Risk haplotype
The genetic variant that increases the risk of severe COVID-19 is inherited from Neanderthals.
Alexander Markov, "Elements"
To date, geneticists have been able to identify only one section of the human genome, in which nucleotide variations significantly affect the chances of getting a severe form of COVID-19. This fragment of the third chromosome with a length of about 50 thousand base pairs is found in modern people in several variants, one of which increases the chances of getting to the hospital with a severe form of COVID-19 by about 1.6 times.
Paleogeneticists Svante Paabo and Hugo Tseberg have shown that this "risk allele" is of Neanderthal origin. Together with other non-standard genes, it got into the gene pool of non-African sapiens as a result of hybridization, which occurred about 50 thousand years ago.
The frequency of occurrence of the "risk allele" varies greatly depending on the region: in Africa and East Asia it is close to zero, in Europe it is 8%, in South Asia it is 30%. Such large differences indicate that in the not very distant past, the allele was subjected to strong selection, sometimes positive, sometimes negative. Most likely, this is due to the fact that the allele affects resistance to some other pathogens besides the new coronavirus.
As you know, COVID-19 is a selective disease: someone gets sick, someone does not, some carry it easily, others – hard, up to a fatal outcome. It depends on many non-genetic factors, among which age, gender and the presence of certain diseases are especially important. It is logical to assume that genetic differences between people also contribute to the observed variation in susceptibility to COVID-19 and the severity of the disease.
Despite diligent searches, to date, geneticists have managed to identify only one section of the human genome, the connection of which with the risk of getting a severe form of COVID-19 is beyond doubt. This site is located on the third chromosome and includes the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. Its effect on resistance to a new infection was first detected using genome-wide association search (GWAS) based on data on 835 patients and 1,255 healthy Italians and 775 patients and 950 healthy Spaniards. This study was conducted during the spring peak of morbidity in Europe (D. Ellinghaus et al., 2020. Genomewide Association Study of Severe Covid-19 with Respiratory Failure).
In the future, the result was successfully reproduced in several independent studies on other European and Asian samples. A meta-analysis conducted within the framework of the COVID-19 Host Genetics Initiative project finally confirmed that one of the variants of this genome site (the "risk allele"), characterized by certain nucleotides in 13 polymorphic positions, increases a person's chances of being hospitalized with severe COVID-19 by about 1.6 times (this is a somewhat simplified formulation, we are talking about the odds ratio, see Odds ratio, which, according to the results of meta-analysis, is 1.6 with a 95 percent confidence interval from 1.42 to 1.79). Apparently, this genetic variant increases both the chances of catching a moderately severe form of COVID-19 (the frequency of this variant is higher in people hospitalized with COVID-19 than the average population), and the risk of very severe disease among those who have already become ill (among hospitalized patients who required artificial ventilation, the frequency of this the options are higher than those who managed only with additional oxygen).
The mentioned 13 polymorphic positions are scattered over a section of the chromosome with a length of about 50 thousand base pairs. At the same time, nucleotide variants correlating with an increased risk of severe COVID-19 in all 13 positions are almost always present together, amicably, forming a single haplotype. In other words, they are characterized by what geneticists call "non-equilibrium coupling of genes."
It is this pattern – several tightly coupled polymorphisms located next door – that is characteristic of DNA fragments obtained by the ancestors of modern humans from Neanderthals and Denisovans as a result of hybridization.
Therefore, paleogeneticists Svante Paabo and Hugo Zeberg decided to check whether this haplotype coincides with Neanderthal or Denisovan genomic sequences. To do this, we need the genomes of extinct human species, read very qualitatively, that is, with high coverage. There are currently four such genomes: three Neanderthal and one Denisovan.
The result was quite unambiguous: out of 13 polymorphisms characteristic of the "risk haplotype", 11 are present in a homozygous state in a Neanderthal from Vindija cave in Croatia (Vindija 33.19). Three polymorphisms are present in two other Neanderthals with qualitatively read genomes – from Denisova and Chagyrskaya caves in Altai (Denisova 5 and Chagyrskaya 8; F. Mafessoni et al., 2020. A high-coverage Neandertal genome from Chagyrskaya Cave). None of the 13 polymorphisms were found in the Denisov genome.
