Last year, researchers at Karolinska Institutet in Sweden and the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany showed that a major genetic risk factor for severe COVID-19 is inherited from Neandertals.
Now the same researchers show, in a study published in PNAS, that Neandertals also contributed a protective variant. Half of all people outside Africa carry a Neandertal gene variant that reduces the risk of needing intensive care for COVID-19 by 20 percent.
Some people become seriously ill when infected with SARS-CoV-2 while others get only mild or no symptoms. In addition to risk factors such as advanced age and diabetes, gene variants also make people more or less sensitive to developing severe COVID-19.
A major genetic risk factor is located on chromosome 3 and dramatically increases the risk of respiratory failure and even death.
Hugo Zeberg and Svante Pääbo at Karolinska Institutet and the Max Planck Institute for Evolutionary Anthropology discovered last year that this risk variant is inherited from Neandertals.
Now the research duo shows that the Neandertals also contributed a protective variant to present-day people.
They find that a region on chromosome 12 that reduces the risk of needing intensive care upon infection with the virus by 20 percent is inherited from Neanderthals
The genes in this region are called OAS and regulate the activity of an enzyme that breaks down viral genomes, and the Neandertal variant of the enzyme seems to do this more efficiently.
“This shows that our heritage from Neandertals is a double-edged sword when it comes to our response to SARS-CoV-2. They have given us variants that we can both curse and thank them for,” says Hugo Zeberg, researcher at the Department of Neuroscience, Karolinska Institutet, and the Max Planck Institute for Evolutionary Anthropology.
The study also shows that the protective variant from Neandertals has increased in frequency since the last Ice Age so that it is now carried by about half of all people outside Africa.
“It is striking that this Neandertal gene variant has become so common in many parts of the world. This suggests that it has been favorable in the past,” says Svante Pääbo, director at the Max Planck Institute for Evolutionary Anthropology. “It is also striking that two genetic variants inherited from Neandertals influence COVID-19 outcomes in opposite directions. Their immune system obviously influences us in both positive and negative ways today.”
As of December 4 2020, SARS-CoV-2, the novel coronavirus that causes COVID-19, has killed more than 1.5 million people in different countries. The number of confirmed COVID-19 infections has surpassed 65.4 million, globally. Environmental factors can change the expression of specific genes. The genetic and molecular basis of human adaptation and evolution has been known for decades.
An accumulating body of evidence now indicates that our genetic background may control the transmissibility of SARS-CoV-2. Moreover, the genetic background can explain why the progress of COVID-19 is so fast in some infected individuals. Both morbidity and mortality of COVID-19 strongly depends on key factors such as age and co-existing health conditions. However, potential classes of human genomic variants can also affect the likelihood of SARS-CoV-2 infection and its progress.
SARS-CoV-2 Variants around the World
SARS-CoV-2, like other coronaviruses, has a single-stranded genomic RNA, approximately 30 kb in length [ 1 ]. RNA viruses mutate and evolve much faster than their hosts (e.g. up to a million times higher than their hosts such as humans). RNA viruses mutate faster than DNA viruses.
These high rates of mutation in RNA viruses have been reported to be associated with enhanced virulence [ 2 ]. Moreover, when an antiviral treatment is not robust and hence unable to eliminate viruses, the exerted selective pressure endangers the fitness of virus and viral evolution is promoted. In this case, the virus has a great opportunity to evolve through adaptive mutations.
This issue may play a key role in limiting the success of infection control. SARS-CoV-2 control must consider its evolutionary and adaptive mutation characteristics. Today, tens of millions of people around the world are infected with the virus. Therefore, the widespread use of non-fully effective antiviral agents/vaccines can trigger a global disaster.
Given this consideration, developing an efficient treatment against SARS-CoV-2 is of key importance. As a 100% selective pressure-free treatment [ 3 ], low dose radiation therapy (LDRT) has opened new horizons in the treatment of COVID-19.
LDRT for COVID-19 associated pneumonia and acute respiratory distress syndrome (ARDS), was introduced by our team in March 2020 and subsequently this idea has been supported by other scientists from different countries. Using LDRT is not only based on anti-inflammatory effects of low dose radiation but also on properties including optimizing the activity of the immune system and preventing thrombosis.
