Are we at a greater risk of serious COVID-19 because of our Neanderthal genes?
A study claims that a DNA fragment from Neanderthals puts many South Asians at higher COVID-19 risk.
A fragment of DNA that is thought to have been acquired from extinct Neanderthals is a strong risk factor for severe COVID-19 in Indians, Pakistanis, and Bangladeshis according to leading researchers who published their work in Nature.
We already know much about risk factors such as advanced age, sex (being male is a risk factor), obesity, social/racial status and other conditions (such as diabetes, heart disease, cancer, and kidney failure). But we don’t yet know much about what inherited genes might act as risk factors as well. To date there have been only a couple of major studies which have tried to establish what genetic factors predispose certain people to greater risk of coronavirus infection and severe COVID-19.
Right now, there two genetic regions that have been linked to different risks of COVID-19.
The first that was identified was associated with the ABO-blood type. Data from various countries seemed to indicate that there was a correlation between blood-type and testing positive. In people with Rh positive blood, those with type A or B were more likely to test positive for SARS-CoV-2 than people with type O. I was intrigued by this, partly because I have type O blood. Now, I’m not sure that the evidence is strong. In the words of one of the authors- “the basic science on this is extremely weak.” Those of us with type O blood should not get our hopes up that we have lower risk of getting infected.
The second study claims that Neanderthal genetic region in a chromosome that some people have puts them at higher risk than others. In people from South Asia, this deleterious Neanderthal genetic region is found in 30% of people, with the highest percent in Bangladeshis, where more than half the population carry at least one copy of the genetic region. It is found in 8% of Europeans and at lower frequencies in East Asians. Almost no one of African origin has it because Neanderthal genes are usually absent. I’ll get to that in a bit.
The authors note that people in the UK of Bangladeshi origin are two times as likely to die from COVID-19 than the general population. On the face of it, this assertion seems to back an increased risk due to a genetic factor. But even this assertion does not tease out any of the other confounding factors. We know, from many countries, that social and racial status (independent of everything else) affects whether someone gets SARS-CoV-2 infection and what outcomes they suffer. In the US, Blacks have suffered some of the worst outcomes of the pandemic. What we don’t know is what role other factors played in the deaths of the Bangladeshis. It is well known that British Bangladeshis are among the most disadvantaged populations in the UK, and its possible that the association could be due to the jobs they often do in the service sector and exposure.
What makes this study hard to decipher— even though it is published in Nature, the most prestigious journal in the world by the world’s foremost Neanderthal genetics expert— is that there is no plausible mechanism or reason why there is such an association, just an observation. In fact, my first reaction was of disbelief because reported cases and fatality is lower in India, Pakistan, and Bangladesh than in many other parts of the world. If there even is an association, it needs further elaboration, because it certainly isn’t as clear cut as the authors suggest. India has a younger population, and that has thought to have helped to avert many of the reported deaths in other countries. In addition, trained immunity (notably from BCG) has been hypothesized as reducing severe outcomes.
The other aspect of the paper which is puzzling is why South Asians have this Neanderthal genetic component at all, when it has been almost completely lost in East Asia. The authors speculate that East Asians were exposed to many coronaviruses (while we, South Asians weren’t) and so over time they lost that Neanderthal genetic component, but it remained in our genomes. But the authors also concede the following:
It is currently not known what feature in the Neanderthal-derived region confers risk for severe COVID-19 and if the effects of any such feature is specific to SARS-CoV-2, to other coronaviruses or to other pathogens.
To understand more about this study we need a little bit of background. We need to look at just when modern humans first came in contact with Neanderthals.
Most of us have Neanderthal genes. Most Africans don’t.
Anthropologists use the term anatomically modern humans to designate members of Homo sapiens, our own species. Now there is, of course, only one species of human alive today. But that was not always the case. The genus Homo evolved in the African heartland and gave rise to at least a dozen species, some of which spread out of the continent over millions of years.
Most Homo species, including our own evolved in Africa, but there is one notable exception. Neanderthals evolved in Europe, likely from Homo heidelbergensis around 250,000 years ago. In Africa, our own species also evolved separately from Homo heidelbergensis. The remarkable thing is that modern humans and Neanderthals evolved separately on two different continents without any knowledge of even the existence of the other for nearly 200,000 years!
What were Neanderthals like? They’ve been almost universally depicted as slow-witted ape-like creatures, but that is far from the truth. Neanderthals lived in social groups, wore clothes, and buried their dead. They developed stone tools and primarily ate meat such as large mammoths. Their facial structure was different from modern humans, but they were almost certainly stronger. Neanderthal lifespans were shorter however: they reached maturity around 12 and seldom lived beyond 40.
