BREAKING! China’s Scientists Say Omicron Most Probably Originated From A Mouse And Not From A Human Host!

Omicron Research: Chinese researchers from the State Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology-Chinese Academy of Sciences-Beijing and the University of Chinese Academy of Sciences, Beijing have in new published study claim that the Omicron variant most probably originated form a mouse and not from a human host!

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The study team from China states that the rapid accumulation of mutations in the SARS-CoV-2 Omicron variant that enabled its outbreak raises questions as to whether its proximal origin occurred in humans or another mammalian host.
 
The study team identified 45 point mutations that Omicron acquired since divergence from the B.1.1 lineage.
 
The team found that the Omicron spike protein sequence was subjected to stronger positive selection than that of any reported SARS-CoV-2 variants known to evolve persistently in human hosts, suggesting the possibility of host-jumping. The molecular spectrum (i.e., the relative frequency of the twelve types of base substitutions) of mutations acquired by the progenitor of Omicron was significantly different from the spectrum for viruses that evolved in human patients, but was highly consistent with spectra associated with evolution in a mouse cellular environment.
 
Importantly, mutations in the Omicron spike protein significantly overlapped with SARS-CoV-2 mutations known to promote adaptation to mouse hosts, particularly through enhanced spike protein binding affinity for the mouse cell entry receptor.
 
The study findings collectively suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.12.14.472632v1
 
The study team used the molecular spectrum of mutations of the SARS-CoV-2 Omicron variant to trace its proximal host origins.

The Omicron Research team found that the molecular spectrum of pre outbreak Omicron mutations was inconsistent with the rapid accumulation of mutations in humans, but rather suggested a trajectory in which the progenitor of Omicron experienced a reverse zoonotic event from humans to mice sometime during the pandemic (most likely in mid-2020) and accumulated mutations in a rodent host (most likely mouse) for more than one year before jumping back to humans in late-2021.
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The study team says that while evolving in mice, the progenitor of Omicron adapted to the mouse host by acquiring amino acid mutations in the spike protein that increased its binding affinity with mouse ACE2.
 
In addition, mutations associated with immune escape also accumulated, which may also be a contributing factor in its rapid spread.
 
Although the study team showed a phylogenetically long branch leading to the MRCA of current Omicron variants (i.e., Branch O), it is worth noting that intermediate versions of Omicron were occasionally reported.
 
For instance, a SARS-CoV-2 variant (EPI_ISL_7136300) was collected by the Utah Public Health Laboratory on December 1st, 2021 which harbored 32 of the 45 pre-outbreak Omicron mutations.
 
Interestingly however, the 13 mutations absent in this variant clustered within residues 371–501 of the spike protein. The absence of these spike protein mutations thus suggested that this variant was a product of recombination between an Omicron variant and another SARS-CoV-2 variant, rather than a direct progenitor of Omicron.
 
Considering the large number of pre-outbreak Omicron mutations (45) combined with the sparsity of intermediate versions identified to date, this long branch leading to Omicron in the phylogenetic reconstruction remains valid.
 
Although the study team primarily focused on point mutations because the molecular spectrum of these mutations can reflect the host cellular environment,
https://www.biorxiv.org/content/10.1101/2021.07.05.451089v1
 
https://pubmed.ncbi.nlm.nih.gov/34485968 they also used the information of deletions and insertions to infer the evolutionary trajectory of Omicron.
 
For example, a B.1.1 variant (EPI_ISL_493480) shared the same deletion (Δ105–107 in non-structural protein 6) as the Omicron variants, which was used to infer that B.1.1 is a close relative of Omicron.
 
In addition, spike Δ69–70 deletion is shared by Omicron and many non-Omicron variants isolated from patients https://www.sciencedirect.com/science/article/pii/S221112472100663X but is absent in the early samples of SARS-CoV-2,
https://pubmed.ncbi.nlm.nih.gov/32015508/ strongly suggesting that the progenitor of Omicron was jumped from humans to mice during the pandemic.
 
In addition, the study findings noted that Omicron harbored a nine nucleotide insertion (GAGCCAGAA, encoding the peptide EPE) after residue 214 in the spike protein. This insertion is identical to the sequence of TMEM245 in the human genome or that of ORF S in the human coronavirus hCoV-229E, which was used as evidence to support a human origin for Omicron. https://osf.io/f7txy/
 
However, the study team provided a simpler explanation for this insertion, namely that it was derived from an RNA fragment of ORF N in the SARS-CoV-2 genome.
 
The study team believes that the insertion of an ORF N fragment is more likely because the RNA abundance of ORF N is much higher than that of mRNA encoded by the human genome. https://pubmed.ncbi.nlm.nih.gov/33713114/
 
That is, in SARS-CoV-2-infected cells, a substantial proportion of RNAs are viral, and especially so for ORF N due to the nested nature of the coronavirus genome and subgenomes.
https://pubmed.ncbi.nlm.nih.gov/32330414/

It also warrants mention that all of the mouse-adapted SARS-CoV-2 variants were amplified/purified in Vero cells (a cell line originally isolated from the kidney of green monkey) at some stage of experimentation, which could impose an additional selection pressure to enhance the spike protein binding affinity towards primate ACE2. https://pubmed.ncbi.nlm.nih.gov/33031744/
 
https://pubmed.ncbi.nlm.nih.gov/32796842/
 
https://pubmed.ncbi.nlm.nih.gov/33993052/
 
https://www.biorxiv.org/content/10.1101/2021.07.10.451880v1.full
 
https://www.nature.com/articles/s41467-021-25903-x
 
https://pubmed.ncbi.nlm.nih.gov/33907749/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139693/
 
Consistent with this experimental process, the amino acid mutations acquired by Omicron and mouse-adapted viruses were not always identical, even if mutations occurred at the same residue. For example, Q493H and Q493K were also detected in the mouse-adapted SARS-CoV-2 at residue 493 of the spike protein, in addition to mutations observed in Omicron (Q493R). Different from the effects of Q493R, these two mutations increased the binding affinity toward both mouse and human ACE2, indicating that SARS-CoV-2 could potentially evolve remarkably high diversity in its adaptation to ACE2 from various host species.
 
Consistent with this possibility, numerous mutations were also identified in the spike protein of SARS-CoV-2 RNA fragment amplified from wastewater samples. 
https://www.medrxiv.org/content/10.1101/2021.07.26.21261142v1
 
Humans represent the largest known reservoir of SARS-CoV-2 but the study findings suggest that SARS-CoV-2 could have spilled over from humans to wild animals, and that the variants which successfully infected animal hosts could then accumulate new mutations before jumping back into humans as a variant of concern.
 
The study team concluded, “Considering the ability of SARS-CoV-2 to jump across various species, it appears likely that global populations will face additional animal-derived variants until the pandemic is well under control. Viral surveillance and sequencing in wild animals will likely help to prevent future outbreaks of dangerous SARS-CoV-2 variants.”

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