What do Neandertals have to do with COVID-19? One might find the question silly, strange, or even outlandish. But researchers say these archaic hominins who were driven to extinction more than 40,000 years ago hold the key to one of the most perplexing questions around COVID-19: Why do some people infected with SARS-CoV-2 have a severe illness while others have no or only mild symptoms?
This high degree of individual variation continues to be an enigma to COVID-19 researchers everywhere. When infected with SARS-CoV-2, as many as 80% of the patients do not develop pneumonia and are classified as mild, while up to 20% progress to the critical stage with the possibility of death due to respiratory failure.
Some degree of variability is common in human infections. But what sets COVID-19 apart is the enormity of individual variations in its clinical manifestations.
In the search for answers, researchers have zoomed in on various causes. Advanced age, for one, has been identified as a major risk factor from the very beginning of the pandemic. Being of male gender is also found to increase the risk of getting severe COVID-19 significantly. Yet another group of people who have an elevated risk of having severe disease are those suffering from comorbid conditions such as obesity, type 2 diabetes and kidney disease.
That said, this risk list remains incomplete.
There is no dearth of cases where youngsters with no apparent ailments get severe COVID-19 and die without showing any gender bias. Similarly, extremely aged people having serious ailments sometimes see only mild symptoms.Obviously, what we have today as the list of major risk factors does not contain all the factors that increase an individual’s risk of SARS-CoV-2 infection, hospitalisation due to COVID-19, or critical illness.
Studies investigating host responses to other infectious diseases such as HIV and influenza indicate that the host’s genetic background plays an essential role in infections.
Similarly, geneticists probing the pathology of COVID-19 are starting to piece together the genetic underpinnings behind the progression of the disease.
A dataset released by COVID-19 Host Genetics Initiative (HGI) suggests that one region on chromosome 3, which contains six genes, is the only region that is significantly associated with severe COVID-19 at the genome-wide level. COVID-19 HGI represents a consortium of over 2,000 scientists from over 54 countries working collaboratively to share data and ideas, recruit patients and disseminate their findings.
The risk variant in this region confers an odds ratio of 1.6 for requiring hospitalisation.
The HGI study found that the genetic variants on chromosome 3 that were most associated with severe COVID-19 were all in high linkage disequilibrium (LD). A higher LD means a stronger association with each other in the population. These shorter variants have a span of 49.4 thousand bases (kb). Researchers found this ‘core’ set of alleles or haplotype to be more in weaker LD with longer haplotypes of up to 333.8 kb. Some such long haplotypes have entered the human population by gene flow from Neandertals or Denisovans — another extinct hominin that roamed the earth around 40,000–60,000 years ago and contributed to the human gene pool.
A dangerous legacy
Further investigations into the origins of these variants led researchers from Max Planck Institute for Evolutionary Anthropology, Germany to the archaic hominins. While comparing the genomic sequence to Neandertals sequenced in their lab in Leipzig, the researchers were surprised to find that the risk alleles of these variants were present in a homozygous form in the genome of the Vindija 33.19 Neandertal, an approximately 50,000-year-old Neandertal from Croatia in southern Europe. Of the 13 single nucleotides polymorphisms constituting the core haplotype, 11 were seen to be occurring in a homozygous form in the Vindija 33.19 Neandertal. Three of these variants were found in the Altai and Chagyrskaya 8 Neandertals. Both the Neandertals come from the Altai Mountains in southern Siberia and are around 120,000 and about 60,000 years old, respectively. The researchers, however, could locate none of the variants in the Denisovan genome.
In the longer 333.8-kb haplotype, the alleles associated with the risk of severe COVID-19 similarly matched alleles in the genome of the Vindija 33.19 Neandertal. But the risk haplotype was less similar to the Neandertals from Siberia, write the researchers in their paper titled: The major genetic risk factor for severe COVID-19 is inherited from Neanderthals published in Nature.
To establish the relationships of the 49.4-kb haplotype to Neandertal and other human haplotypes, the researchers analysed all 5,008 haplotypes in the 1000 Genomes Project for this genomic region. The 1000 Genomes Project, an international research effort which ran between 2008 and 2015, created the largest public catalogue of human variation and genotype data. They found that all the risk haplotypes linked to severe COVID-19 formed a clade with the three high-coverage Neandertal genomes. Within this clade, the haplotypes were most closely related to the Vindija 33.19 Neandertal.
The authors, citing several previous studies which have identified gene flow from Neandertals in this chromosomal region, argue that the risk haplotype entered the modern human population from Neandertals. The close relationship of the risk haplotype to the Vindija 33.19 Neandertal is compatible with this Neandertal being closer to the majority of the Neandertals who contributed DNA to present-day people than the other two Neandertals.
