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1.
Brief Bioinform ; 23(1)2022 01 17.
Article in English | MEDLINE | ID: covidwho-1406466

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has triggered an unprecedented international effort to sequence complete viral genomes. We leveraged this wealth of information to characterize the substitution spectrum of SARS-CoV-2 and to compare it with those of other human and animal coronaviruses. We show that, once nucleotide composition is taken into account, human and most animal coronaviruses display a mutation spectrum dominated by C to U and G to U substitutions, a feature that is not shared by other positive-sense RNA viruses. However, the proportions of C to U and G to U substitutions tend to decrease as divergence increases, suggesting that, whatever their origin, a proportion of these changes is subsequently eliminated by purifying selection. Analysis of the sequence context of C to U substitutions showed little evidence of apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-mediated editing and such contexts were similar for SARS-CoV-2 and Middle East respiratory syndrome coronavirus sampled from different hosts, despite different repertoires of APOBEC3 proteins in distinct species. Conversely, we found evidence that C to U and G to U changes affect CpG dinucleotides at a frequency higher than expected. Whereas this suggests ongoing selective reduction of CpGs, this effect alone cannot account for the substitution spectra. Finally, we show that, during the first months of SARS-CoV-2 pandemic spread, the frequency of both G to U and C to U substitutions increased. Our data suggest that the substitution spectrum of SARS-CoV-2 is determined by an interplay of factors, including intrinsic biases of the replication process, avoidance of CpG dinucleotides and other constraints exerted by the new host.


Subject(s)
COVID-19/genetics , Evolution, Molecular , Genome, Viral , Mutation , Pandemics , SARS-CoV-2/genetics , APOBEC Deaminases/genetics , APOBEC Deaminases/metabolism , Animals , COVID-19/epidemiology , Humans , Phylogeny , SARS-CoV-2/metabolism
2.
Scand J Immunol ; 94(5): e13100, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1388399

ABSTRACT

The SARS-CoV-2 epidemic infections in Australia during 2020 were small in number in epidemiological terms and are well described. The SARS-CoV-2 genomic sequence data of many infected patients have been largely curated in a number of publicly available databases, including the corresponding epidemiological data made available by the Victorian Department of Health and Human Services. We have critically analysed the available SARS-CoV-2 haplotypes and genomic sequences in the context of putative deficits in innate immune APOBEC and ADAR deaminase anti-viral responses. It is now known that immune impaired elderly co-morbid patients display clear deficits in interferon type 1 (α/ß) and III (λ) stimulated innate immune gene cascades, of which APOBEC and ADAR induced expression are part. These deficiencies may help explain some of the clear genetic patterns in SARS-CoV-2 genomes isolated in Victoria, Australia, during the 2nd Wave (June-September, 2020). We tested the hypothesis that predicted lowered innate immune APOBEC and ADAR anti-viral deaminase responses in a significant proportion of elderly patients would be consistent with/reflected in a low level of observed mutagenesis in many isolated SARS-CoV-2 genomes. Our findings are consistent with this expectation. The analysis also supports the conclusions of the Victorian government's Department of Health that essentially one variant or haplotype infected Victorian aged care facilities where the great majority (79%) of all 820 SARS-CoV-2 associated deaths occurred. The implications of our data analysis for other localized epidemics and efficient coronavirus vaccine design and delivery are discussed.


Subject(s)
APOBEC Deaminases/genetics , Adenosine Deaminase/genetics , COVID-19 Vaccines/immunology , COVID-19/immunology , RNA-Binding Proteins/genetics , SARS-CoV-2/physiology , APOBEC Deaminases/metabolism , Adenosine Deaminase/metabolism , Age Factors , Aged, 80 and over , COVID-19/epidemiology , COVID-19/virology , Female , Gene Regulatory Networks , Haplotypes , Humans , Immunity, Innate , Immunologic Deficiency Syndromes , Interferon Type I/genetics , Male , RNA-Binding Proteins/metabolism , Victoria/epidemiology
3.
PLoS Pathog ; 17(6): e1009596, 2021 06.
Article in English | MEDLINE | ID: covidwho-1249581

