About that Unnatural Evolution of Omicron Again

The scientists say it couldn't have happened naturally. And not just Omicron?

“Unnaturalness in the evolution process of the SARS-CoV-2 variants and the possibility of deliberate natural selection” (preprint, 2023.08.05):

The artificial generation of mutant viruses in the laboratory and the study of viral phenotypes by introducing mutations is called "reverse genetics" and is a common technique in virology.

Despite the accumulation of many mutations in the S protein of Omicron mutants, most of the mutations are non-synonymous, with only one synonymous mutation of c25000u, which is highly unnatural, leading to the hypothesis that the Omicron mutants are artificially synthesized.

The following results presented in this study may support the hypothesis that the Omicron variants may have been artificially synthesized rather than naturally occurring:

1. The presence of Omicron variant-associated isolates with one mutation site being Wuhan type [AO: which makes it impossible to trace the continuous evolution of the Omicron variant];

2. The almost complete absence of synonymous mutations in the S protein in these isolates [AO: which indicates that Omicron wasn’t a result of natural process of accumulation of random mutations, in which case a large number of synonymous mutations would be expected];

3. The Omicron variant, which should have been first reported to WHO from South Africa on November 24, 2021, was already endemic in Puerto Rico in 2020, and that there were isolates that were recombinants between Omicron strains BA1 and BA2 [AO: which indicates that there was no time for Omicron to naturally mutate to such a degree].

In addition, the Omicron mutant-related isolates (BA.1-0.1, BA.1.1-0.1, and BA.2-0.1 isolates) with a Wuhan-type mutation at one of the mutation sites were established. Some had synonymous mutations after establishing the Omicron mutant-related isolates (Fig. 2 and Supplemental Figure 2 Synonymous Others).

It is reasonable to assume that viruses with the reversion amino acid mutations caused by non-synonymous mutations in the S protein were artificially synthesized and then acquired further synonymous mutations in the natural environment.

This preprint makes for a tough reading, probably because of being Google-translated from Japanese to English, so, I will also use this article from 2022 as an aid in deciphering the former: “Omicron: What Makes the Latest SARS-CoV-2 Variant of Concern So Concerning?” (Virology, 2022.03.23). It says that SARV-CoV-2 has a built-in protection against random translation mutations:

With about 30,000 nucleotides, coronaviruses, such as SARS-CoV-2, have the largest genome of all known RNA viruses. Despite the large size, the integrity of the genome is retained by the proofreading function of the viral polymerase. Specifically, the nonstructural protein 14 (Nsp14) and its cofactor Nsp10 exert exonuclease activity that substantially reduces the accumulation of mutations in the viral genome. The widespread view of SARS-CoV-2 as a highly variable pathogen is thus somewhat misleading. For example, the genomes of different subtypes of HIV-1 may differ by up to 15%, while the Omicron VOC differs in less than 0.2% of its nucleotides from the early pandemic Wuhan strain of SARS-CoV-2.

, and yet Omicron specifically has mutated in surprising (alarming) ways:

Our initial alignment of 77 Omicron full-genome sequences available at GISAID (www.gisaid.org) by early December revealed that this VOC differs by about 55 mutations (range 48 to 92; mean 54.6 ± 5.2 sequences) from the initial Wuhan Hu-1 strain of SARS-CoV-2. This number is not that much higher than that found for the dominating Delta VOC, ranging from about 21 to 44 substitutions (34.4 ± 2.6; n = 475). What is alarming is the distribution of mutations, with about 30 of them being located in the viral Spike gene that is critical for virus infection and the key target of protective immune responses. In addition, most nucleotide changes distinguishing the Omicron VOC from the early Wuhan Hu-1 strain are nonsynonymous, i.e., associated with amino acid changes, suggesting high positive selection pressure for change.

What’s more, there is no evolution path from other/previous strains to Omicron, so no step-wise evolution. Boom! Here comes Omicron?

Phylogenetic analysis shows that the Omicron VOC clearly did not emerge from other VOCs, including the Delta VOC (Fig. 1B). This is unexpected, as it would seem plausible that zoonotic pathogens, such as SARS-CoV-2, adapt to the new human host in a stepwise process, i.e., they initially acquire key mutations promoting viral replication and spread and subsequently changes associated with more subtle advantages.

Yet, it seems unlikely that Omicron developed in an animal reservoir and then jumped back to humans:

…some researchers raised the possibility that the Omicron may have evolved in a nonhuman species from which it spilled back to humans (41). Coronaviruses are notorious for their ability to cross species barriers, and recent findings suggest that SARS-CoV-2 can be detected, e.g., in household pets and farm and captive animals as well as wildlife (42). It has been suggested that SARS-CoV-2 VOCs show an expanded host range and thus possess an increased capacity to generate new animal reservoirs (43, 44). However, the fact that a significant portion of changes in the Omicron genome is identical to human-specific adaptations found in other VOCs and the preliminary evidence for high replication and transmission fitness suggest emergence in humans.

Whadda?! The article further suggests that increased mutation of Omicron might have been stimulated with ABOBEC-1 protein:

As mentioned above, the proofreading activity of the Nsp14 exoribonuclease of SARS-CoV-2 usually repairs errors during replication. However, several antiviral restriction factors are known to target and introduce mutations in viral RNAs. For example, APOBEC proteins deaminate cytosine to uracil, resulting in C-to-U or G-to-A changes depending on whether the plus or minus strand of the viral RNA is targeted (45). Notably, about 30% of all nucleotide substitutions in the Delta and Omicron VOC compared to an early pandemic reference strain are C to U (Fig. 1C). This rate is about 5-fold higher than expected from random changes. G-to-A changes are also very common and occur at a 2-fold-increased frequency (Fig. 1C). It has been previously suggested that APOBEC-induced mutations contribute to SARS-CoV-2 evolution.

So the scoop is, Omicron appeared out of the blue with a large number of non-synonymous, and just ONE [sic!] synonymous, mutations. As the preprint says:

The analysis we have shown here is that the Omicron variants are formed by an entirely new mechanism that cannot be explained by previous biology, and knowing the way how the SARS-CoV-2 variants were formed prompts a reconsideration of the SARS-CoV-2 pandemic.

, then Omicron diverged into different sub-strains that acquired more synonymous mutations in the process of natural mutations:

It is reasonable to assume that viruses with the reversion amino acid mutations caused by non-synonymous mutations in the S protein were artificially synthesized and then acquired further synonymous mutations in the natural environment.

To boot, this also raises a real possibility that other variants, such as Alpha and Delta, were also lab-engineered:

Suppose the SARS-CoV-2 Omicron variant and its one amino acid reversion mutants were artificially and systematically generated. In that case, we should suspect that the other variants (Alpha to Delta) may also be artificially generated viruses. Indeed, the lack of findings to date that many of the various mutations seen, especially in the early variants, are indeed associated with increased viral infection supports the hypothesis that each variant was artificially synthesized to identify the amino acids of the S protein responsible for infectivity and pathogenicity. The possibility that the set of mutants was artificially generated to identify amino acids of the S protein involved in the infectivity and virulence is supported.

So, there you have it — SARS-CoV-2 wasn’t a one off release of a biological weapon. Rather, it’s an [ongoing?] series of releases of such related biological agents (the Covid variants).

“And now we sit because we know…”, as Raymond from “Everybody Loves Raymond” famously pronounced?