New research highlights "the evolutionary aspects" of Covid-19.
It's known certain risk factors are associated with severe symptoms of Covid-19: Older individuals and people with certain comorbidities — such as lung disease or diabetes — face higher risks of hospitalization, and even death, from contracting SARS-CoV-2.
But two recent studies, one published last fall in Nature and another released Tuesday in the Proceedings of the National Academy of Sciences, suggest we should look to a more evolutionary cause to explain why some people experience severe COVID and others don't.
The studies analyze two different Neanderthal chromosomes, finding that a haplotype (a group of genes inherited together) on one chromosome confers certain protections against severe symptoms of Covid-19, while a haplotype on another chromosome actually increases the risk of hospitalization associated with the virus.
"Our study highlights the evolutionary aspects of why some people get severely ill while others have experienced mild disease," Hugo Zeberg, one of the study co-authors from the Max Planck Institute for Evolutionary Anthropology, tells Inverse.
Some background — When it comes to Neanderthals — and their recently discovered sister species, the Denisovans — it feels like we're still learning new information every day.
Neanderthals diverged from modern humans roughly 550,000 years ago. But due to our shared ancestry and interbreeding, we still see their traits manifest in modern humans, from our teeth to our brains.
Previously, researchers thought Neanderthals possessed lower intelligence than humans, but recent studies have debunked that idea.
This recent batch of COVID-19 studies further illustrates the genetic connections between Neanderthals and humans, which may have serious implications for our health. The link goes beyond coronavirus: According to the study, previous research suggests certain Neanderthal genes have aided in modern human immunity when it comes to the West Nile virus and hepatitis C infections.
How they did it — In both studies, the researchers compared genes from ancient Neanderthal specimens to DNA in modern humans using databases like the 1000 Genomes project.
The second study analyzed all 5,000 haplotypes in the 1000 Genomes project. These haplotypes are almost completely absent in individuals from Africa, suggesting, the scientists write, "gene flow from Neanderthals into African populations was limited and probably indirect." (This is disputed by some scientists.)
What's new — The researchers studied two different haplotypes with very different implications for the risk of Covid-19.
First: The researchers found that at least one copy of a Neanderthal-inherited haplotype on chromosome 3 — known as the "risk haplotype" — occurs in about 50 percent of people in South Asia, compared to only 16 percent of Europeans.
The risk haplotype is almost entirely absent in East Asia, perhaps due to a different evolutionary history related to the coronaviruses — though it's not entirely certain.
This risk haplotype significantly increases the likelihood of severe symptoms and hospitalization from Covid-19, according to the researchers.
Second: The researchers later found another Neanderthal-inherited haplotype on chromosome 12 — known as the protective variant — is associated with a 22 percent reduction in severe Covid-19 symptoms.
"The risk variant increases the risk with [approximately] 100 percent whereas the protective variant reduces the risk with [approximately] 20 percent," Zeberg says.
Unlike the risk haplotype, this protective haplotype exists at frequencies of 25 to 30 percent across Eurasian populations, though it is almost entirely absent in Africa. Due to genetic overlap with Europeans and Native Americans, people of African ancestry in the Americas have lower frequencies of this gene.
The study suggests that these haplotypes may exist as a result of ancient evolutionary advantages.
Although the researchers state that "it is clear that gene flow from Neanderthals has tragic consequences," this risk haplotype may have actually provided certain benefits against pathogens to ancient people in South Asia.
Furthermore, the protective haplotype may have evolved as a result of ancient epidemics involving RNA viruses — not unlike the coronavirus.
Digging into the details — Why does the protective variant of Neanderthal DNA have this impact, in contrast with the risk haplotype? It has to do with the way that the DNA encodes proteins, according to researchers.
Zeberg tells Inverse:
"The Neandertal haplotype encodes the three proteins OAS1/OAS2/OAS3 that are a part of a machinery that degrades viral genomes. The Neandertal proteins do so more efficiently (actually we believe it is OAS1 that is more active)."
The proteins ultimately "degrade the virus genomes in the cell" leading to less of the virus that "the innate immune system needs to deal with," Zeberg explains. Fewer virus genomes ultimately lead to a milder infection.
Finally, the researchers suggest that the haplotypes may have evolved more in the last millennium.
The frequency of the Neanderthal protective haplotype was only 20 percent about 1,000-3,000 years ago, but the current frequency of the gene hovers around 30 percent in Eurasia.
The researchers found a similarly recent increase in the risk haplotype which, according to researchers, did not exist in any specimens more than 20,000 years old.
The study also suggests modern humans living in Oceania inherited the OAS locus from Denisovans.
Why it matters — Covid-19 has stumped many in the medical community, and there's still a lot we don't know about this mysterious disease.
This research team argues for an evolutionary explanation for why people with certain types of Neanderthal genes may experience different symptoms of the disease than someone who lacks that DNA.
However, Covid-19 is a complex disease. There's still much we don't understand about how this virus impacts humans. Evolutionary traits from Neanderthals are just one of many factors that could potentially contribute to the severity of the disease. Importantly, risk factors do not mean a person will definitely contract severe Covid-19.
For example, the researchers point to the higher incidence of fatal Covid-19 in people of Bangladeshi origin in the UK. The scientists suggest that evolutionary factors may play a role, as a greater percentage of people from South Asia — especially from Bangladesh – carry one copy of the risk haplotype.
However, other factors, such as a high percentage of essential workers and language barriers, may also help explain the higher death rate in the UK Bangladeshi community.
And while India — the most populous country in South Asia — has a high number of total COVID-19 cases, it has experienced fewer deaths per 100,000 people than the U.S and many European nations.
What's next — The authors note that their study is limited due to a lack of comprehensive data from ancient Neanderthals.
"We caution that the prehistoric data available are heavily biased toward western Eurasia and are still sparse, particularly for older periods," the team writes.
In particular, current genome data lacks significant representation from populations outside of Eurasia.
However, the scientists also note that "additional data from ancient human remains are rapidly being generated, making us confident." They expect they will eventually be able to study the frequency of certain genes in specific geographic regions.
In the future, the team is hopeful the genome data they used can help devise better Covid-19 treatments for vulnerable populations.
Abstract from the PNAS study: It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is inherited from Neandertals. New, larger genetic association studies now allow additional genetic risk factors to be discovered. Using data from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region on chromosome 12 associated with requiring intensive care when infected with the virus is inherited from Neandertals. This region encodes proteins that activate enzymes that are important during infections with RNA viruses. In contrast to the previously described Neandertal haplotype that increases the risk for severe COVID-19, this Neandertal haplotype is protective against severe disease. It also differs from the risk haplotype in that it has a more moderate effect and occurs 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 y ago and again during the past 1,000 y.
Abstract from Nature study: A recent genetic association study1 identified a gene cluster on chromosome 3 as a risk locus for respiratory failure after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A separate study (COVID-19 Host Genetics Initiative)2 comprising 3,199 hospitalized patients with coronavirus disease 2019 (COVID-19) and control individuals showed that this cluster is the major genetic risk factor for severe symptoms after SARS-CoV-2 infection and hospitalization. Here we show that the risk is conferred by a genomic segment of around 50 kilobases in size that is inherited from Neanderthals and is carried by around 50% of people in south Asia and around 16% of people in Europe.