This result in itself is a convincing argument in favor of the fact that the "risk haplotype" is inherited by modern humans from Neanderthals close to the individual from the Vindiya cave. Other Neanderthal admixtures in modern genomes are also closer to the genome of the Croatian Neanderthal than to individuals from Altai. This is explained by the fact that those Neanderthals, with whom the Sapiens who came out of Africa 60-50 thousand years ago interbred, were closer relatives of the Croatian Neanderthal than the Altai.
Additional tests confirmed the conclusion about the Neanderthal origin of the "risk haplotype". In particular, the probability that such a long haplotype could have been inherited by a Croatian Neanderthal and modern humans from a common ancestor turned out to be, according to the authors' calculations, negligibly low. For more than half a million years of separate existence of Sapiens and Neanderthals, the haplotype would have to crumble into small pieces due to crossing over.
The authors also constructed a phylogenetic tree for all variants (alleles) of the genome section in question available to modern humans. On this tree, all modern alleles associated with an increased risk of severe COVID-19 (they differ from each other only by single nucleotide substitutions) formed a single compact branch with the Croatian Neanderthal, and the Neanderthal variants from Altai turned out to be sister to this branch. In other words, the "risk allele" (in all its minor variations) is closer to any of the three Neanderthal variants than to any other variant of this genome region found in modern humans. Thus, the Neanderthal origin of the "risk haplotype" has been proven quite reliably.
The frequency of occurrence of a Neanderthal genetic variant that increases the risk of severe COVID-19. In Africa and East Asia, the "risk allele" is practically absent, and the maximum frequency is observed in South Asia, especially in Bangladesh. A drawing from the article in Nature under discussion (according to The 1000 Genomes Project).
The frequency of occurrence of the Neanderthal "risk haplotype" in modern human populations varies greatly depending on the region. It is practically absent in Africa, which is logical, since the influx of Neanderthal genes into the gene pool of modern Africans living south of the Sahara was insignificant (and probably indirect). East Asians (Chinese, Japanese) almost do not have it either. This is an unexpected result, because there are a lot of other Neanderthal genes in East Asians – even slightly more than in Europeans. In Europe, the Neanderthal haplotype occurs with a frequency of about 8%, in South Asia – 30%. The highest frequency is characteristic of Bangladesh: 63% of the inhabitants of this country carry at least one copy of the Neanderthal haplotype, and 13% have two copies (that is, they are homozygous), which gives a total frequency of 13+(63-13)/2=38%. This is consistent with the fact that in the UK, according to official data, the chances of dying from COVID-19 for people from Bangladesh are about twice as high (by 95%, confidence interval: 1.7–2.4) as for white Britons. People from other countries have a much better situation than Bangladeshis.
Explain why in In East Asia, the frequency of occurrence of the Neanderthal haplotype is almost zero, and in South Asia it is very high, apparently, it is possible only by strong selection, which acted differently in different regions. It is logical to assume that the main selection factor was some pathogens. Maybe the Neanderthal haplotype, which reduces the resistance of a new coronavirus infection, was subjected to negative selection in China during some previous epidemics caused by other coronaviruses, and in the Ganges Delta it was affected by positive selection because it provided protection from some other pathogens. But so far, all this is just speculation, because it is unknown exactly which features of the Neanderthal haplotype are responsible for the increased risk of severe COVID–19 and what is the mechanism of their action. As already mentioned, the haplotype includes six genes, among which it is not possible to uniquely identify a candidate for the role of the main risk factor. It may be, for example, the SLC6A20 gene, because the protein encoded by this gene interacts with the ACE2 protein – the "entrance gate" of the new coronavirus. The CCR9 and CXCR6 genes are also suspected, because they encode chemokine receptors, and the work of the second of them is directly related to immune processes in the lungs, for example, in influenza.
Someday, perhaps, we will find out from which pathogens this haplotype of Neanderthals (as well as the ancestors of the current population of South Asia) protected from, but it's too early to fantasize about it. One thing is for sure: in 2020, the Neanderthal heritage played a cruel joke on some of our contemporaries.
Source: Hugo Zeberg & Svante Pääbo. The major genetic risk factor for severe COVID-19 is inherited from Neanderthals // Nature. 2020.
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