ABSTRACT

The rapid evolution of RNA viruses has been long considered to result from a combination of high copying error frequencies during RNA replication, short generation times and the consequent extensive fixation of neutral or adaptive changes over short periods. While both the identities and sites of mutations are typically modelled as being random, recent investigations of sequence diversity of SARS coronavirus 2 (SARS-CoV-2) have identified a preponderance of C->U transitions, proposed to be driven by an APOBEC-like RNA editing process. The current study investigated whether this phenomenon could be observed in datasets of other RNA viruses. Using a 5% divergence filter to infer directionality, 18 from 36 datasets of aligned coding region sequences from a diverse range of mammalian RNA viruses (including Picornaviridae, Flaviviridae, Matonaviridae, Caliciviridae and Coronaviridae) showed a >2-fold base composition normalised excess of C->U transitions compared to U->C (range 2.1x-7.5x), with a consistently observed favoured 5' U upstream context. The presence of genome scale RNA secondary structure (GORS) was the only other genomic or structural parameter significantly associated with C->U/U->C transition asymmetries by multivariable analysis (ANOVA), potentially reflecting RNA structure dependence of sites targeted for C->U mutations. Using the association index metric, C->U changes were specifically over-represented at phylogenetically uninformative sites, potentially paralleling extensive homoplasy of this transition reported in SARS-CoV-2. Although mechanisms remain to be functionally characterised, excess C->U substitutions accounted for 11-14% of standing sequence variability of structured viruses and may therefore represent a potent driver of their sequence diversification and longer-term evolution.


Subject(s)
Mammals/virology , Mutation , RNA Viruses/genetics , SARS-CoV-2/genetics , APOBEC Deaminases/metabolism , Animals , Base Sequence , COVID-19/virology , Cytidine/genetics , DNA Damage/physiology , Evolution, Molecular , Gene Expression Regulation, Viral , Genome, Viral , Host-Pathogen Interactions/genetics , Humans , Nucleic Acid Conformation , Phylogeny , RNA Editing/physiology , RNA Viruses/classification , RNA, Viral/chemistry , RNA, Viral/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/classification , Sequence Analysis, RNA , Transcription, Genetic/genetics , Uridine/genetics
4.
Biochem Biophys Res Commun ; 538: 35-39, 2021 01 29.
Article in English | MEDLINE | ID: covidwho-1139448

ABSTRACT

The extensive sequence data generated from SARS-CoV-2 during the 2020 pandemic has facilitated the study of viral genome evolution over a brief period of time. This has highlighted instances of directional mutation pressures exerted on the SARS-CoV-2 genome from host antiviral defense systems. In this brief review we describe three such human defense mechanisms, the apolipoprotein B mRNA editing catalytic polypeptide-like proteins (APOBEC), adenosine deaminase acting on RNA proteins (ADAR), and reactive oxygen species (ROS), and discuss their potential implications on SARS-CoV-2 evolution.


Subject(s)
APOBEC Deaminases/metabolism , Adenosine Deaminase/metabolism , COVID-19/virology , Gene Editing , Genome, Viral , Host-Pathogen Interactions/genetics , RNA-Binding Proteins/metabolism , SARS-CoV-2/genetics , COVID-19/epidemiology , Humans , Reactive Oxygen Species/metabolism
5.
Clin Immunol ; 226: 108699, 2021 05.
Article in English | MEDLINE | ID: covidwho-1101151

ABSTRACT

RNA editing is a fundamental biological process with 2 major forms, namely adenosine-to-inosine (A-to-I, recognized as A-to-G) and cytosine-to-uracil (C-to-U) deamination, mediated by ADAR and APOBEC enzyme families, respectively. A-to-I RNA editing has been shown to directly affect the genome/transcriptome of RNA viruses with significant repercussions for viral protein synthesis, proliferation and infectivity, while it also affects recognition of double-stranded RNAs by cytosolic receptors controlling the host innate immune response. Recent evidence suggests that RNA editing may be present in SARS-CoV-2 genome/transcriptome. The majority of mapped mutations in SARS-CoV-2 genome are A-to-G/U-to-C(opposite strand) and C-to-U/G-to-A(opposite strand) substitutions comprising potential ADAR-/APOBEC-mediated deamination events. A single nucleotide substitution can have dramatic effects on SARS-CoV-2 infectivity as shown by the D614G(A-to-G) substitution in the spike protein. Future studies utilizing serial sampling from patients with COVID-19 are warranted to delineate whether RNA editing affects viral replication and/or the host immune response to SARS-CoV-2.


Subject(s)
APOBEC Deaminases/metabolism , Adenosine Deaminase/metabolism , COVID-19/immunology , Immunity, Innate , RNA Editing , RNA Viruses/genetics , RNA-Binding Proteins/metabolism , SARS-CoV-2/genetics , APOBEC Deaminases/genetics , Adenosine Deaminase/genetics , COVID-19/enzymology , COVID-19/virology , Humans , Mutation , RNA Viruses/pathogenicity , RNA, Double-Stranded/metabolism , RNA-Binding Proteins/genetics , SARS-CoV-2/metabolism
6.
Virology ; 556: 62-72, 2021 04.
Article in English | MEDLINE | ID: covidwho-1065649

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.


