By Ann Gibbons
ScienceThe COVID-19 statement is supported by the Pulitzer Center and the Heising-Simons Foundation.
If you become infected with the SARS-CoV-2 coronavirus, you may want to have a quick way to check your Neanderthal ancestry. A small number of people from the extinct hominin have a small but significant generation number that may double or even quadruple the risk of COVID-19 complications.
The discovery, posted last week as an introduction to Biorxiv, sheds light on an enzyme called dipeptidyl peptidase-4 (DPP4). Scientists already know that the protein releases another coronavirus, which causes Middle East Respiratory Syndrome (MERS), binding into and out of human cells. The new analysis, of DPP4 gene mutations in COVID-19 patients, suggests that the enzyme also provides a second door for SARS-CoV-2 into our cells, along with the its normal infectious pathway through the ACE-2 receptor on the cell surface.
The decision remains doubtful. Other groups that look in genetic databases for factors influencing COVID-19 depth have not revealed the DPP4 gene. But the work is encouraging because it suggests that some diabetes drugs, which target cell surface proteins, may help treat the disease. “We want to roll out this finding quickly so that people can be tested regularly for the potential of DPP4. [therapeutic] target in patients with COVID, ”said study co-author Svante Pääbo, an evolutionary geneticist at the Max Planck Institute for Evolutionary Anthropology.
The introduction “adds to the evidence… that DPP4 may play a major role in the disease for SARS-CoV-2,” said virologist Jianhong Lu of Central South University in China who was not involved in the work new. 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 the comparison of amino acid sequences and the crystal structures of the enzyme and companach estbal spike, ACE-2. Another team, however, had earlier regulated DPP4 as a SARS-CoV-2 receptor after discovering that the virus did not bind to it in cell line studies.
Pääbo and co-author Hugo Zeberg, who was also a geneticist at the Max Planck, have now clarified DPP4. 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 with these close relatives. The researchers had already found evidence that one chromosomal segment found back to Neanderthals could protect against COVID-19 while another, on chromosome 3, could make it worse.
Studies of ancient DNA in Neanderthal fossils have shown that the DPP4 gene of the hominin is somewhat different from the normal human. Pääbo and Zeberg studied whether these or other Neanderthal gene variants of the extinct species occur more frequently in people with severe cases of COVID-19 than in unprotected people. For that they turned to the latest data release in October from Host Covid-19 Genetics Initiative, which has collected genome and COVID-19 status information on many individuals from studies or other data.
They only studied for Neanderthal versions of genes in people with severe COVID, which gave them a quick way to see if these ancient genes had an effect on how living humans responded to the coronavirus. The Neanderthal version of DPP4 “popped up” at a higher frequency in the genomes of 7,885 hospitalized individuals with severe COVID than in a control group, Zeberg said. If a person had one copy of the Neanderthal gene variant, there was twice the risk of developing COVID when it was contagious; if they had two copies of DPP4 Neanderthal, their threat was quadrangular, the team reports.
The researchers estimate that between 1 and 4% of Europeans and Asians have acquired a Neanderthal version of the DPP4 gene. A key question now is, how do the Neanderthal differences in the gene alter its activity or alter the function of the protein? In addition to revealing the link to the MERS coronavirus, previous studies have shown that it plays a role in breaking down glucose, or sugars, in the cell. That is why DPP4 has become a target of diabetes drugs. But the Neanderthal mutations to the DPP4 gene may not directly affect the shape or function of the enzyme – they are all in its promotional area, which usually affects exactly where in the body and what the extent to which the gene is active.
Such research includes evolutionary biologists because it shows that modern humans have inherited gene mutations from Neanderthals that may affect how some of us diseases today. A 2018 study by population geneticist David Enard of the University of Arizona found that humans live on an unbalanced number of Neanderthal mutations of immune genes that target RNA viruses such as coronaviruses, compared to genes that responding to DNA viruses. This gives the impression that Neanderthals suffered from different RNA viruses than humans today, and when the two were breeding, our ancestors picked up new pathogens from Neanderthals, as well as immune genes to fight against these microbes. However, the DPP4 finding suggests that gene mutations “which have been flexible in the past, can be destructive, following changes in lifestyle and environment,” says population geneticist Lluis Quintana-Murci of the Institut Pasteur in Paris.
One way to highlight the risk of COVID-19 from Neanderthal genes, Enard adds, is to compare it to the higher rates of developing severe infection from SARS-CoV-2 which along with living in poverty and with poor access to health care. These socio-economic factors play a much stronger role than any Neanderthal genetic influences, ”he says.