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The Long-Term Evolutionary History of Gradual Reduction of CpG Dinucleotides in the SARS-CoV-2 Lineage.

ABSTRACT: Recent studies suggested that the fraction of CG dinucleotides (CpG) is severely reduced in the genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The CpG deficiency was predicted to be the adaptive response of the virus to evade degradation of the viral RNA by the antiviral zinc finger protein that specifically binds to CpG nucleotides. By comparing all representative genomes belonging to the genus Betacoronavirus, this study examined the potential time of origin of CpG depletion. The results of this investigation revealed a highly significant correlation between the proportions of CpG nucleotide (CpG content) of the betacoronavirus species and their times of divergence from SARS-CoV-2. Species that are distantly related to SARS-CoV-2 had much higher CpG contents than that of SARS-CoV-2. Conversely, closely related species had low CpG contents that are similar to or slightly higher than that of SARS-CoV-2. These results suggest a systematic and continuous reduction in the CpG content in the SARS-CoV-2 lineage that might have started since the Sarbecovirus + Hibecovirus clade separated from Nobecovirus, which was estimated to be 1213 years ago. This depletion was not found to be mediated by the GC contents of the genomes. Our results also showed that the depletion of CpG occurred at neutral positions of the genome as well as those under selection. The latter is evident from the progressive reduction in the proportion of arginine amino acid (coded by CpG dinucleotides) in the SARS-CoV-2 lineage over time. The results of this study suggest that shedding CpG nucleotides from their genome is a continuing process in this viral lineage, potentially to escape from their host defense mechanisms.

SUBMITTER: Subramanian S

PROVIDER: S-EPMC7828247 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The Long-Term Evolutionary History of Gradual Reduction of CpG Dinucleotides in the SARS-CoV-2 Lineage.

Subramanian Sankar S

Biology 20210112 1

Recent studies suggested that the fraction of CG dinucleotides (CpG) is severely reduced in the genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The CpG deficiency was predicted to be the adaptive response of the virus to evade degradation of the viral RNA by the antiviral zinc finger protein that specifically binds to CpG nucleotides. By comparing all representative genomes belonging to the genus <i>Betacoronavirus,</i> this study examined the potential time of origin of ...[more]

PMID: 33445785

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Project description:BackgroundPapillomaviruses and polyomaviruses are small ds-DNA viruses infecting a wide-range of vertebrate hosts. Evidence supporting co-evolution of the virus with the host does not fully explain the evolutionary path of papillomaviruses and polyomaviruses. Studies analyzing CpG dinucleotide frequencies in virus genomes have provided interesting insights on virus evolution. CpG dinucleotide depletion has not been extensively studied among papillomaviruses and polyomaviruses. We sought to analyze the relative abundance of dinucleotides and the relative roles of evolutionary pressures in papillomaviruses and polyomaviruses.MethodsWe studied 127 full-length sequences from papillomaviruses and 56 full-length sequences from polyomaviruses. We analyzed the relative abundance of dinucleotides, effective codon number (ENC), differences in synonymous codon usage. We examined the association, if any, between the extent of CpG dinucleotide depletion and the evolutionary lineage of the infected host. We also investigated the contribution of mutational pressure and translational selection to the evolution of papillomaviruses and polyomaviruses.ResultsAll papillomaviruses and polyomaviruses are CpG depleted. Interestingly, the evolutionary lineage of the infected host determines the extent of CpG depletion among papillomaviruses and polyomaviruses. CpG dinucleotide depletion was more pronounced among papillomaviruses and polyomaviruses infecting human and other mammals as compared to those infecting birds. Our findings demonstrate that CpG depletion among papillomaviruses is linked to mutational pressure; while CpG depletion among polyomaviruses is linked to translational selection. We also present evidence that suggests methylation of CpG dinucleotides may explain, at least in part, the depletion of CpG dinucleotides among papillomaviruses but not polyomaviruses.ConclusionsThe extent of CpG depletion among papillomaviruses and polyomaviruses is linked to the evolutionary lineage of the infected host. Our results highlight the existence of divergent evolutionary pressures leading to CpG dinucleotide depletion among small ds-DNA viruses infecting vertebrate hosts.

