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Neanderthal-Origin Haplotype Provides Protection Against Severe COVID-19

NEW YORK — A stretch of the human genome that provides protection against developing severe COVID-19 appears to have been inherited from Neanderthals, according to a new study.

Data from the Genetics of Mortality in Critical Care (GenOMICC) consortium of 2,244 critically ill COVID-19 patients and controls has uncovered more than half a dozen genetic loci associated with the risk of becoming severely ill after SARS-CoV-2 infection, and Hugo Zeberg and Svante Pääbo, both at the Max Planck Institute for Evolutionary Anthropology, traced an apparently protective locus on chromosome 12 back to Neanderthals, as they reported on Tuesday in the Proceedings of the National Academy of Sciences.

Last September, the same pair of researchers homed in on a different part of the human genome, on chromosome 3, that is also inherited from Neanderthals, but that is a risk factor for respiratory failure following SARS-CoV-2 infection. This new finding of a protective Neanderthal-origin haplotype underscores the complex influence Neanderthals have had on modern humans.

"This shows that our heritage from Neanderthals is a double-edged sword when it comes to our response to SARS-CoV-2. They have given us variants that we can both curse and thank them for," Zeberg, who is also a researcher at Karolinska Institutet, said in a statement.

This new 75-kilobase haplotype, though, is associated with about a 22 percent reduction in relative risk of developing severe COVID-19. 

The researchers zeroed in on this haplotype as being from Neanderthals since it is present in all three high-quality Neanderthal genomes, but it is absent among genomes from African Yorubans. They further noted that segments of this length are unlikely to have survived unbroken since the time of a common ancestor of Neanderthals and humans, further supporting the notion that the haplotype entered the human gene pool through gene flow from Neanderthals.

This Neanderthal-origin haplotype includes part or all of three OAS genes — OAS1, OAS2, and OAS3 — which encode oligoadenylate synthetases. These enzymes are induced by interferons and activated by double-stranded RNA and, in turn, activate an enzyme that degrades intracellular double-stranded RNA and activates other antiviral mechanisms.

The researchers additionally pointed out alleles on the haplotype that could be functionally important. For instance, one SNP affects a splice acceptor site in OAS1 that leads to the production of several different protein isoforms and is thought to provide protection against the West Nile Virus, while a missense variant in OAS1 has been tied to moderate to strong protection against SARS, though in a limited study.

This haplotype is largely absent among sub-Saharan Africans but is found at frequencies of 25 percent to 30 percent among Eurasian populations. That frequency has changed over time, though, the researchers found. Based on available genomes, prior to about 20,000 years ago, this haplotype had a frequency of about 10 percent, then between 20,000 and 10,000 years ago rose to about a 15 percent allele frequency, and then between 3,000 and 1,000 years ago to around 20 percent. As it now has a higher allele frequency among Eurasians, this suggests the haplotype may have been under positive selection. 

"It is striking that this Neanderthal gene variant has become so common in many parts of the world. This suggests that it has been favorable in the past," Pääbo said in a statement. "It is also striking that two genetic variants inherited from Neanderthals influence COVID-19 outcomes in opposite directions. Their immune system obviously influences us in both positive and negative ways today."

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