These variants were almost completely absent from Africa among the individuals in the 1000 Genomes Project, concurring with prevailing theories that suggest that gene flow from Neandertals into African populations was limited and probably indirect. The allele frequency of the Neandertal core haplotype occurred in south Asia at 30%. In Europe, it was found to be 8%, whereas among admixed Americans the allele frequency was as low as 4%.
In terms of carrier frequencies, 50% of people in South Asia carried at least one copy of the risk haplotype, whereas 16% of people in Europe and 9% of admixed American individuals carried it. Each copy of this haplotype approximately doubles the risk of its carriers requiring intensive care when infected by SARS-CoV-2.
Curiously, the people in Bangladesh had the highest carrier frequency. As much as 63% of the population in this south Asian nation carried at least one copy of the Neandertal risk haplotype and 13% is homozygous for the haplotype. This indicates that more than half of the people in Bangladesh have this risky haplotype.
The finding is further corroborated by some recent studies that show individuals of Bangladeshi origin in the UK have about two times higher risk of dying from COVID-19 than the general population.
This underscores the fact the Neandertal haplotype may be a substantial contributor to COVID-19 risk in some populations in addition to other risk factors, including advanced age, according to the paper.
Strikingly, there was a great South Asian and East Asian divide in terms of allele frequency, the analysis found. The difference of allele frequency of Neandertal risk haplotype among the two Asian populations had been unusual. It was present at a frequency of 30% in the former while was found to be almost nil in the latter. Several reasons have been attributed to this disparity. It may have been affected by selection in the past. The Neandertal haplotype has been positively selected in Bangladesh, studies suggest. Likewise, the decreased frequency of the haplotype in East Asia could be owing to the fact that it might have been eliminated by negative selection, perhaps because of coronaviruses or other pathogens.
In any case, the COVID-19 risk haplotype on chromosome 3 is similar to some other Neandertal and Denisovan genetic variants that have reached high frequencies in some populations owing to positive selection or drift, but is now under negative selection owing to the COVID-19 pandemic, say the authors.
Neandertals, say researchers, are likely to have adapted to infectious diseases in different environments outside Africa where they lived for several hundred thousands of years. During this time, they might have been exposed to infections which are known to be strong selective factors.
Studies show that several genetic variants contributed by archaic hominins to modern humans affect genes involved in immunity. Variants seen at several loci containing genes involved in innate immunity came from Neandertals and Denisovans. Toll-like receptor (TLRs) gene variants which play a vital role in lowering the susceptibility to Helicobacter pylori infections and the risk for allergies, is an example. Furthermore, proteins interacting with RNA viruses have been shown to be encoded by DNA regions introgressed from Neandertals more often than expected, and RNA viruses themselves might have driven many adaptive events in humans, according to the authors.
The researchers, however, are not quite certain what feature in the Neandertal-derived region confers risk for severe COVID-19. It is also unclear whether the effects of any such feature are specific to SARS-CoV-2, to other coronaviruses, or to other pathogens. However, with respect to the current pandemic, it is clear that gene flow from Neandertals has tragic consequences.
East Asians generally have more Neandertal DNA than other groups. However, this haplotype didn’t get passed down in East Asia, but people of South Asian ancestry are more likely to carry this Neandertal legacy.
Protector on chromosome 12
Interestingly, the particular genes on chromosome 3 are not the only pieces of Neandertal DNA that determine the severity of COVID-19 in modern humans. In contrast to the haplotype on chromosome 3 that increases the risk for severe COVID-19, some of the other Neandertal haplotypes seem to be protective against severe disease.
Using data from the Genetics of Mortality in Critical Care (GenOMICC) consortium, the very same Max Planck researchers showed in a study that a haplotype located in human chromosome 12 is associated with a nearly 22% reduction in relative risk of becoming severely ill with COVID-19 when infected by SARS-CoV-2.
GenOMICC consortium included 2,244 critically ill COVID-19 patients and controls.
Apart from the risk locus on chromosome 3, this study identified seven loci with genome-wide significant effects located on chromosomes 6, 12, 19, and 21.
These regions encode proteins that activate enzymes that are important during infections with RNA viruses.
Researchers looked for the index single-nucleotide polymorphisms (SNPs) with the strongest association at the seven loci associated with the risk of requiring intensive care upon SARS-CoV-2 infection on the four chromosomes that harbour Neandertal-like alleles. They found that none among them fulfilled the criteria like those on chromosome 12. They noticed that SNPs in the chromosome 12 locus associated with COVID-19 hospitalisation are in linkage disequilibrium (LD) in Europeans and formed a haplotype of about 75 kb. Again, haplotypes of this length were likely to have been introduced into the gene pool of modern humans due to interbreeding with Neandertals, they contend.
The index variant of the protective haplotype in the GenOMICC study matches all three — Chagyrskaya, Vindija and Denisova — Neandertal genomes available. The presence of the protective haplotype reduces the relative risk of needing intensive care by around 22% per copy of the Neandertal haplotype, shows the study titled: A genomic region associated with protection against severe COVID-19 is inherited from Neandertals published in PNAS March issue.
