An old enemy left his scars in your genetic code

Sorry, I’m a nerd and I don’t think any amount of psychedelics is still going to change that. So today, I once again wish to explain something important to you: You’re the descendant of those primates that survived historical outbreaks of coronaviruses that decimated our ancestors. The fingerprints of these previous outbreaks can be found in our primate genomes, whether you like it or not (and no, I know you don’t like it).

I’ve probably explained this a few times by now, but coronaviruses have caused large death tolls among human beings before. We know this, because we can see the genetic evidence of natural selection among East Asian populations today. People would have had to be getting killed, handicapped or sterilized by these viruses for generations, to explain the kind of impact we see on their genome.

But it’s always worse than you think. Take a look at this:

We performed high-throughput evolutionary and positive selection screens of 334 SARS-CoV-2 interacting proteins (4) using the Detection of Genetic INNovation (DGINN) pipeline (21), followed by comprehensive (phylo)genetic analyses of seven VIPs of interest. We provide the results in the searchable VirHostNet 2.0 web portal. Using this approach, we identified 38 bat and 81 primate genes with strong evidence of positive selection. Of these, we found 17 proteins, including the ACE2 receptor, subjected to adaptative evolution in both clades, 1) confirming that past SARS-CoV epidemics occurred during both bat and primate evolution, and 2) identifying core VIPs that shaped universal SARS-CoV–host molecular arms races. We also identified 84 VIPs with lineage-specific adaptations that likely contributed to SARS CoV pathogenicity in different mammalian hosts. Among these, we uncover the important role of several genes, including TMPRSS2, FYCO1 (FYVE and coiled-coil domain containing 1), or RIPK1 that play important roles in entry, trafficking, or inflammatory responses, respectively. We hypothesize that these past adaptation events in bats and primates underlie differences in susceptibility to SARS-CoV-2 infections and key determinants in COVID-19 severity in modern humans.

I go where the evidence leads me. But bear with me, as we look further at what the study says:

To identify the precise residues that have diversified during primate evolution, we performed site-specific positive selection analyses. We identified five residues (173, 260, 263, 360, and 448, numbering from the human TMPRSS2 sequence) that were significantly detected under positive selection by at least two independent methods (Table 1SI Appendix, Table S3, and Fig. 3B). Of note, position 197, which is polymorphic in human TMPRSS2 (rs12329760, V197M) and may be associated with COVID-19 severity (41) (P value around 10−5, above the 10−8 significance threshold commonly used in GWAS multiple testing), encoded for a conserved valine in all nonhuman primate sequences. The SARS-CoV-2–TMPRSS2 interface is currently unknown. Only in silico molecular docking studies have predicted the SARS-CoV-2 binding region on TMPRSS2 (374244). Remarkably, the sites under positive selection cluster nearby or within the predicted SARS-CoV-2-host interface (Fig. 3C), suggesting that SARS-CoVs played a significant role in TMPRSS2 diversification. 

TMPRSS2 is very important for SARS-COV-2 to enter our cells, it’s the most relevant protein we produce after ACE2. Here you can see that this protein has been placed under selective pressure by something, IN HUMANS, BUT NOT IN NON-HUMAN PRIMATES! So, something has taken place after the separation between humans and chimpanzees, that caused our TMPRSS2 gene to start changing. And we already have evidence that the position where this gene in changing in our species, is associated with COVID-19 severity.

Other positions in TMPRSS2 also show positive selection in humans, gorillas, chimpanzees and orangutans:

Finally, by analyzing the physicochemical nature of the positively selected sites, we found that they encode for residues with very different properties, which would significantly impact the TMPRSS2 protein structure over primate evolution and lead to species specificity at the virus–host interface. In particular, variation at key residues 260 and 448 was particularly high in Hominoids but low in Old World monkeys (Fig. 3D), suggesting lineage-specific adaptations within primates. To determine whether this domain of TMPRSS2 has been rapidly evolving in other mammals, we extended our analyses by retrieving other mammalian sequences. We found that most of these sites were overall conserved, except in rodents that exhibited high variability at positions 263, 360 and 448 (Fig. 3E).

