NEW YORK – A major genetic risk factor for respiratory failure as a result of SARS-CoV-2 infection is a gene cluster on chromosome 3 that was inherited by modern humans from Neanderthals, according to a new study.
In an accelerated article preview published on Wednesday in Nature, Hugo Zeberg and Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology wrote that while it is now known that advanced age, male sex, and some comorbidities are major risk factors for severe COVID-19 infection, they don't fully explain why some people who become infected with SARS-CoV-2 have mild or no symptoms while others become seriously ill.
A genetic association study published in the New England Journal of Medicine in June found severe COVID-19-related variants in around half a dozen genes at a chromosome 3 locus known as 3p21.31. The same locus turned up in a preliminary analysis of data collected by the COVID-19 Host Genetics Consortium, which noted there may be an enrichment of the gene cluster in patients with severe disease.
In their paper, Zeberg and Pääbo said the risk from this locus is conferred by a genomic segment of about 50 kilobases that is inherited from Neanderthals, and is carried by about 50 percent of people in South Asia and about 16 percent of people in Europe today.
"It turns out that this gene variant was inherited by modern humans from the Neanderthals when they interbred some 60,000 years ago," Zeberg said in a statement. "Today, the people who inherited this gene variant are three times more likely to need artificial ventilation if they are infected by the novel coronavirus Sars-CoV-2."
The genetic variants which are most associated with severe COVID-19 on chromosome 3 are all in high linkage disequilibrium, and they span more than 49,000 bases, the researchers said. Further, this core haplotype is in weaker linkage disequilibrium with longer haplotypes of up to 333.8 kilobases.
Knowing that some haplotypes of this length entered the human population by gene flow from Neanderthals or Denisovans, the investigators looked to see whether this particular haplotype also made its way into the modern human genome from these related groups. They found that the risk alleles of two variants in the chromosome 3 gene cluster were present in a homozygous form in the genome of the Vindija 33.19 Neanderthal, a 50,000-year-old Neanderthal from Croatia. They also found three of the chromosome 3 variants in the Altai as well as in the Chagyrskaya 810 Neanderthals, both of whom came from the Altai Mountains in southern Siberia and are about 120,000 and 50,000 years old, respectively. In the 333.8 kb-haplotype, the alleles associated with risk for severe COVID-19 similarly matched alleles in the Vindija 33.19 Neanderthal genome.
From further analyses, Zeberg and Pääbo were also able to conclude that the risk variants did not derive from the common ancestor between Neanderthals and humans, but that the risk haplotype entered the modern human population directly from Neanderthals.
Importantly, an analysis of the individuals in the 1000 Genomes Project found that the Neanderthal-derived haplotypes are almost completely absent in Africa, consistent with previous studies that have shown that gene flow from Neanderthals into African populations was limited and probably indirect. The Neanderthal core haplotype occurs in South Asia at a frequency of 30 percent, in Europe at 8 percent, among admixed Americans at 4 percent, and at lower frequencies in East Asia, the researcher said.
The highest frequency occurs in Bangladesh, where 63 percent of the population carries at least one copy of the Neanderthal risk haplotype and 13 percent of the population is homozygous for it, making the Neanderthal haplotype a substantial contributor to COVID-19 risk in certain populations.
In fact, the researchers said, individuals of Bangladeshi origin in the UK have about two times higher risk of death from COVID-19 than the general population.
"It is striking that the genetic heritage from the Neanderthals has such tragic consequences during the current pandemic. Why this is must now be investigated as quickly as possible," Pääbo said in a statement.