Svante Pääbo created the science of detecting Neanderthal DNA in archeological samples (and living humans) almost single-handedly (see Neanderthal Man: In Search of Lost Genomes). So it will come as little surprise to many that he published a paper in September describing his discovery of a gene derived from our Neanderthal ancestors (and inherited by modern humans) that encodes a risk factor for infection with the etiological agent for COVID-19, SARS-CoV-2.
The paper, entitled "The major genetic risk factor for severe COVID-19 is inherited from Neanderthals" and published in Nature, builds on genetic association studies that disclosed a gene cluster located on human chromosome 3 that relates to respiratory failure in response to COVID infection. Separately, other researchers had shown that this cluster was a "major risk factor" for severe COVID symptoms in 3,200 infected, hospitalized patients. In this paper, Dr. Pääbo and his collaborator show that the genetic element responsible for this phenotype resides in a 50 kilobase (kb) genomic segment inherited from our Neanderthal ancestors and is disproportionately found in humans from South Asia (50%) as compared with Europeans (16%).
The portion of the human genome on chromosome 3 showed high linkage disequilibrium in non-African populations (meaning that the genes in this region tend to be co-inherited at higher frequencies than expected for random parts of the chromosome), indicating the action of some selective pressure in favor of co-inheritance. The "risk" alleles in this segment are associated with the genome of a ~50,000 year-old Neanderthal specimen from Croatia reported by Dr. Pääbo and his collaborators in 2017 in Science, as reflected in the presence of 11 single nucleotide polymorphisms (SNPs) in common between Neanderthal and modern human DNA from this segment. None of these diagnostic SNPs are found in Denisovan specimens, whereas some (3) of them are found in older Neanderthal specimens (60000 – 120,000 years old) from Siberia. The paper thus hypothesizes that the presence of these genes in modern human DNA was the result of Neanderthal-human crossbreeding.
The paper also reports that the alternative hypothesis -- that this segment in inherited from the common ancestor between Neanderthals and modern humans -- was not supported (albeit a conclusion reliant on a number of reasonable yet hypothetical conditions). In addition, the conclusion that this segment was the result of Neanderthal-human crossbreeding is consistent with other studies regarding "gene flow" from Neanderthal ancestors in this region of the chromosome.
From a population genetic perspective, the Neanderthal-derived risk segment (or "haplotype) is almost completely absent from Africa, which is consistent with most human-Neanderthal interbreeding occurring in populations that had migrated from Africa (see Who We Are and How We Got Here: Ancient DNA and the New Science of the Human Past). The paper reports that the "core" Neanderthal risk haplotype occurs "in south Asia at an allele frequency of 30%, in Europe at an allele frequency of 8%, among admixed Americans with an allele frequency of 4% and at lower allele frequencies in east Asia," resulting in their finding that "50% of people in South Asia carry at least one copy of the risk haplotype, whereas 16% of people in Europe and 9% of admixed American individuals carry at least one copy of the risk haplotype." Perhaps surprisingly, the highest frequency of modern carriers was found in Bangladesh where 63% of the population carries at least one copy of the risk factor DNA and 13% of the population is homozygous for this haplotype. This result its consistent with the experience in the UK of individuals from Bangladesh, who have about twice the risk of dying from COVID than members of the general population. There is also some evidence that these population differences reflect initial positive selection in South Asia in ancestral populations (although the only speculative basis for positive selection the authors provide would be against another unknown pathogen).
Unfortunately, the paper does not report what is encoded in this segment inherited from Neanderthals. When elucidated, such results may be beneficial, providing for example a genetic screen for individuals at particular risk (and hence motivated to take particular cautions) of SRAS-CoV-2 infection. Nevertheless, the paper provides a fascinating (albeit tragic) insight into the consequences of the persistent presence of Neanderthal-derived DNA in modern humans, particularly as they relate to resistance and susceptibility to even the most novel of diseases.