And finally, here’s the conclusion they wrote:

This study over millions of years of evolution (at the interspecies level) shows evidence of very ancient epidemics of SARS-CoVs that have shaped both primate and bat genomes. Marks of adaptation in SARS-CoV-2 VIPs at the human population level further identified evidence of past SARS-CoV epidemics in more recent human history (20). 

So remember, this mess has been going on for a very long time, because you see evidence of genetic selection by coronaviruses in different periods of evolution:

  1. Before the chimpanzee-human split.
  2. In all humans, so after the chimpanzee-human split.
  3. In just East-Asians, so a few thousand years ago.

What this means is that we have constantly been suffering through very deadly coronavirus pandemics, throughout human evolution. These viruses would have been killing, disabling and/or sterilizing numerous people, even though 99% of humans born back then would have died before reaching what we now consider to be old age.

If you look around, you’ll notice the people who died from SARS-COV-2 are mostly elderly people and people who suffer from various pre-existing conditions. So how do we reconcile this, with these coronaviruses decimating the human population in the past? There are different explanations to consider:

-We lucked out with SARS-COV-2, which happened to be a rare nothingburger variant.

-SARS-COV-2 has just shown a fraction of its evolutionary potential.

-SARS-COV-2 is causing silent damage to our bodies, that ends up decimating us in the future.

And if you have been reading my articles for a while now, you’ll realize that I’m leaning towards the latter two explanations. Evidence for that is not hard to find:

-Increased risk of dementia after infection.

-Decline in T-cell function after infection.

-All sorts of other pathogens are now jumping into our species (see: Monkeypox).

-Gradual increase in ACE2 affinity in newer variants.

And so now we live another episode where a “bomb burst”. For our ancestors, encounters with bats in caves would have been the most likely cause of these outbreaks, either direct contact, or contact with an animal that entered these caves where the bats live.

The bats live in huge groups together in caves and depend on them for survival. Many different animals would love to have control over these caves, they are rare highly desirable places to live. The bats have no real way to defend themselves, they are small fragile creatures. And so rather than defending themselves directly with their teeth or claws, as the other animals tend to do, the bats ended up defending themselves in a different way: Their immune systems tolerate a bunch of viruses that will kill animals that enter into contact with them and would steal their caves.

One of these bat viruses seems to have had a helping hand from human beings and ended up jumping into our species as a result. It’s now bouncing back and forth, between humans and non-human species. Whenever it seems to get stuck in an evolutionary dead end in humans, the humans tend to breathe a sigh of relief, only for a variant to jump back from non-human animals into humans, that is nowhere close to reaching an evolutionary dead-end.

In previous eras, outbreaks like this would come to an end because the world was a bigger place: There were just a few million humans and they lived very isolated from each other, so something that happened in one part of the world would never end up affecting human populations in other parts of the world.

Today that’s no longer the case. We’re all getting multiple waves of this virus. China seems to be the only exception so far where most people haven’t been infected yet, but this will not last. It’s easy to see why:

They could keep the first variants under control, but the measures they used won’t work with the newer variants. They have no real solution how to deal with people who are chronically infected. Because BA.2.75 evolved in a chronically infected person, it will be relatively good at causing chronic infections. Unless they want to lock up infected people forever, they have no solution.

2 Comments

  1. We live in a time where it is very hard to get people to understand basic concepts. Like the idea that vaccination works best for diseases that don’t mutate very much over a human lifetime. But for a rapidly mutating and diversifying disease…not an effective tool, although it may show promise for the first year or two.
    But people want to believe in a simple fix or a magic potion.
    “Safe and effective, safe and effective, safe and effective”.
    Just say it three times and click your heels and think of home.

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