Extreme Genomic CpG Deficiency in SARS-CoV-2 and Evasion of Host Antiviral Defense
Open accessAbstract
Wild mammalian species, including bats, constitute the natural reservoir of betacoronavirus (including SARS, MERS, and the deadly SARS-CoV-2). Different hosts or host tissues provide different cellular environments, especially different antiviral and RNA modification activities that can alter RNA modification signatures observed in the viral RNA genome. The zinc finger antiviral protein (ZAP) binds specifically to CpG dinucleotides and recruits other proteins to degrade a variety of viral RNA genomes. Many mammalian RNA viruses have evolved CpG deficiency. Increasing CpG dinucleotides in these low-CpG viral genomes in the presence of ZAP consistently leads to decreased viral replication and virulence. Because ZAP exhibits tissue-specific expression, viruses infecting different tissues are expected to have different CpG signatures, suggesting a means to identify viral tissue-switching events. The author shows that SARS-CoV-2 has the most extreme CpG deficiency in all known betacoronavirus genomes. This suggests that SARS-CoV-2 may have evolved in a new host (or new host tissue) with high ZAP expression. A survey of CpG deficiency in viral genomes identified a virulent canine coronavirus (alphacoronavirus) as possessing the most extreme CpG deficiency, comparable with that observed in SARS-CoV-2. This suggests that the canine tissue infected by the canine coronavirus may provide a cellular environment strongly selecting against CpG. Thus, viral surveys focused on decreasing CpG in viral RNA genomes may provide important clues about the selective environments and viral defenses in the original hosts.
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Host zinc finger antiviral proteins (ZAP, gene name ZC3HAV1) target CpG dinucleotides in viral RNA and recruit cellular RNA degradation complexes to degrade the viral RNA genome.
“This avoidance of CGN codons makes evolutionary sense given that the host zinc finger antiviral proteins (ZAP, gene name ZC3HAV1) target CpG dinucleotides in viral RNA and recruit cellular RNA degradation complexes to degrade the viral RNA genome [27,28,29].”
From Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines (2021) · cites this paper as [28]
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- Authors
- Xia, X.
- Affiliations
- University of Ottawa (CA)
- Corresponding author
- Xia, Xuhua
- ORCID
- Xia, Xuhua
- Venue
- Molecular Biology and Evolution
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-04-14
- Volume
- 37
- Issue
- 9
- Pages
- 2699-2705
- ISSN
- 0737-4038 (ISSN-L)
- 1537-1719
- PMC
- PMC7184484
- OpenAlex
- W3015361654
- Cited by
- 160
- References
- 3
- Citations by year
- 2026: 7 · 2025: 1 · 2024: 8 · 2023: 15 · 2022: 21 · 2021: 50 · 2020: 58
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Biology and Evolution (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- uO Research (University of Ottawa) (submittedVersion, public-domain)
- University of Ottawa - Library
- Funders
- Natural Science and Engineering Research Council (No. RGPIN/2018-03878, No. ACCN KC175339)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- SARS-CoV-2, zinc-finger antiviral protein, Betacoronavirus, viral RNA modification, canine coronavirus, alphacoronavirus, viral evolution, host switching, viral virulence
- MeSH terms
- Alphacoronavirus, Betacoronavirus, COVID-19, SARS-CoV-2, Animals, Camelus, Chiroptera, Dogs, Biological Evolution, Hedgehogs, Humans, Pneumonia, Viral, Protein Binding, Rabbits, RNA, Viral, Virus Replication, RNA-Binding Proteins, Genome, Viral, Reassortant Viruses, Coronavirus Infections, CpG Islands, Mice, Rats, Immune Evasion, Pandemics
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