS), to bind to and enter human cells. The new analysis, of DPP4 gene variants among COVID-19 patients, suggests the enzyme also provides SARS-CoV-2 with a second door into our cells, along with its usual infection route via the angiotensin-converting enzyme 2 (ACE2) receptor on cell surfaces.
The conclusion remains tentative. Other groups looking in genetic databases for factors that influence COVID-19 severity have not flagged the DPP4 gene. But the work is provocative because it suggests some diabetes drugs, which target the cell surface protein, could help treat the disease. “We want to put this finding out there quickly so people can systematically test if DPP4 could be a [therapeutic] target in patients with COVID,” says study co-author Svante Pääbo, an evolutionary geneticist at the Max Planck Institute for Evolutionary Anthropology.
The preprint “adds to the evidence … that DPP4 may really play a role in the infection for SARS-CoV-2,” says virologist Jianhong Lu of China’s Central South University, who wasn’t involved in the new work. In June, he and colleagues reported in iScience that DPP4 should be a good binding partner for the protein called spike on the surface of the SARS-CoV-2 virus, based on comparing amino acid sequences and crystal structures of the enzyme and spike’s established partner, ACE2. Another team, however, had earlier ruled out DPP4 as a SARS-CoV-2 receptor after finding the virus did not bind with it in cell line studies.
Pääbo and co-author Hugo Zeberg, also an evolutionary geneticist at Max Planck, have now highlighted DPP4 again. Most Europeans, Asians, and Native Americans harbor a handful of genes from Neanderthals, up 1.8% to 2.6% of their DNA, thanks to ancient dalliances between some of our ancestors and this close relative. The researchers had already uncovered evidence that having one chromosomal section traced back to Neanderthals could protect against COVID-19, whereas another, on chromosome 3, could make it worse.
Studies of ancient DNA in Neanderthal fossils have shown the hominin’s DPP4 gene subtly differs from the typical human one. Pääbo and Zeberg examined whether that Neanderthal gene variant or others from the extinct species appear more often in people with severe cases of COVID-19 than in uninfected people. For that, they turned to the latest data release in October from the COVID-19 Host Genetics Initiative, which has collected genome information and COVID-19 status on many people from other studies or data banks.
They only searched for Neanderthal versions of genes in people who had had severe COVID-19, which gave them a quick way to see whether these archaic genes influenced how living people responded to the coronavirus. The Neanderthal version of DPP4 “popped up” at higher frequency in the genomes of 7885 people hospitalized with severe COVID-19 than in a control group, Zeberg says. If a person had a single copy of the Neanderthal gene variant, they had double the risk of severe COVID-19 when infected; if both their copies of DPP4 were Neanderthal, their risk quadrupled, the team reports.
The researchers estimate that between 1% and 4% of Europeans and Asians have inherited a Neanderthal version of the DPP4 gene. A key question now is, how do the Neanderthal differences in the gene change its activity or alter the function of the protein? In addition to revealing the link to the MERS coronavirus, past studies have shown it plays a role in the breakdown of glucose, or sugars, in the cell. That’s why DPP4 has become the target of diabetes drugs. Yet the Neanderthal changes to the DPP4 gene likely don’t affect the shape or function of the enzyme directly—they are all in its promoter region, which typically affects just where in the body and how much the gene is active.
Such research intrigues evolutionary biologists because it shows modern humans quickly acquired gene variants from Neanderthals that may still influence how some of us respond to diseases today. A 2018 study by population geneticist David Enard of the University of Arizona found that living humans have inherited a disproportionate number of Neanderthal variants of immune genes that target RNA viruses like coronaviruses, compared with genes that respond to DNA viruses. This suggests Neanderthals suffered from different RNA viruses than modern humans, and when the two mated, our ancestors picked up new pathogens from Neanderthals, as well as immune genes to fight those microbes. Still, the DPP4 finding suggests gene variants “that were adaptive in the past can be detrimental, following changes in lifestyle and environment,” says population geneticist Lluis Quintana-Murci of the Pasteur Institute.
One way to put the COVID-19 risk from Neanderthal genes in perspective, Enard adds, is to compare it with the much higher odds of developing severe disease from SARS-CoV-2 posed by living in poverty and having poor access to health care. These socioeconomic factors “have a much stronger role than any genetic effect inherited from a Neanderthal,” he says.