Could COVID-19 Have Wiped Out the Neanderthals?

Everyone loves Neanderthals, those brutal beasts we’ve supposedly outcompeted and eventually replaced with our sharp tongues and swift, delicate minds. But did we really do that? Is it mathematically possible that we could still be them, and they us?

Likewise, the impossibly unique mitochondrial Eve, her modern-day Y chromosome Adam, and even the ‘Out of Africa’ hypothesis could not simply be handy fictions that paleogenists tell each other at conferences to give their largely arbitrary haplotype designations and then inferred evolutionarily. trees more credibility?

Perhaps one of the best ways to answer this question is to ask what the coronavirus has to say on the matter. Svante Pääbo, director of the genetics department at the Max Planck Institute certainly believes that Homo sapiens Neanderthalensis, or simply Homo Neanderthalensis, if you prefer, is extinct. Pääbo, the son of Nobel Prize winner Sune Bergström from 1982, has made a living from Neanderthals’ bones and found gene after gene that is clearly “Neanderthal.” In 1997, Pääbo successfully sequenced mitochondrial DNA from a specimen found in the Feldhofer Cave in the Neander Valley. Fast-forwarding past a few recent PR disasters, the Germans were able to capture the prolific Swede and give him the task of dealing with these uncomfortable heirloom skeletons that kept popping up.

In September Pääbo and colleague Hugo Zeberg announced this the main genetic risk factor for severe COVID-19 is inherited from Neanderthals. (We note that Nature publications prefer to include the h.) This is a bold statement anyway. The team found that severe COVID-19 disease is associated with specific genetic variants in six genes within a 50K base pair-long region of chromosome 3 derived directly from a Neanderthal heritage. Similar studies have 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 the ABO blood groups.

Not content to rest on their laurels, Pääbo and Zeberg have taken things up a notch. The pair recently reported on the bioRxiv preprint server that has another exclusive Neanderthal variant, this time in the promoter region of the DPP4 gene on chr2q24.2, really pulling the strings in COVID sensitivity. DPP4 is a widely expressed extracellular dipeptidyl peptidase involved in immune function and glucose metabolism. DPP4 is also the receptor gene for the MERS coronavirus. Now we’re getting somewhere.

While other researchers have maintained that DPP4 is not a SARS-CoV-2 receptor, it can be difficult to ignore casual findings such as these when therapeutic options are desperately needed. Inhibitors of DPP4 already used clinically to treat diabetes appear to have effects on COVID-19 patients. Amid the flurry of ongoing genetic research on SARS, we reported on Monday that a handful of immune-related gene variants, including IFNAR2 and TYK2, also control COVID results. Curiously, this study also identified DDP9, a sister gene of DD4 located at chr19p13.3, as an important mediator of inflammatory lung damage. DPP9 has a similar serine protease activity to DPP4, but differs in that it is not membrane bound.

The DPP4 gene is not far from a long-defunct centromere found nearby in the chr2q21.3-q22.1 region. There is also an extra rudimentary telomere that is in the q13 band. What are these structures doing here? If the question of what makes us human requires an unambiguous answer, an excellent answer is the fusion of two small monkey chromosomes to make the human chr2. Do Neanderthals have a fused chr2?

Of course it is. In fact, they seem to have the same version of the speech gene, FOXP2, that put Pääbo on the map in 2002. The human FOXP2, which differs from the chimpanzee in two important places, was famously mutated in the ‘KE’ family of Great Britain, all of which had specific disabilities in the use of consonants. In the more recent COVID risk factor studies, Pääbo searched for single nucleotide polymorphisms using data from the 1000 Genomes Project, and then checked with the COVID-19 Host Genetics Initiative whether Neanderthal haplotypes for DDP4 associated with disease severity.

The problem with this work is that we don’t have that much sequence data to tell us what makes a Neandertal a Neandertal. Only a few good genomes are available from skeletal remains of ~ 120,000 years old and ~ 50,000 years old. These come from Europe and South Siberia. These kinds of statistical flaws make normal people suspicious when their 23AndMe scorecard lists them as 0.98 or 1.67 Neanderthals.

One point that the COVID epidemic is now successfully driving home is that blind medicine is no longer cutting it. Blind medicine refers to anything done without the patient’s personal sequence information. Above, we’ve taken a few inexpensive shots on paleogenetics and their historical haplotype attributions. This was not for nothing, and we still have to take a few more pictures. When genomics data is given with respect to a reference sequence, problems can often arise. This is simply because there is no such thing as a reference sequence – it is also completely random. Updates and improvements are made to various reference sequences from time to time, but a true reference sequence will never be achieved.

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

Perhaps of more immediate concern, as the vaccines hit the market, the question is who could help the vaccine, and in some cases, who could harm it. The latter prospect is usually framed in terms of the now known phenomenon of antibody dependent enhancement (ADE). While ADE for other illnesses like Dengue or Respiratory Syncytial Virus is taken very seriously, these three bad words are usually dismissed quite conveniently in discussions of COVID. However, recent research now suggests that ADE in COVID is very much a thing.

In particular, researchers have found that some anti-spike monoclonal antibodies from COVID-19 patients, particularly those against the N-terminal domain (NTD) of the spike, drastically increased binding capacity to ACE2 and thereby SARS-CoV2 infectivity. increased. Mutation analysis was used to locate a specific surface area of ​​the NTD. All patients studied had antibodies against this infectivity-enhancing site. Because information on peak sequence mutations and ADE risk factors is updated much faster than vaccine development times, it is important for the public to get information about the RNA vaccines currently on offer. Namely, what exact spike sequences are used to generate the vaccine?

Recent reports of new proliferations of spike mutants have raised new questions. How do the potentially vaccine-evading N501Y variant in the receptor binding domain or the NTD double-deletion variants change the game? Or how does the new D614G spike variant that enables more efficient replication affect transmissibility and pathogenicity? Answers come in fast and furiously, and they should be ignored at your own risk.

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