A new study published in Nature suggests that a segment of DNA that has been linked to an increased risk of developing severe COVID-19 is inherited from Neanderthal ancestors.
What's the deal with chromosome three?
Why do some COVID-19 patients present as asymptomatic, whilst others contract the virus and ultimately die? This question has been a focus for scientists across the globe over the last nine months, and despite extensive research, we still lack a confident answer. Nonetheless, genomics research has contributed largely to what we do know so far about COVID-19 clinical variability.
In June, Ellinghaus and colleagues published the results of a large genome-wide association study (GWAS) analyzing COVID-19 patients across seven hospitals in Italy and Spain.1 The scientists identified a specific gene cluster on chromosome three (chr3p21.31) as a genetic susceptibility locus in COVID-19 patients that had respiratory failure, in addition to a genetic region on chromosome nine which determines an individual's blood group.
What is a GWAS?
A GWAS is a particular method of study adopted in genetics research. It involves studying a sample of individuals who are classified based on a particular phenotype – e.g., having a disease or not having a disease – that undergo genetic analysis via single nucleotide polymorphism (SNP) arrays which probes their DNA for specific genetic variants. If a variant occurs in higher frequencies in certain phenotypes when compared to other phenotypes, the variant is classed as being associated with the phenotype. Association implies a link but it does not prove causation.
In September, personal genomics and biotechnology company 23andMe shared results from the first four months of its COVID-19 genetic study of over 1 million individuals.2 Once again, the scientists identified an association at the chr3p21.31 locus with disease severity. This association was particularly strong in phenotypes relating to respiratory clinical signs.
What is the role of this gene cluster, where has it come from, and why is it associated with increased disease severity in COVID-19 patients? The what and the why are still being explored, but scientists may have an answer as to where this cluster has come from – Neanderthals.
Historical insights for a modern-day pandemic
Hugo Zeberg is an assistant professor at the Karolinska Institute in Sweden. He studies gene flow from Neanderthals and Densiovans into modern humans, specifically in relation to the impact of genetic variability. Together with one of the founders of palaeogenetics, Svante Pääbo – director of the Max Planck Institute for Evolutionary Anthropology – Zeberg has published a study in Nature reporting that the gene cluster on chromosome three associated with higher risk of severe COVID-19 respiratory signs is very similar to the DNA sequence of a 50,000-year-old Neanderthal.3
“It turns out that this gene variant was inherited by modern humans from the Neandertals when they interbred some 60,000 years ago,” said Zeberg in a press release. “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.”
Zeberg and Pääbo also explored the frequency of the gene cluster in modern humans. Their results show that approximately half of the population in South Asia carry the variant, whereas in Europe only one in six individuals are carriers. In Africa and East Asia, interestingly, the variant is almost completely absent. The highest frequency occurs in Bangladesh where 63% of the population carry at least one copy of the risk variant, and 13% are homozygous. In the paper, the authors comment: "The Neanderthal haplotype may thus be a substantial contributor to COVID-19 risk in certain populations besides other risk factors, most notably advanced age. In apparent agreement with this, individuals of Bangladeshi origin in the UK have about two times higher risk to die from COVID-19 than the general population (hazard ratio 95% CI: 1.7-2.4)."
The study by Zeberg and Pääbo does not provide an explanation as to why this particular variant is associated with a higher risk of severe COVID-19, but the researchers believe their findings are of historical interest and should be explored further: "It is striking that the genetic heritage from the Neandertals has such tragic consequences during the current pandemic. Why this is must now be investigated as quickly as possible,” says Svante Pääbo. Such research may offer insights as to why our Neanderthal ancestors were either suspectable or unsusceptible to pathogens that inhabited the Earth at that time.
1. Ellinghaus D, Degenhardt F, Bujanda L, et al. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med. 2020. doi:10.1056/NEJMoa2020283.
2. Shelton JF, Shastri AJ, Ye C, et al. Trans-ethnic analysis reveals genetic and non-genetic associations with COVID-19 susceptibility and severity. medRxiv. 2020. doi:10.1101/2020.09.04.20188318.
3. Zeberg H, Pääbo S. The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature. doi:10.1038/s41586-020-2818-3.