Neanderthal gene found in many people may open cells to coronavirus and increase COVID-19 severity

 

 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 (ACE-2) receptor on cell surfaces. 

he 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, ACE-2. 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 the 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 that 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 databanks.

They searched only 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.

 

Source: Science Mag