Potential APOBEC-mediated RNA editing of the genomes of SARS-CoV-2 and other coronaviruses and its impact on their longer term evolution.
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ABSTRACT:
SUBMITTER: Ratcliff J
PROVIDER: S-EPMC7831814 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:During COVID-19 pandemic, mutations of SARS-CoV-2 produce new strains that can be more infectious or evade vaccines. Viral RNA mutations can arise from misincorporation by RNA-polymerases and modification by host factors. Analysis of SARS-CoV-2 sequence from patients showed a strong bias toward C-to-U mutation, suggesting a potential mutational role by host APOBEC cytosine deaminases that possess broad anti-viral activity. We report the first experimental evidence demonstrating that APOBEC3A, APOBEC1, and APOBEC3G can edit on specific sites of SARS-CoV-2 RNA to produce C-to-U mutations. However, SARS-CoV-2 replication and viral progeny production in Caco-2 cells are not inhibited by the expression of these APOBECs. Instead, expression of wild-type APOBEC3 greatly promotes viral replication/propagation, suggesting that SARS-CoV-2 utilizes the APOBEC-mediated mutations for fitness and evolution. Unlike the random mutations, this study suggests the predictability of all possible viral genome mutations by these APOBECs based on the UC/AC motifs and the viral genomic RNA structure.One-sentence summaryEfficient Editing of SARS-CoV-2 genomic RNA by Host APOBEC deaminases and Its Potential Impacts on the Viral Replication and Emergence of New Strains in COVID-19 Pandemic.
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Project description:During COVID-19 pandemic, mutations of SARS-CoV-2 produce new strains that can be more infectious or evade vaccines. Viral RNA mutations can arise from misincorporation by RNA-polymerases and modification by host factors. Analysis of SARS-CoV-2 sequence from patients showed a strong bias toward C-to-U mutation, suggesting a potential mutational role by host APOBEC cytosine deaminases that possess broad anti-viral activity. We report the first experimental evidence demonstrating that APOBEC3A, APOBEC1, and APOBEC3G can edit on specific sites of SARS-CoV-2 RNA to produce C-to-U mutations. However, SARS-CoV-2 replication and viral progeny production in Caco-2 cells are not inhibited by the expression of these APOBECs. Instead, expression of wild-type APOBEC3 greatly promotes viral replication/propagation, suggesting that SARS-CoV-2 utilizes the APOBEC-mediated mutations for fitness and evolution. Unlike the random mutations, this study suggests the predictability of all possible viral genome mutations by these APOBECs based on the UC/AC motifs and the viral genomic RNA structure.
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Project description:The ultimate outcome of the coronavirus disease 2019 (COVID-19) pandemic is unknown and is dependent on a complex interplay of its pathogenicity, transmissibility, and population immunity. In the current study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was investigated for the presence of large-scale internal RNA base pairing in its genome. This property, termed genome-scale ordered RNA structure (GORS) has been previously associated with host persistence in other positive-strand RNA viruses, potentially through its shielding effect on viral RNA recognition in the cell. Genomes of SARS-CoV-2 were remarkably structured, with minimum folding energy differences (MFEDs) of 15%, substantially greater than previously examined viruses such as hepatitis C virus (HCV) (MFED of 7 to 9%). High MFED values were shared with all coronavirus genomes analyzed and created by several hundred consecutive energetically favored stem-loops throughout the genome. In contrast to replication-associated RNA structure, GORS was poorly conserved in the positions and identities of base pairing with other sarbecoviruses-even similarly positioned stem-loops in SARS-CoV-2 and SARS-CoV rarely shared homologous pairings, indicative of more rapid evolutionary change in RNA structure than in the underlying coding sequences. Sites predicted to be base paired in SARS-CoV-2 showed less sequence diversity than unpaired sites, suggesting that disruption of RNA structure by mutation imposes a fitness cost on the virus that is potentially restrictive to its longer evolution. Although functionally uncharacterized, GORS in SARS-CoV-2 and other coronaviruses represents important elements in their cellular interactions that may contribute to their persistence and transmissibility.IMPORTANCE The detection and characterization of large-scale RNA secondary structure in the genome of SARS-CoV-2 indicate an extraordinary and unsuspected degree of genome structural organization; this could be effectively visualized through a newly developed contour plotting method that displays positions, structural features, and conservation of RNA secondary structure between related viruses. Such RNA structure imposes a substantial evolutionary cost; paired sites showed greater restriction in diversity and represent a substantial additional constraint in reconstructing its molecular epidemiology. Its biological relevance arises from previously documented associations between possession of structured genomes and persistence, as documented for HCV and several other RNA viruses infecting humans and mammals. Shared properties potentially conferred by large-scale structure in SARS-CoV-2 include increasing evidence for prolonged infections and induced immune dysfunction that prevents development of protective immunity. The findings provide an additional element to cellular interactions that potentially influences the natural history of SARS-CoV-2, its pathogenicity, and its transmission.
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Project description:Mutations of DNA organisms are introduced by replication errors. However, SARS-CoV-2, as an RNA virus, is additionally subjected to rampant RNA editing by hosts. Both resources contributed to SARS-CoV-2 mutation and evolution, but the relative prevalence of the two origins is unknown. We performed comparative genomic analyses at intra-species (world-wide SARS-CoV-2 strains) and inter-species (SARS-CoV-2 and RaTG13 divergence) levels. We made prior predictions of the proportion of each mutation type (nucleotide substitution) under different scenarios and compared the observed versus the expected. C-to-T alteration, representing C-to-U editing, is far more abundant that all other mutation types. Derived allele frequency (DAF) as well as novel mutation rate of C-to-T are the highest in SARS-CoV-2 population, and C-T substitution dominates the divergence sites between SARS-CoV-2 and RaTG13. This is compelling evidence suggesting that C-to-U RNA editing is the major source of SARS-CoV-2 mutation. While replication errors serve as a baseline of novel mutation rate, the C-to-U editing has elevated the mutation rate for orders of magnitudes and accelerates the evolution of the virus.
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