Could COVID-19 wipe out the Neanderthals?

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Everyone loves Neanderthals, those big brains that we supposedly overcame and eventually replaced with our sharp tongues and fast, gentle minds. But are we really? Is it mathematically possible that we could still be them and they they?

Likewise, the impossibly unique Mitochondrial Eve, its modern Y-chromosome Adam, and even the “Out of Africa” hypothesis are not simply appropriate fabrications. Paleogenetic experts tell each other at conferences to give their mostly arbitrary haplotype designations and then derived evolutionary trees of more belief?

Perhaps one of the best ways to try to answer this question is to ask what the coronavirus says about that question. Svante Pääbo, director of the genetics department at the Max Planck Institute, certainly believes that Homo sapiens Neanderthalensis, or just Homo Neanderthalensis, if you will, is extinct. Pääbo, the son of 1982 nobleman Sune Bergström, lived nicely from Neanderthal bones, finding a gene for a genome that is distinctly “Neanderthal”. In 1997, Pääbo successfully sequenced mitochondrial DNA from a sample found in the Feldhofer hatch in the Neander Valley. Rewinding a few recent PR disasters, the Germans managed to capture the productive Swede and set him the task of dealing with those awkward skeletons from the legacy that were constantly being displayed.

This September, it was announced by Pääbo and colleague Hugo Zeberg the major genetic risk factor for severe COVID-19 is inherited from Neanderthals. (We notice that Nature publications prefer to include h.) Either way, this is a bold statement. The team found that severe COVID-19 disease was associated with specific genetic variants in six genes within a 50K base chromosome 3 region that was directly derived from Neanderthal inheritance. Similar studies also identified a protective Neanderthal haplotype on chromosome (chr) 12 that reduces the risk of severe COVID-9 and a protective region on chromosome 9 that is associated with ABO blood groups.

Dissatisfied with resting on their laurels, Pääbo and Zeberg had just started things up. The couple recently reported on bioRxiv pretprint server that another exclusively Neanderthal variant, this time in the promoter region of the DPP4 gene at chr2q24.2, really pulls the concept of sensitivity to COVID. DPP4 is a widely expressed extracellular dipeptidyl peptidase involved in immune function and glucose metabolism. As it happens, DPP4 is also a receptor gene for MERS coronavirus. We’re getting somewhere now.

Although other researchers have insisted that DPP4 is not a receptor for SARS-CoV-2, it can be difficult to ignore accidental discoveries like this when therapeutic options are desperately needed. DPP4 inhibitors already used clinically to treat diabetes appear to have effects on patients with COVID-19. Amid a flurry of ongoing SARS genetic research, we reported Monday that a handful of immune gene variants, including IFNAR2 and TYK2, also control COVID outcomes. Interestingly, this study also identified DDP9, a sister gene of DD4 residing on chr19p13.3, as a key mediator of inflammatory lung injury. DPP9 has similar serine protease activity to DPP4, but differs in that it is not membrane bound.

The DPP4 gene is not too far from the long-lost centromere of the residue located nearby in the region chr2q21.3 – q22.1. There is also an additional telomere residue sitting in the q13 band. What do these structures do? If one is pressed for the answer in one line to the question of what it is that makes us human, a great answer is the fusion of two small monkey chromosomes in order for man to create chr2. Do Neanderthals have fused chr2?

Of course they have. In fact, they appear to have the same version of the speech gene, FOXP2, which Pääbo put on the map in 2002. The human FOXP2, which differs in two key places from the chimpanzee version, was famously mutated in the “KE” family from Britain that had specific disturbances in the use of consonants. In recent COVID risk factor studies, Pääbo looked for single nucleotide polymorphisms using data from the 1000 Genome Project and then checked with the COVID-19 Host Genetics Initiative to see if Neanderthal haplotypes for DDP4 were associated with disease severity.

The problem with this type of work is that we don’t have enough sequence data to tell us what makes a Neanderthal a Neanderthal. Only a few good genomes from ~ 120,000-year-old and ~ 50,000-year-old bone remains are available. They come from Europe and southern Siberia. These kinds of statistical deficiencies make normal people suspicious when their 23AndMe scoreboard calls them 0.98 or 1.67 Neanderthals.

One thing that the COVID epidemic is now successfully driving home is that blind medicine no longer cuts it. Blind medicine refers to everything done in the absence of personal data about the patient’s sequence. Above we have taken some cheap images of paleogenetics and their historical attributes of haplotypes. This was for a good reason, and we have a few more shots. When genomic data are given with respect to a reference sequence, problems can often arise. This is because, simply put, there is no such thing as a reference sequence – and it is completely arbitrary. Occasionally updates and improvements are made to various reference sequences, but there will never be true reference sequences.

Unlike the MERS DPP4 receptor, no ACE2 receptor variant emerged as a locus of risk for severe COVID-19. However, many other genes associated with the process and life cycle of SARS-CoV-2 infection have come to light. For example, four variants (rs464397, rs469390, rs2070788, and rs383510) strongly influence the expression of serp protease TMPRSS2 in lung tissue. TMPRSS2 regulation variants are present at higher frequencies in European and American populations than in Asian populations.

Perhaps more directly troubling, now that vaccines are on display, is the question of who the vaccine could help, and in some cases, whom it could harm. The latter prospects are usually framed in terms of the now well-known phenomenon of antibody-dependent amplification (ADE). While for other diseases like dengue or respiratory syncytial virus, ADE is taken very seriously, these three bad words are usually quite discarded in discussions about COVID. However, recent research now suggests that ADE in COVID is quite a thing.

In particular, the researchers found that some monoclonal antibodies against spike in patients with COVID-19, especially those against the N-terminal domain (NTD) of spike, dramatically increased the binding capacity to ACE2, and thus increased the infectivity of SARS-CoV2. . Mutation analysis was used to determine a specific surface area of ​​NTD. All patients examined had antibodies against this site to increase infectivity. As information on spike sequence mutations and ADE risk factors is updated much faster than the time of vaccine development, it is important that the public receives information on the RNA vaccines currently offered. Namely, what exact sequences of classes are used to create a vaccine?

Recent reports of new proliferation of spike mutants have raised additional questions. How does a variant of the N501Y that avoids a vaccine in the domain of receptor binding or a variant of double NTD deletion change the game? Or how does the new D614G spike variant, which provides more efficient replication, affect transferability and pathogenicity? The answers arrive quickly and furiously, and they should be ignored at your own peril.

Study: Neanderthal genes are responsible for patients with COVID

More information:
Hugo Zeberg et al. The MERS-CoV receptor gene is among the risk factors for COVID-19 inherited from Neanderthals, bioRxiv (2020). DOI: 10.1101 / 2020.12.11.422139

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Citation: Could COVID-19 wipe out Neanderthals? (2020, December 24) retrieved December 24, 2020 from

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