Subject(s)
APOBEC Deaminases/metabolism , Coronavirus/genetics , Evolution, Molecular , Genome, Viral/genetics , RNA Editing , APOBEC Deaminases/chemistry , APOBEC Deaminases/genetics , Animals , Coronavirus Infections/virology , Humans , Mutation , SARS-CoV-2/genetics
8.
Viruses ; 13(1)2021 Jan 17.
Article in English | MEDLINE | ID: covidwho-1040990

ABSTRACT

The APOBEC3 family of proteins in mammals consists of cellular cytosine deaminases and well-known restriction factors against retroviruses, including lentiviruses. APOBEC3 genes are highly amplified and diversified in mammals, suggesting that their evolution and diversification have been driven by conflicts with ancient viruses. At present, lentiviruses, including HIV, the causative agent of AIDS, are known to encode a viral protein called Vif to overcome the antiviral effects of the APOBEC3 proteins of their hosts. Recent studies have revealed that the acquisition of an anti-APOBEC3 ability by lentiviruses is a key step in achieving successful cross-species transmission. Here, we summarize the current knowledge of the interplay between mammalian APOBEC3 proteins and viral infections and introduce a scenario of the coevolution of mammalian APOBEC3 genes and viruses.


Subject(s)
APOBEC Deaminases/metabolism , Host-Pathogen Interactions , Retroviridae Infections/metabolism , Retroviridae Infections/virology , Retroviridae/physiology , APOBEC Deaminases/genetics , Animals , Disease Resistance/genetics , Evolution, Molecular , Genetic Variation , Genome, Viral , Host-Pathogen Interactions/genetics , Humans , Lentivirus/physiology , Phylogeny , Retroviridae Infections/transmission , Species Specificity , vif Gene Products, Human Immunodeficiency Virus
9.
Sci Rep ; 10(1): 17766, 2020 10 20.
Article in English | MEDLINE | ID: covidwho-882928

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces severe pneumonia and is the cause of a worldwide pandemic. Coronaviruses, including SARS-CoV-2, have RNA proofreading enzymes in their genomes, resulting in fewer gene mutations than other RNA viruses. Nevertheless, variants of SARS-CoV-2 exist and may induce different symptoms; however, the factors and the impacts of these mutations are not well understood. We found that there is a bias to the mutations occurring in SARS-CoV-2 variants, with disproportionate mutation to uracil (U). These point mutations to U are mainly derived from cytosine (C), which is consistent with the substrate specificity of host RNA editing enzymes, APOBECs. We also found the point mutations which are consistent with other RNA editing enzymes, ADARs. For the C-to-U mutations, the context of the upstream uracil and downstream guanine from mutated position was found to be most prevalent. Further, the degree of increase of U in SARS-CoV-2 variants correlates with enhanced production of cytokines, such as TNF-α and IL-6, in cell lines when compared with stimulation by the ssRNA sequence of the isolated virus in Wuhan. Therefore, RNA editing is a factor for mutation bias in SARS-CoV-2 variants, which affects host inflammatory cytokines production.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , APOBEC Deaminases/metabolism , Adenosine Deaminase/metabolism , Betacoronavirus/classification , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , COVID-19 , Cell Line, Tumor , Coronavirus Infections/immunology , Coronavirus Infections/virology , Humans , Interleukin-6/metabolism , Pandemics , Phylogeny , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Point Mutation , RNA Editing , SARS-CoV-2 , Tumor Necrosis Factor-alpha/metabolism , Uracil/metabolism
10.
Sci Adv ; 6(25): eabb5813, 2020 06.
Article in English | MEDLINE | ID: covidwho-619103

ABSTRACT

The COVID-19 outbreak has become a global health risk, and understanding the response of the host to the SARS-CoV-2 virus will help to combat the disease. RNA editing by host deaminases is an innate restriction process to counter virus infection, but it is not yet known whether this process operates against coronaviruses. Here, we analyze RNA sequences from bronchoalveolar lavage fluids obtained from coronavirus-infected patients. We identify nucleotide changes that may be signatures of RNA editing: adenosine-to-inosine changes from ADAR deaminases and cytosine-to-uracil changes from APOBEC deaminases. Mutational analysis of genomes from different strains of Coronaviridae from human hosts reveals mutational patterns consistent with those observed in the transcriptomic data. However, the reduced ADAR signature in these data raises the possibility that ADARs might be more effective than APOBECs in restricting viral propagation. Our results thus suggest that both APOBECs and ADARs are involved in coronavirus genome editing, a process that may shape the fate of both virus and patient.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/metabolism , Coronavirus Infections/genetics , Host-Pathogen Interactions/genetics , Pneumonia, Viral/genetics , RNA Editing/genetics , Transcriptome , APOBEC Deaminases/genetics , APOBEC Deaminases/metabolism , Adenosine Deaminase/genetics , Adenosine Deaminase/metabolism , Base Sequence/genetics , Bronchoalveolar Lavage Fluid/virology , COVID-19 , Coronavirus Infections/virology , Genome, Viral/genetics , Humans , Mutation Rate , Nucleotides/genetics , Nucleotides/metabolism , Pandemics , Pneumonia, Viral/virology , RNA, Viral/genetics , SARS-CoV-2 , Virus Replication/genetics
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