The haplotype also differed from the risk haplotype in that it had a more moderate effect and occurred at substantial frequencies in all regions of the world outside Africa. Among ancient human genomes in western Eurasia, the frequency of the protective Neandertal haplotype may have increased between 20,000 and 10,000 years ago and again during the past 1,000 years.
“At least 50% of the Neandertal genome is scattered among present-day people, and it is perhaps not surprising that some of the gene variants inherited from Neandertals are beneficial and some deleterious,” said Hugo Zeberg, Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology and a co-author of the study.
The researchers believe that both these haplotypes have been beneficial for modern humans at some point given how common they are today, he added.
The study found the protective haplotype contained parts or all of the three genes OAS1, OAS2, and OAS3, which encode oligoadenylate synthetases. These enzymes are induced by interferons and activated by double-stranded RNA. They produce short-chain polyadenylates, which activate ribonuclease L, an enzyme that degrades intracellular double-stranded RNA and activates other antiviral mechanisms in cells infected by viruses.
Earlier studies had identified certain SNPs on the chromosome 12 haplotype providing protection against other viral infections including West Nile virus, hepatitis C etc. The Neandertal variant in OAS1 itself has been shown to be associated with moderate to strong protection against SARS-CoV, as was shown in 2003 in a small study.
Studies cite several lines of evidence to support the hypothesis that a region of DNA containing the OAS genes introgressed from Neandertals into anatomically modern humans.
Genome-wide data show that the allele frequency of the Neandertal OAS haplotype in Eurasia is about 30%, suggesting that the Neandertal OAS haplotype may have increased in frequency relatively recently. The frequency of the Neandertal risk haplotype on chromosome 3 locus looked lower in the period prior to 20,000 years ago than in the later periods.
However, note the authors, it is interesting that the Neandertal-derived OAS locus has recently increased in frequency in Eurasia. The protective haplotype is present in populations in Eurasia and the Americas at carrier frequencies that often reach and exceed 50%. The ancestral Neandertal OAS locus variants may thus have been advantageous to modern humans throughout Eurasia, perhaps due to one or many epidemics involving RNA viruses, especially given that the Neandertal haplotype has been found to be protective for at least three RNA viruses (West Nile virus, hepatitis C virus, SARS-CoV).
Still, they caution that the prehistoric data available are heavily biased toward western Eurasia and are sparse. But they are hopeful that it will soon be possible to identify loci that may have been the targets of positive and negative selection as additional data from ancient human remains are rapidly being generated.
Genes not alone
Evidently, the studies pinpoint certain culprit genetic variants and establish their association with the Neandertal genome. They also further elucidate how the genes play a crucial role in the progression of COVID-19. The presence of the alleles of Neandertal-inherited genetic variants in different population groups at varying frequencies can provide some explanation as to the susceptibility of these groups to severe or critical COVID-19.
While underscoring the point that the course of the disease can be altered by the archaic genetic footprints, the studies keep the question rather open-ended. They leave ample room for a myriad of other factors that could affect the host response to the pathogen.
Consider the following instances.
At 4%, the allele frequency of the risk haplotype in chromosome number 3 was found to be the lowest among admixed Americans. Race data published online last year in the US Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report revealed that African Americans accounted for 33 percent of the hospitalisations in the US.
The study looked at hospitalisations for COVID-19 across 14 states from March 1 to 30, 2020 to evaluate 1,482 patients.
Demographic data publicly shared by officials in the early days of the pandemic also showed that, of the first two thousand deaths in the US, about 42% were black, often for reasons that may have nothing to do with their genes.
In Bangladesh, more than half the population have the risky haplotype. The haplotype may have given people an evolutionary advantage in fighting off other diseases, such as cholera, allowing it to increase in frequency, studies indicate.
Despite having the highest level of Neandertal DNA among all groups, East Asians did not inherit the risky genes. Yet, tens of thousands of people in China and other parts of East Asia have died of COVID-19. In East Asia, it might have been an evolutionary disadvantage when dealing with other illnesses, leading to its decline, researchers say.
Similarly, the severity and associated mortality remain comparatively high in some regions of the world, especially in Europe, despite the fact that the protective haplotype occurs at substantial frequencies in all regions of the world.
“The most important risk factor for severe COVID-19 is high age. The median age in Europe is ~20 years or more compared to many Asian or African countries,” emphasised Hugo Zeberg who is also associated with the Department of Neuroscience, Karolinska Institutet, Sweden.
Clearly, there’s a genetic component that is important with COVID-19, but social and other environmental factors seem much more important in determining risk and severity.
“First of all, one should stress that other factors are more important than these genetic factors. For example, the age structure of the population and socioeconomic and cultural factors,” concluded Svante Paabo, Director, Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, and the lead author of the studies.