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Potential APOBEC-mediated RNA editing of the genomes of SARS-CoV-2 and other coronaviruses and its impact on their longer term evolution.

ABSTRACT: Members of the APOBEC family of cytidine deaminases show antiviral activities in mammalian cells through lethal editing in the genomes of small DNA viruses, herpesviruses and retroviruses, and potentially those of RNA viruses such as coronaviruses. Consistent with the latter, APOBEC-like directional C→U transitions of genomic plus-strand RNA are greatly overrepresented in SARS-CoV-2 genome sequences of variants emerging during the COVID-19 pandemic. A C→U mutational process may leave evolutionary imprints on coronavirus genomes, including extensive homoplasy from editing and reversion at targeted sites and the occurrence of driven amino acid sequence changes in viral proteins. If sustained over longer periods, this process may account for the previously reported marked global depletion of C and excess of U bases in human seasonal coronavirus genomes. This review synthesizes the current knowledge on APOBEC evolution and function and the evidence of their role in APOBEC-mediated genome editing of SARS-CoV-2 and other coronaviruses.

SUBMITTER: Ratcliff J

PROVIDER: S-EPMC7831814 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Potential APOBEC-mediated RNA editing of the genomes of SARS-CoV-2 and other coronaviruses and its impact on their longer term evolution.

Ratcliff Jeremy J Simmonds Peter P

Virology 20210107

Members of the APOBEC family of cytidine deaminases show antiviral activities in mammalian cells through lethal editing in the genomes of small DNA viruses, herpesviruses and retroviruses, and potentially those of RNA viruses such as coronaviruses. Consistent with the latter, APOBEC-like directional C→U transitions of genomic plus-strand RNA are greatly overrepresented in SARS-CoV-2 genome sequences of variants emerging during the COVID-19 pandemic. A C→U mutational process may leave evolutionar ...[more]

PMID: 33545556

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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.

Project description:Severe acute respiratory syndrome (SARS) is a novel human illness caused by a previously unrecognized coronavirus (CoV) termed SARS-CoV. There are conflicting reports on the animal reservoir of SARS-CoV. Many of the groups that argue carnivores are the original reservoir of SARS-CoV use a phylogeny to support their argument. However, the phylogenies in these studies often lack outgroup and rooting criteria necessary to determine the origins of SARS-CoV. Recently, SARS-CoV has been isolated from various species of Chiroptera from China (e.g., Rhinolophus sinicus) thus leading to reconsideration of the original reservoir of SARS-CoV. We evaluated the hypothesis that SARS-CoV isolated from Chiroptera are the original zoonotic source for SARS-CoV by sampling SARS-CoV and non-SARS-CoV from diverse hosts including Chiroptera, as well as carnivores, artiodactyls, rodents, birds and humans. Regardless of alignment parameters, optimality criteria, or isolate sampling, the resulting phylogenies clearly show that the SARS-CoV was transmitted to small carnivores well after the epidemic of SARS in humans that began in late 2002. The SARS-CoV isolates from small carnivores in Shenzhen markets form a terminal clade that emerged recently from within the radiation of human SARS-CoV. There is evidence of subsequent exchange of SARS-CoV between humans and carnivores. In addition SARS-CoV was transmitted independently from humans to farmed pigs (Sus scrofa). The position of SARS-CoV isolates from Chiroptera are basal to the SARS-CoV clade isolated from humans and carnivores. Although sequence data indicate that Chiroptera are a good candidate for the original reservoir of SARS-CoV, the structural biology of the spike protein of SARS-CoV isolated from Chiroptera suggests that these viruses are not able to interact with the human variant of the receptor of SARS-CoV, angiotensin-converting enzyme 2 (ACE2). In SARS-CoV we study, both visually and statistically, labile genomic fragments and, putative key mutations of the spike protein that may be associated with host shifts. We display host shifts and candidate mutations on trees projected in virtual globes depicting the spread of SARS-CoV. These results suggest that more sampling of coronaviruses from diverse hosts, especially Chiroptera, carnivores and primates, will be required to understand the genomic and biochemical evolution of coronaviruses, including SARS-CoV. © The Willi Hennig Society 2008.

Dataset Information

Potential APOBEC-mediated RNA editing of the genomes of SARS-CoV-2 and other coronaviruses and its impact on their longer term evolution.

Publications

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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