Characterizing Transcriptional Regulatory Sequences in Coronaviruses and Their Role in Recombination

Yi, Yang; Yan, Wei; Hall, Andrew Brantley; Jiang, Xiaofang

doi:10.1093/molbev/msaa281

Cited by 52 publications

(54 citation statements)

References 46 publications

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“…S11C-E). We are able to detect noncanonical sgRNAs just 3 ′ of the predicted start codon of ORF7b (27,760 and 27,761) and at least 10 bases downstream from a predicted TRS-B site (Yang et al 2020). These sgRNAs have strong support in both the Sheffield (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 75%

Subgenomic RNA identification in SARS-CoV-2 genomic sequencing data

et al. 2021

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We have developed periscope, a tool for the detection and quantification of subgenomic RNA (sgRNA) in SARS-CoV-2 genomic sequence data. The translation of the SARS-CoV-2 RNA genome for most open reading frames (ORFs) occurs via RNA intermediates termed "subgenomic RNAs." sgRNAs are produced through discontinuous transcription, which relies on homology between transcription regulatory sequences (TRS-B) upstream of the ORF start codons and that of the TRS-L, which is located in the 5 ′ UTR. TRS-L is immediately preceded by a leader sequence. This leader sequence is therefore found at the 5 ′ end of all sgRNA. We applied periscope to 1155 SARS-CoV-2 genomes from Sheffield, United Kingdom, and validated our findings using orthogonal data sets and in vitro cell systems. By using a simple local alignment to detect reads that contain the leader sequence, we were able to identify and quantify reads arising from canonical and noncanonical sgRNA. We were able to detect all canonical sgRNAs at the expected abundances, with the exception of ORF10. A number of recurrent noncanonical sgRNAs are detected. We show that the results are reproducible using technical replicates and determine the optimum number of reads for sgRNA analysis. In VeroE6 ACE2+/− cell lines, periscope can detect the changes in the kinetics of sgRNA in orthogonal sequencing data sets. Finally, variants found in genomic RNA are transmitted to sgRNAs with high fidelity in most cases. This tool can be applied to all sequenced COVID-19 samples worldwide to provide comprehensive analysis of SARS-CoV-2 sgRNA.

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Section: Discussionmentioning

confidence: 75%

Subgenomic RNA identification in SARS-CoV-2 genomic sequencing data

et al. 2021

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“…Two exceptions are noted for lineages B. The breakpoint is inferred by GARD to have occurred around position 21308 (a TTT codon), corresponding to the signal peptide region at the N-terminus of the spike protein (18 nucleotides downstream of the canonical sarbecovirus transcription regulatory sequence AACGAAC; Yang et al, 2021). However, some variation in the results is observed when using different subsampling approaches; an analysis that excludes the B.1.634 lineage indicates a recombination breakpoint is inferred position 22775-22778 (at a GAT codon) in the Spike protein reading frame (Δc-AICnull model = 562.098), corresponding to amino acid residue 390D located in the core region of the receptor binding domain (RBD) adjacent to beta sheet 3 (β3; Lan et al, 2020).…”

Section: Exploring the Phylogenetic Discrepancies Of The Lineages Under Investigation Relative To Other B1 Lineagesmentioning

confidence: 99%

Emergence and widespread circulation of a recombinant SARS-CoV-2 lineage in North America