Neanderthals ran into modern humans in the Middle East. Those modern humans are the ancestors of everyone except those who are in sub-Saharan Africa. This human-Neanderthal interaction happened first in the Middle East around 60,000 years ago, but by 40,000 years ago Neanderthals were extinct everyone.
In 2010, the sequencing of the Neanderthal genome revealed a shocking fact. Most modern humans contain a small percentage (around 1% to 2%) of Neanderthal genes in our genomes, suggesting that there had been interbreeding between Neanderthals and people likely during the first contacts in the Middle East. The only modern humans who do not possess any Neanderthal genes are those in Sub-Saharan Africa, and again, the reason is their ancestors never left Africa. As a result, they never encountered Neanderthals.
Modern humans in Africa are the most genetically diverse on the planet.
Our modern human species evolved in Africa and acquired diverse traits over hundreds of thousands of years. Africans descended from this diverse gene pool. The rest of us are derived from a smaller group of modern humans in Europe and Asia who came out of Africa from 60,000 to 50,000 years ago. We are all less genetically diverse than the descendants of those who stayed in Africa and this is due to something called the serial founder effect. A serial founder effect happens when a subset of a population migrates long distances. Descendants have less genetic diversity because fewer and fewer ancestors made and survived the migration. This is such an important concept that I feel I need to explain this using maps.
All anatomically modern humans were in the southern part of Africa, from where some ancestors moved to the northern part of Africa. The thick arrows in the first map above shows each major migration event and dates. In relatively short time from a geological and evolutionary perspective, modern humans covered the planet. But it was not easy sailing.
As the second map shows, because only a few people out of the whole population migrate (colored dots), genetic diversity declined in a manner that was roughly proportional to the distance from Africa. In fact, the linear correlation between loss of genetic diversity and distance from the origin of expansion in Africa is around 90%.
Also, wherever our ancestors went, they faced animals, diseases, and other other species (like Neanderthals). There were at least two bottleneck events that nearly wiped out all modern humans who had left Africa. Our ancestors were all nearly wiped us out and reduced us to a few thousand people. There was no inevitability in their survival. One of the defining characteristics of those of us who have historically resided outside of Africa is our lack of genetic diversity. We are the descendants of those who almost never made it.
Sometimes, I think about the early history of those humans. What would’ve happened if anatomically modern humans had not left Africa in the Great Expansion? What would’ve happened had the Neanderthals not gone extinct?
Genetic links to infectious diseases are complicated.
I started this newsletter talking about a piece of DNA that many South Asians have acquired from Neanderthals that makes us possibly at higher risk for severe COVID-19. Pulling that one single thread caused me to unravel quite a bit more about human origin and migration. I want to tie it back to the original study.
The relative risk from the acquired gene does not seem to mesh well with the ground reality of the outcomes we are seeing in a heterogenous population in South Asia. Many other factors also come into play besides genetics such as age, general health, and immune responses. I would like to see a broader statistic correlation with a larger population in India that more strongly establishes a relative genetic risk.
Nobel Laureate Theodosius Dobzhansky famously said, “nothing in biology makes sense except in the light of evolution.” The biggest hole in the study is the presence of the detrimental Neanderthal component in South Asians, but not in East Asians. Presumably we all had that genetic piece inherited from Neanderthals at once. If that is so, then why did East Asians lose it?
Clearly, there is more here that needs to be uncovered.
Additional reading on human migration:
There are very few Indian books on natural history and anthropology that cover modern discoveries (especially in comparison to Indian books on economics, history, or politics), but I can recommend Tony Joseph’s Early Indians (which has coverage of modern human and Neanderthal interactions in an early chapter) and Pranay Lal’s Indica (where it is included in the last chapter).
Bernard Wood’s Human Evolution: A Very Short Introduction is also eminently readable (and can be finished in a short sitting).
Svante Pääbo is a lead author on the Neanderthal Nature paper. He is unmistakably the world’s foremost expert on Neanderthal genomes and the author of Neanderthal Man: In Search of Lost Genomes.
For those who don’t mind a technical perspective, I highly recommend “The great human expansion” in P.N.A.S. by Brenna M. Henn, L. L. Cavalli-Sforza, and Marcus W. Feldman.
The link for the hardcover “COVID-19: Separating Fact from Fiction” is now available on Amazon’s Indian site.
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Have you considered this aspect http://www.geologyin.com/2016/05/12-facts-you-should-know-about-plate.html