Response on the Origin of SARS-CoV-2
Those who know of the longtime proximity and collaboration between Bob Garry and myself will not find it surprising that I concur with the above post. Indeed, I publicly endorsed the “natural origin” hypothesis for SARS-CoV-2 at midnight Feb 6, 2020, two weeks before the Andersen et al. analysis appeared.
The reader will be surprised that, given the long collaborative history of Bob and myself, I will now publicly correct him.
Just prior to the Discussion in the foregoing post, Garry states that : “The Guangdong (GD) strain of pangolin coronavirus carries a receptor binding domain (RBD) that is highly similar to the RBD of SARS-CoV-2 .“ He cites references that deal only with the amino acid sequences of the pangolin and SARS-CoV-2 isolates. At the amino acid level, this statement is true.
However, as Boni et al (1) alluded to in passing, and I detailed later (2), this is far from true at the RNA level. Over a relevant span of 268 nucleotides, the GD pangolin and SARS-CoV-2 RNA sequences differ by 10.4%, virtually all of that difference in an accumulation of synonymous wobble-base substitutions. This degree of difference indicates several decades of evolution, and is completely incompatible with the sequence found in pangolins being the proximal source of the sequence found in the RBD of SARS-CoV-2.
SARS-CoV-2 is a mosaic derived from distinct bat coronavirus lineages. The proximal sources of these mosaic segments are far from identical to any known viral isolates, but rather to inferred second or third cousin divergent RNA sequences with common ancestors dating back decades.
In addition to the RBD just discussed, I also detailed (3) the dissimilar region in orf1A that follows the acidic region of nsp3. From nt 3059 to nt3335, the RNA sequences of SARS-CoV-2 and BatRaTG13 differ by 9.3% and the corresponding amino acid sequence by 18.1%. The sequence in SARS-CoV-2 bears no significant resemblance to any known sampled source.
One can create suspicion by talking about amino acids, but the proof must account for the divergence of RNA that takes a very long time. After sixteen months of evolution in humans, isolates from April 2021 differ by about 0.1% from the December 2019 Hu-1 reference strain, roughly 30 out of 30,000 nucleotides.
My second correction relates to the ongoing speculation about animal intermediates. There are zero data that any animal but a bat served as a host to SARS-CoV-2 prior to its introduction into humans. The 2012 Tongguan mine outbreak in six miners in Yunnan province, of a COVID like pneumonia with thromboembolism, that killed three of the miners, is ample precedent for direct infection of humans from bats (3). The closest known relative to SARS-CoV-2, Bat RaTG13, was isolated from that same mineshaft the following year. That mine is now closed, and referred to by locals as the “mine of death”. That sounds like a “hot zone” to me.
My final correction to my good friend concerns hypothesis vs. theory. In common parlance the “hypothetical” and “theoretical” tend to be used interchangeably. However, in science there is a very clear distinction. A “Theory” arises to that status only when there is a substantial body of evidence that supports what was previously regarded as a hypothesis. As in, Theory of Evolution, Germ Theory of Disease, or Tectonic Plate Theory. Even the Fusion Peptide is still only a hypothesis. So, we should not be throwing around the designation of Theory for hypotheses with zero to little supportive factual information to support them.
The bedrock of science must continue to be data and the RNA code.
William R. Gallaher, Ph.D.
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Boni MF, Lemey P, Jiang X, Lam TT, Perry BW, Castoe TA, Rambaut A, Robertson DL. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. Nat Microbiol. 2020 Nov;5(11):1408-1417. doi: 10.1038/s41564-020-0771-4. Epub 2020 Jul 28. PMID: 32724171.
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Gallaher WR. A palindromic RNA sequence as a common breakpoint contributor to copy-choice recombination in SARS-COV-2. Arch Virol. 2020 Oct;165(10):2341-2348. doi: 10.1007/s00705-020-04750-z. Epub 2020 Jul 31. PMID: 32737584; PMCID: PMC7394270.
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Rahalkar MC, Bahulikar RA. Lethal Pneumonia Cases in Mojiang Miners (2012) and the Mineshaft Could Provide Important Clues to the Origin of SARS-CoV-2. Front Public Health. 2020 Oct 20;8:581569. doi: 10.3389/fpubh.2020.581569. PMID: 33194988; PMCID: PMC7606707.