RNA genome conservation and secondary structure in SARS-CoV-2 and SARS-related viruses

Rangan, Ramya; Zheludev, I.N.; Das, Rhiju

doi:10.1101/2020.03.27.012906

Cited by 45 publications

(60 citation statements)

References 41 publications

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“…3b ). The ScanFold-Fold model of the FSE is largely consistent with recent models 7,19 . This model consists of two stable hairpins: the first of which contains a loop sequence which forms a pseudoknot by pairing with nucleotides upstream of the second hairpin ( Fig.…”

Section: Resultssupporting

confidence: 81%

“…The ScanFold model leaves 75% of the basal stem nucleotides unpaired, indicating that local folds may not strongly compete against formation of the larger stem. Further, though the basal stem of SL5 is not present in the ScanFold model, the terminal stem loops (SL5a-c) are modeled consistent with recent global models of SL5 7,18 ( Fig. 2b) .…”

Section: Resultssupporting

confidence: 79%

“…b) Overall distribution of raw z-score values calculated across the genome are shown alongside two other positive strand RNA genomes, ZIKV and HIV-1, which were analyzed using the same parameters as SARS-CoV-2. c) Generic model of the first four stem loops found in the 5′ UTR of Betacoronavirus genomes 7,18 (based on the Rfam entry for SL1-2; RF02910). d) Generic model showing the general architecture of the frameshift element (FSE) found in the similar coronavirus genomes 11 (based on Rfam entry RF00507).…”

Section: Resultsmentioning

confidence: 99%

“…The start codon has been modeled as being unpaired, as opposed to previous global models which placed the start codon within a large multibranch structure (known as SL5; Fig. S1 ) 7,17,18 . As reported above, the scanning data around the start codon resulted in positive ΔG° z-scores, which in this case favor the formation of a small hairpin where the 5′ end of the SL5 basal stem would form and keeps the start codon nucleotides unpaired ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To help address this important need, we have analyzed the SARS-CoV-2 genome using an RNA structural analysis and motif discovery pipeline, ScanFold, which has been previously applied to two other RNA viruses: Zika and HIV-1 4 ; as well as human mRNAs for MYC 5 and α-synuclein 6 . A significant innovation of ScanFold is that unique consensus secondary structural motifs are generated from bases pairs with the strongest evidence of being functional, while not necessarily focusing on evolutionary conservation (as in a recent analysis of SARS-CoV-2 7 ). This provides a means of deducing novel structural elements that may only occur in this most recent pathogenic strain and, additionally, gives a global view of local structure that may not be forming specific structures – but still makes use of molecular stability.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

An in silico map of the SARS-CoV-2 RNA Structurome

Andrews

Haniff

et al. 2020

Preprint

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SARS-CoV-2 is a positive-sense single-stranded RNA virus that has exploded throughout the global human population. This pandemic coronavirus strain has taken scientists and public health researchers by surprise and knowledge of its basic biology (e.g. structure/function relationships in its genomic, messenger and template RNAs) and modes for therapeutic intervention lag behind that of other human pathogens. In this report we used a recently-developed bioinformatics approach, ScanFold, to deduce the RNA structural landscape of the SARS-CoV-2 transcriptome. We recapitulate known elements of RNA structure and provide a model for the folding of an essential frameshift signal. Our results find that the SARS-CoV-2 is greatly enriched in unusually stable and likely evolutionarily ordered RNA structure, which provides a huge reservoir of potential drug targets for RNA-binding small molecules. Our results also predict regions that are accessible for intermolecular interactions, which can aid in the design of antisense therapeutics. All results are made available via a public database (the RNAStructuromeDB) where they may hopefully drive drug discovery efforts to inhibit SARS-CoV-2 pathogenesis. Δ G° z-score region is the 3′UTR, which was found to yield mostly positive z-scores; despite a higher than average GC content for this region (0.45 on average; Table S1), MFE values here were less stable than expected, averaging Δ G° z-scores of +0.98 (or roughly one standard deviation less stable than random). Scans were also performed in the negative sense of the genome, revealing slightly less propensity for structure. The MFE values ranged from -42.9 to -6.0 and averaged -23.25 kcal/mol; z-scores in the negative sense had a similar range of Δ G° z-scores as the positive sense (-5.76 to 2.66) but averaged lower at -1.12 (Table S1). Interestingly, Δ G° z-scores for the 3′ UTR in negative sense were more skewed to the negative (finding minimums as low as -2.32) resulting in an average z-score of 0.16 for the region.

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Section: Resultssupporting

confidence: 81%

Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

An in silico map of the SARS-CoV-2 RNA Structurome

Andrews

Haniff

et al. 2020

Preprint

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Coronaviruses: What Should We Know About the Characteristics of Viruses?

2021

Advances in Experimental Medicine and Biology

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Epistasis-Driven Evolution of the SARS-CoV-2 Secondary Structure

2022

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Epistasis is an evolutionary phenomenon whereby the fitness effect of a mutation depends on the genetic background in which it arises. A key source of epistasis in an RNA molecule is its secondary structure, which contains functionally important topological motifs held together by hydrogen bonds between Watson–Crick (WC) base pairs. Here we study epistasis in the secondary structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by examining properties of derived alleles arising from substitution mutations at ancestral WC base-paired and unpaired (UP) sites in 15 conserved topological motifs across the genome. We uncover fewer derived alleles and lower derived allele frequencies at WC than at UP sites, supporting the hypothesis that modifications to the secondary structure are often deleterious. At WC sites, we also find lower derived allele frequencies for mutations that abolish base pairing than for those that yield G·U “wobbles,” illustrating that weak base pairing can partially preserve the integrity of the secondary structure. Last, we show that WC sites under the strongest epistatic constraint reside in a three-stemmed pseudoknot motif that plays an essential role in programmed ribosomal frameshifting, whereas those under the weakest epistatic constraint are located in 3’ UTR motifs that regulate viral replication and pathogenicity. Our findings demonstrate the importance of epistasis in the evolution of the SARS-CoV-2 secondary structure, as well as highlight putative structural and functional targets of different forms of natural selection.

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RNA genome conservation and secondary structure in SARS-CoV-2 and SARS-related viruses

Cited by 45 publications

References 41 publications

An in silico map of the SARS-CoV-2 RNA Structurome

An in silico map of the SARS-CoV-2 RNA Structurome

Coronaviruses: What Should We Know About the Characteristics of Viruses?

Epistasis-Driven Evolution of the SARS-CoV-2 Secondary Structure

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