Project description:We have detected two mutations in the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at amino acid positions 1163 and 1167 that appeared independently in multiple transmission clusters and different genetic backgrounds. Furthermore, both mutations appeared together in a cluster of 1,627 sequences belonging to clade 20E. This cluster is characterized by 12 additional single nucleotide polymorphisms but no deletions. The available structural information on the S protein in the pre- and postfusion conformations predicts that both mutations confer rigidity, which could potentially decrease viral fitness. Accordingly, we observed reduced infectivity of this spike genotype relative to the ancestral 20E sequence in vitro, and the levels of viral RNA in nasopharyngeal swabs were not significantly higher. Furthermore, the mutations did not impact thermal stability or antibody neutralization by sera from vaccinated individuals but moderately reduce neutralization by convalescent-phase sera from the early stages of the pandemic. Despite multiple successful appearances of the two spike mutations during the first year of SARS-CoV-2 evolution, the genotype with both mutations was displaced upon the expansion of the 20I (Alpha) variant. The midterm fate of the genotype investigated was consistent with the lack of advantage observed in the clinical and experimental data. IMPORTANCE We observed repeated, independent emergence of mutations in the SARS-CoV-2 spike involving amino acids 1163 and 1167, within the HR2 functional motif. Conclusions derived from evolutionary and genomic diversity analysis suggest that the co-occurrence of both mutations might pose an advantage for the virus and therefore a threat to effective control of the epidemic. However, biological characterization, including in vitro experiments and analysis of clinical data, indicated no clear benefit in terms of stability or infectivity. In agreement with this, continuous epidemiological surveillance conducted months after the first observations revealed that both mutations did not successfully outcompete other variants and stopped circulating 9 months after their initial detection. Additionally, we evaluated the potential of both mutations to escape neutralizing antibodies, finding that the presence of these two mutations on their own is not likely to confer antibody escape. Our results provide an example of how newly emerged spike mutations can be assessed to better understand the risk posed by new variants and indicate that some spike mutations confer no clear advantage to the virus despite independently emerging multiple times and are eventually displaced by fitter variants.

Project description:BackgroundRooted phylogenetic networks are used to display complex evolutionary history involving so-called reticulation events, such as genetic recombination. Various methods have been developed to construct such networks, using for example a multiple sequence alignment or multiple phylogenetic trees as input data. Coronaviruses are known to recombine frequently, but rooted phylogenetic networks have not yet been used extensively to describe their evolutionary history. Here, we created a workflow to compare the evolutionary history of SARS-CoV-2 with other SARS-like viruses using several rooted phylogenetic network inference algorithms. This workflow includes filtering noise from sets of phylogenetic trees by contracting edges based on branch length and bootstrap support, followed by resolution of multifurcations. We explored the running times of the network inference algorithms, the impact of filtering on the properties of the produced networks, and attempted to derive biological insights regarding the evolution of SARS-CoV-2 from them.ResultsThe network inference algorithms are capable of constructing rooted phylogenetic networks for coronavirus data, although running-time limitations require restricting such datasets to a relatively small number of taxa. Filtering generally reduces the number of reticulations in the produced networks and increases their temporal consistency. Taxon bat-SL-CoVZC45 emerges as a major and structural source of discordance in the dataset. The tested algorithms often indicate that SARS-CoV-2/RaTG13 is a tree-like clade, with possibly some reticulate activity further back in their history. A smaller number of constructed networks posit SARS-CoV-2 as a possible recombinant, although this might be a methodological artefact arising from the interaction of bat-SL-CoVZC45 discordance and the optimization criteria used.ConclusionOur results demonstrate that as part of a wider workflow and with careful attention paid to running time, rooted phylogenetic network algorithms are capable of producing plausible networks from coronavirus data. These networks partly corroborate existing theories about SARS-CoV-2, and partly produce new avenues for exploration regarding the location and significance of reticulate activity within the wider group of SARS-like viruses. Our workflow may serve as a model for pipelines in which phylogenetic network algorithms can be used to analyse different datasets and test different hypotheses.

Dataset Information

The Long-Term Evolutionary History of Gradual Reduction of CpG Dinucleotides in the SARS-CoV-2 Lineage.

Publications

The Long-Term Evolutionary History of Gradual Reduction of CpG Dinucleotides in the SARS-CoV-2 Lineage.

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