Iran and Mongolia, Two Countries with Puzzling COVID-19 Mortalities
Today, there is a global race to determine which factors drive the severity of COVID-19. These efforts are focused on finding which human or viral factors determine an individual infected by SARS-CoV-2 will develop severe symptoms [ 4 ]. Although some studies show that Iran and Mongolia may share the same SARS-CoV-2 mutation cluster (Figure 1), the COVID-19 mortality rates in these two countries are drastically different (Figure 2). While the population in Iran is about 26 times higher than that of Mongolia, the number of confirmed cases is 1170 times higher (Figure 2).
Iran and Mongolia share the same SARS-CoV-2 mutation cluster (Figure reproduced from Chen M, et al. J Mol Biol. 2020;432(19):5212-6. [5])
The COVID-19 cases and total deaths in Iran and Mongolia (Figure reproduced from data provided by Wikimedia and illustrated by Google)
Moreover, the death rate shows a drastic difference. Hundreds of genetic variants that can be traced to the Neanderthals have been identified. According to currently accepted theories, Neanderthals interbred with modern humans in Middle East between 47,000 and 65,000 years ago before going extinct 40,000 years ago (Figure 3). Thus, it’s not puzzling that some Iranians have much more Neanderthal DNA than other people (Figure 4).
Neanderthals interbred with modern humans in Middle East between 47,000 and 65,000 years ago before going extinct 40,000 years ago. a. The geographical range of Homo Neanderthalenisis. b. About 60,000-70,000 years ago, the ancestors of modern human began interbreeding with Neanderthals. Estimates show that the majority of the Neanderthal DNA in the genomes of modern human is originated from interbreeding that occurred around 50,000-55,000 years ago in the Middle East. (Figure reproduced from: https://www.the-scientist.com/features/neanderthal-dna-in-modern-human-genomes-is-not-silent-66299 [6]).
The genome analysis of an Iranian man that indicates he has more Neanderthal DNA than about 90% of other people tested. (Based on the results of genome analysis of an Iranian customer; www.23andme.com).
It was previously reported that Neanderthal genes possibly gave modern human protection against viruses. In 2018, Stanford scientists reported that the genomes of humans and other species contain signatures of ancient epidemics. They concluded that Inherited Neanderthal genes protect us against viruses [ 7 ].
However, a recent study revealed that a gene cluster on chromosome 3 is a risk locus for respiratory failure in severe COVID-19 patients. Zeberg and Pääbo have recently reported that a long sequence of DNA that can be linked to severe COVID-19 infection and hospitalization is inherited from our Neanderthal ancestors [ 8 ].
It is worth noting that the sequence is not evenly distributed across modern human populations [ 9 ]. Figure 5 shows the frequency at which the risk factor is found in various populations around the globe. The map shows the geographic distribution of the Neanderthal core haplotype that determines the risk for severe COVID-19.
It should be noted that genetic background and environmental factors alone do not determine our risk of developing severe COVID-19. However, both the development and progression of any infectious diseases such as COVID-19 can be clearly determined by our genes [ 9 ].
The frequency at which the genetic risk factor is found in various populations around the globe. The geographic distribution of the Neanderthal core haplotype that determines the risk for severe COVID-19 is illustrated in the map.
In summary, Iran and Mongolia are two Asian countries that share the same SARS-CoV-2 mutation cluster. However, the COVID-19 mortality rates in these two countries are drastically different. The Neanderthals interbred with modern humans in Middle East between 47,000 and 65,000 years ago before disappearing 40,000 years ago.
Thus, some Iranians have much more Neanderthal DNA than people in other countries. Neanderthal genes possibly gave modern human protection against viruses. However, a recent study revealed that that a long sequence of DNA that is inherited from our Neanderthal ancestors can be linked to severe COVID-19 infection and hospitalization.
Neither our genetic background nor environmental factors alone determine our risk of developing severe COVID-19. However, our genes clearly affect both the development and progression of infectious diseases including COVID-19.
Given these considerations, it can be hypothesized that the great differences observed, at least to some extent, can be due to the proportion of Neanderthal genes among the people of these two countries.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859372/
More information: Hugo Zeberg and Svante Pääbo, A genomic region associated with protection against severe COVID-19 is inherited from Neandertals, PNAS, online 16 February 2021, DOI: 10.1073/pnas.2026309118, www.pnas.org/content/118/9/e2026309118
