BREAKING! COVID-19 Genomics: SARS-CoV-2 Evolves By Decreasing CpG Dinucleotide At 5’UTR_c-241-t Mutation Site To Avoid Human Zinc Finger Antiviral Protein
: A new genomic and molecular biology study by American and Chinese researchers from the Chinese Academy of Sciences-Shanghai, Harvard Medical School, University Of Michigan, Fudan University –Shanghai and various genomic labs in China has revealed that the SARS-CoV-2 coronavirus is mutating and evolving constantly to evade the human immunity responses.
The study results which has just been released on a preprint server and is being peer-reviewed has many implications in terms of all the efforts so far in vaccine developments, antibody treatments and even in drug-repurposing studies to find suitable antivirals. https://www.biorxiv.org/content/10.1101/2020.07.21.213405v1
The researchers did a detailed analysis of 6698 SARS-CoV-2 whole genome sequences with specific sample collection dates in NCBI database,ranging from Dec. 20, 2019 to Jun. 8, 2020. By extensive sequence analysis, they identified the significant and convergent features of the accumulated viral mutations and CpG variations over time.
Of these mutations, it was found on specifically, in the 29903nt viral genome, four significant mutations, i.e., 5'UTR_c-241-t, NSP3_c-3037-t, NSP12_ c-14408-t, and S_ a-23403-g, that had become the dominant variants since early March, 2020.
The S_ 92 a-23403-g mutation resulted in the amino acid change (D614G) that enhances viral infectivity.
In particular, each of these 4 mutations covered almost 100% of all virus sequences since the middle May 2020.
Focusing on eight mutation sites (5'UTR_c-241-t, NSP3_c-3037-t, 95 NSP12_ c-14408-t, S_a-23403-g, ORF3a_g-25563-t, N_ g-28881-a, N_ g-28882-a, and N_g-28883-c), all the sites sites began to have very high mutation rates since May 2020. Notably, mutations in three adjacent sites in N (N_g-28881-a, N_g-28882-a, and N_g-28883-c) 98 co-occurred, suggesting a strong selection pressure.
Notably, the researchers found that co-occurrence rates of three significant multi-site co-mutational patterns, i.e., (i) S_a-23403-g, NSP12_c-14408-t, 5'UTR_c-241-t, NSP3_c-3037-t, and ORF3a_c-25563-t; (ii) ORF8_t-28144-c, NSP4_c-8782-t, NSP14_c-18060-t, NSP13_a-17858-g, and NSP13_c-17747-t; and (iii) N_g-28881-a, N_g-28882-a, and N_g-28883-c, reached 66%, 90%, and nearly 100% of recent sequences, respectively.
Significantly, the CpG content of viral genome is restricted by human host intrinsic zinc finger antiviral protein that interacts with CpG rich-region and mediates depletion of foreign viral RNAs.
Comparing with other coronaviruses, SARS-CoV-2 genome exhibits extreme CpG deficiency. However, the evolutional trajectory of SARS-CoV-2 CpG-content within the same species is still unclear.
The researchers investigated the CpG-content changes in SARS-CoV-2 since the outbreak. The CpG dinucleotide content exhibited a decreased trend over time. The CpG-content in each SARS-CoV-2 genome regions varied, with high CpG-contents the 5'UTR, NSP1, E and ORF10 169 regions and low CpG-contents in NSP8, ORF6 regions.
gt;Notably, the NSP7 region was free of CpG dinucleotide. Comparing with the first posted SARS-CoV-2 genome (NC_045512), in the very recent SARS-CoV-2 genomes, only the CpG-contents of 5'UTR decreased significantly but not the other CpG high content regions NSP1, E and ORF10, suggesting a biased evolution pressure on this region.
The study shows that The SARS-CoV-2 coronavirus is constantly mutating and evolving at a rather rapid phase contrary to what was being perceived and that it is constantly finding ways to evade any kind of human host immunity responses and making itself more potent in terms of various characteristics to ensure its survival.
The significant decrease of CpG dinucleotide at positions 241(c)-242(g) in the 5’UTR during the evolution, which was verified as a potential target of human zinc finger 43 antiviral protein (ZAP) is a strong example of this one of the many mutations and evolutionary pathways it is taking to ensure its survival by evading the human host immunity responses.
Thailand Medical News would also like to point out a possible hypothetical scenario: With the phase at which the SARS-CoV-2 is mutating and evolving, human attempts of trying to eradicate it via antibody therapies, vaccines and also antivirals could in fact possibly backfire and force it to even use its inbuilt adaptive evolutionary mechanisms to create newer strains that are far more resistant and potent. Timing and speed at which treatment or preventive protocols are administered to the masses are going to be critical to prevent such a scenario.
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