Generation of a novel SARS-CoV-2 sub-genomic RNA due to the R203K/G204R variant in nucleocapsid: homologous recombination has potential to change SARS-CoV-2 at both protein and RNA level

Leary, Shay; Gaudieri, Silvana; Parker, Matthew; Chopra, Abha; James, Ian; Pakala, Suman B.; Alves, Eric; John, Mina; Lindsey, Benjamin B.; Keeley, Alexander J; Rowland‐Jones, Sarah; Swanson, Maurice S.; Ostrov, David A.; Bubenik, Jodi L.; Das, Suman; Sidney, John; Sette, Alessandro; Silva, Thushan I. de; Phillips, Elizabeth; Mallal, S.

doi:10.1101/2020.04.10.029454

Cited by 42 publications

(57 citation statements)

References 54 publications

(73 reference statements)

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“…Our results also showed that some mutations were widely distributed, and their occurrence rates had different dynamic fluctuations. Take R203K/G204R in N as an example, this mutation combination with increased incidence was found mainly in Europe till March 2020 [39,40], while our data showed its high frequency was also in Asian countries as of July 2020, suggesting that these two mutations might be conducive to SARS-CoV-2 adaptability and spread. Therefore, it is particularly important to pay attention to the difficulties in COVID-19 diagnosis and treatment that probably caused by these mutations, especially in countries with high occurrence rates.…”

Section: Orf3a-s Complexes But Weaker Affinities In G251v Orf3a-m Anmentioning

confidence: 53%

Effects of SARS-CoV-2 Mutations on Protein Structures and Intraviral Protein-Protein Interactions

Tian

Liu

et al. 2020

Preprint

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Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has infected ten millions of people across the globe, and massive mutations in virus genome have occurred during the rapid spread of this novel coronavirus. Variance in protein sequence might lead to change in protein structure and interaction, then further affect the viral physiological characteristics, which could bring tremendous influence on the pandemic. In this study, we investigated 18 non-synonymous mutations in SARS-CoV-2 genome which incidence rates were all ≥1% as of July 15th, 2020, then modeled the mutated protein structures and compared them with the reference ones. The results showed that four types of mutations could cause dramatic changes in protein structures (RMSD ≥5.0 Å), which were Q57H and G251V in open reading frames 3a (ORF3a), S194L and R203K/G204R in nucleocapsid (N). Next, we found that these mutations could affect the binding affinity of intraviral protein interactions. In addition, the hot spots within these docking complexes were altered, among which the mutation Q57H was involved in both Orf3a-Orf8 and Orf3a-S protein interactions. Besides, these mutations were widely distributed all over the world, and their occurrences fluctuated as time went on. Notably, the incidences of R203K/G204R in N and Q57H in Orf3a were both over 50% in some countries. Overall, our findings suggest that SARS-CoV-2 mutations can change viral protein structure, binding affinity and hot spots of the interface, thereby may have impacts on SARS-CoV-2 transmission, diagnosis and treatment of COVID-19.

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Section: Orf3a-s Complexes But Weaker Affinities In G251v Orf3a-m Anmentioning

confidence: 53%

Effects of SARS-CoV-2 Mutations on Protein Structures and Intraviral Protein-Protein Interactions

Tian

Liu

et al. 2020

Preprint

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“…We designed a tool, periscope (https://github.com/sheffield-bioinformatics-core/periscope), to re-analyse raw data from SARS-CoV-2 isolates to identify sgRNA based on the detection of the leader sequence at the 5' end of reads as described previously (Leary et al 2020).…”

Section: Resultsmentioning

confidence: 99%

“…Non-Canonical Sub-Genomic RNA In addition to estimating sgRNA for known ORFs, we can use periscope to detect novel, non-canonical sgRNA (Figure 4). We previously applied periscope to detect one such novel sgRNA (N*) which is a result of the creation of a new TRS site by a triplet variation at position 28881 to 28883 which results in production of a truncated N ORF (Leary et al 2020). To classify sgRNA as non-canonical, supporting reads must fulfil two criteria; First, the start position does not fall in a known TRS-B region (+/-20bp from the leader junction), and second, in ONT data the start position must not fall within +/-5bp from a primer sequence.…”

Section: Lower Limit Of Detectionmentioning

confidence: 99%

periscope: sub-genomic RNA identification in SARS-CoV-2 Genomic Sequencing Data

Parker

Lindsey

Leary

et al. 2020

Preprint

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AbstractWe have developed periscope, a tool for the detection and quantification of sub-genomic RNA in ARTIC network protocol generated Nanopore SARS-CoV-2 sequence data. We applied periscope to 1155 SARS-CoV-2 sequences from Sheffield, UK. Using a simple local alignment to detect reads which contain the leader sequence we were able to identify and quantify reads arising from canonical and non-canonical sub-genomic RNA. We were able to detect all canonical sub-genomic RNAs at expected abundances, with the exception of ORF10, suggesting that this is not a functional ORF. A number of recurrent non-canonical sub-genomic RNAs are detected. We show that the results are reproducible using technical replicates and determine the optimum number of reads for sub-genomic RNA analysis. Finally variants found in genomic RNA are transmitted to sub-genomic RNAs with high fidelity in most cases. This tool can be applied to tens of thousands of sequences worldwide to provide the most comprehensive analysis of SARS-CoV-2 sub-genomic RNA to date.

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“…D614G (Aspartate to Glycine) mutation in the S gene has been reported to result in increased transduction into human epithelial cells ( Daniloski et al, 2020 ). N gene mutations R203K and G204R are believed to increase viral fitness, survival and adaptation to humans ( Leary et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Genomes From Oklahoma, United States

et al. 2021

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Genomic sequencing has played a major role in understanding the pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With the current pandemic, it is essential that SARS-CoV-2 viruses are sequenced regularly to determine mutations and genomic modifications in different geographical locations. In this study, we sequenced SARS-CoV-2 from five clinical samples obtained in Oklahoma, United States during different time points of pandemic presence in the state. One sample from the initial days of the pandemic in the state and four during the peak in Oklahoma were sequenced. Previously reported mutations including D614G in S gene, P4715L in ORF1ab, S194L, R203K, and G204R in N gene were identified in the genomes sequenced in this study. Possible novel mutations were also detected in the S gene (G1167V), ORF1ab (A6269S and P3371S), ORF7b (T28I), and ORF8 (G96R). Phylogenetic analysis of the genomes showed similarity to other SARS-CoV-2 viruses reported from across the globe. Structural characterization indicates that the mutations in S gene possibly influences conformational flexibility and motion of the spike protein, and the mutations in N gene are associated with disordered linker region within the nucleocapsid protein.

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Generation of a novel SARS-CoV-2 sub-genomic RNA due to the R203K/G204R variant in nucleocapsid: homologous recombination has potential to change SARS-CoV-2 at both protein and RNA level

Cited by 42 publications

References 54 publications

Effects of SARS-CoV-2 Mutations on Protein Structures and Intraviral Protein-Protein Interactions

Effects of SARS-CoV-2 Mutations on Protein Structures and Intraviral Protein-Protein Interactions

periscope: sub-genomic RNA identification in SARS-CoV-2 Genomic Sequencing Data

SARS-CoV-2 Genomes From Oklahoma, United States

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