Gutierrez

Castelan

Cândido

et al. 2021

Preprint

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Genetic recombination is an important driving force of coronavirus evolution. While some degree of virus recombination has been reported during the COVID-19 pandemic, previously detected recombinant lineages of SARS-CoV-2 have shown limited circulation and been observed only in restricted areas. Prompted by reports of unusual genetic similarities among several Pango lineages detected mainly in North and Central America, we present a detailed phylogenetic analysis of four SARS-CoV-2 lineages (B.1.627, B.1.628, B.1.631 and B.1.634) in order to investigate the possibility of virus recombination among them. Two of these lineages, B.1.628 and B.1.631, are split into two distinct clusters (here named major and minor). Our phylogenetic and recombination analyses of these lineages find well-supported phylogenetic differences between the Orf1ab region and the rest of the genome (S protein and remaining reading frames). The lineages also contain several deletions in the NSP6, Orf3a and S proteins that can augment reconstruction of reliable evolutionary histories. By reconciling the deletions and phylogenetic data, we conclude that the B.1.628 major cluster originated from a recombination event between a B.1.631 major virus and a lineage B.1.634 virus. This scenario inferred from genetic data is supported by the spatial and temporal distribution of the three lineages, which all co-circulated in the USA and Mexico during 2021, suggesting this region is where the recombination event took place. We therefore support the designation of the B.1.628 major cluster as recombinant lineage XB in the Pango nomenclature. The widespread circulation of lineage XB across multiple countries over a longer timespan than the previously designated recombinant XA lineage raises important questions regarding the role and potential effects of recombination on the evolution of SARS-CoV-2 during the ongoing COVID-19 pandemic.

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“…Although their function is not completely known, the leader sequence and the IGS sequences, later referred to as cis-acting transcription-regulating sequences (TRSs), are crucial for proper gene expression during viral replication [122,123]. A putatively conserved TRS sequence TAAACGAAAC has also been identified through manual alignment that is upstream from the leader sequence and conserved among SARS-CoV and SARS-CoV-2, indicating a similar replication process to those of other coronaviruses [123][124][125][126]. Genome sequence comparison identified a conserved CUAAAC consensus in the leader sequence in all SARS and coronavirus genomes.…”

Section: The 5 Leader Sequence Of Sars-cov-2 As Target For Ncrna-based Therapiesmentioning

confidence: 99%

“…Genome sequence comparison identified a conserved CUAAAC consensus in the leader sequence in all SARS and coronavirus genomes. Both TRSs and the leader sequence are needed to guarantee efficient accumulation of SARS-CoV-2 mRNA transcripts and proteins during infection since they protect viral mRNAs from endonucleolytic cleavage of the mRNAs cap [123][124][125][126].…”

Section: The 5 Leader Sequence Of Sars-cov-2 As Target For Ncrna-based Therapiesmentioning

confidence: 99%

SARS-CoV-2, Cardiovascular Diseases, and Noncoding RNAs: A Connected Triad

Natarelli¹,

Virgili

Weber

2021

IJMS

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Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is characterized by important respiratory impairments frequently associated with severe cardiovascular damages. Moreover, patients with pre-existing comorbidity for cardiovascular diseases (CVD) often present a dramatic increase in inflammatory cytokines release, which increases the severity and adverse outcomes of the infection and, finally, mortality risk. Despite this evident association at the clinical level, the mechanisms linking CVD and COVID-19 are still blurry and unresolved. Noncoding RNAs (ncRNAs) are functional RNA molecules transcribed from DNA but usually not translated into proteins. They play an important role in the regulation of gene expression, either in relatively stable conditions or as a response to different stimuli, including viral infection, and are therefore considered a possible important target in the design of specific drugs. In this review, we introduce known associations and interactions between COVID-19 and CVD, discussing the role of ncRNAs within SARS-CoV-2 infection from the perspective of the development of efficient pharmacological tools to treat COVID-19 patients and taking into account the equally dramatic associated consequences, such as those affecting the cardiovascular system.

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Characterizing Transcriptional Regulatory Sequences in Coronaviruses and Their Role in Recombination

Cited by 52 publications

References 46 publications

Subgenomic RNA identification in SARS-CoV-2 genomic sequencing data

Subgenomic RNA identification in SARS-CoV-2 genomic sequencing data

Emergence and widespread circulation of a recombinant SARS-CoV-2 lineage in North America

SARS-CoV-2, Cardiovascular Diseases, and Noncoding RNAs: A Connected Triad

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