The influence of secondary structure, selection and recombination on rubella virus nucleotide substitution rate estimates

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dc.contributor.authorCloete, Leenderten_ZA
dc.contributor.authorTanov, Emilen_ZA
dc.contributor.authorMuhire, Brejneven_ZA
dc.contributor.authorMartin, Darrenen_ZA
dc.contributor.authorHarkins, Gordonen_ZA
dc.date.accessioned2015-11-27T09:30:13Z
dc.date.available2015-11-27T09:30:13Z
dc.date.issued2014en_ZA
dc.description.abstractBACKGROUND: Annually, rubella virus (RV) still causes severe congenital defects in around 100 000 children globally. An attempt to eradicate RV is currently underway and analytical tools to monitor the global decline of the last remaining RV lineages will be useful for assessing the effectiveness of this endeavour. RV evolves rapidly enough that much of this information might be inferable from RV genomic sequence data. METHODS: Using BEASTv1.8.0, we analysed publically available RV sequence data to estimate genome-wide and gene-specific nucleotide substitution rates to test whether current estimates of RV substitution rates are representative of the entire RV genome. We specifically accounted for possible confounders of nucleotide substitution rate estimates, such as temporally biased sampling, sporadic recombination, and natural selection favouring either increased or decreased genetic diversity (estimated by the PARRIS and FUBAR methods), at nucleotide sites within the genomic secondary structures (predicted by the NASP method). RESULTS: We determine that RV nucleotide substitution rates range from 1.19 x 10-3 substitutions/site/year in the E1 region to 7.52 x 10-4 substitutions/site/year in the P150 region. We find that differences between substitution rate estimates in different RV genome regions are largely attributable to temporal sampling biases such that datasets containing higher proportions of recently sampled sequences, will tend to have inflated estimates of mean substitution rates. Although there exists little evidence of positive selection or natural genetic recombination in RV, we show that RV genomes possess pervasive biologically functional nucleic acid secondary structure and that purifying selection acting to maintain this structure contributes substantially to variations in estimated nucleotide substitution rates across RV genomes. CONCLUSION: Both temporal sampling biases and purifying selection favouring the conservation of RV nucleic acid secondary structures have an appreciable impact on substitution rate estimates but do not preclude the use of RV sequence data to date ancestral sequences. The combination of uniformly high substitution rates across the RV genome and strong temporal structure within the available sequence data, suggests that such data should be suitable for tracking the demographic, epidemiological and movement dynamics of this virus during eradication attempts.en_ZA
dc.identifier.apacitationCloete, L., Tanov, E., Muhire, B., Martin, D., & Harkins, G. (2014). The influence of secondary structure, selection and recombination on rubella virus nucleotide substitution rate estimates. <i>Virology Journal</i>, http://hdl.handle.net/11427/15380en_ZA
dc.identifier.chicagocitationCloete, Leendert, Emil Tanov, Brejnev Muhire, Darren Martin, and Gordon Harkins "The influence of secondary structure, selection and recombination on rubella virus nucleotide substitution rate estimates." <i>Virology Journal</i> (2014) http://hdl.handle.net/11427/15380en_ZA
dc.identifier.citationCloete, L. J., Tanov, E. P., Muhire, B. M., Martin, D. P., & Harkins, G. W. (2014). The influence of secondary structure, selection and recombination on rubella virus nucleotide substitution rate estimates. Virology journal, 11(1), 1-12.en_ZA
dc.identifier.ris TY - Journal Article AU - Cloete, Leendert AU - Tanov, Emil AU - Muhire, Brejnev AU - Martin, Darren AU - Harkins, Gordon AB - BACKGROUND: Annually, rubella virus (RV) still causes severe congenital defects in around 100 000 children globally. An attempt to eradicate RV is currently underway and analytical tools to monitor the global decline of the last remaining RV lineages will be useful for assessing the effectiveness of this endeavour. RV evolves rapidly enough that much of this information might be inferable from RV genomic sequence data. METHODS: Using BEASTv1.8.0, we analysed publically available RV sequence data to estimate genome-wide and gene-specific nucleotide substitution rates to test whether current estimates of RV substitution rates are representative of the entire RV genome. We specifically accounted for possible confounders of nucleotide substitution rate estimates, such as temporally biased sampling, sporadic recombination, and natural selection favouring either increased or decreased genetic diversity (estimated by the PARRIS and FUBAR methods), at nucleotide sites within the genomic secondary structures (predicted by the NASP method). RESULTS: We determine that RV nucleotide substitution rates range from 1.19 x 10-3 substitutions/site/year in the E1 region to 7.52 x 10-4 substitutions/site/year in the P150 region. We find that differences between substitution rate estimates in different RV genome regions are largely attributable to temporal sampling biases such that datasets containing higher proportions of recently sampled sequences, will tend to have inflated estimates of mean substitution rates. Although there exists little evidence of positive selection or natural genetic recombination in RV, we show that RV genomes possess pervasive biologically functional nucleic acid secondary structure and that purifying selection acting to maintain this structure contributes substantially to variations in estimated nucleotide substitution rates across RV genomes. CONCLUSION: Both temporal sampling biases and purifying selection favouring the conservation of RV nucleic acid secondary structures have an appreciable impact on substitution rate estimates but do not preclude the use of RV sequence data to date ancestral sequences. The combination of uniformly high substitution rates across the RV genome and strong temporal structure within the available sequence data, suggests that such data should be suitable for tracking the demographic, epidemiological and movement dynamics of this virus during eradication attempts. DA - 2014 DB - OpenUCT DO - 10.1186/1743-422X-11-166 DP - University of Cape Town J1 - Virology Journal LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - The influence of secondary structure, selection and recombination on rubella virus nucleotide substitution rate estimates TI - The influence of secondary structure, selection and recombination on rubella virus nucleotide substitution rate estimates UR - http://hdl.handle.net/11427/15380 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/15380
dc.identifier.urihttp://dx.doi.org/10.1186/1743-422X-11-166
dc.identifier.vancouvercitationCloete L, Tanov E, Muhire B, Martin D, Harkins G. The influence of secondary structure, selection and recombination on rubella virus nucleotide substitution rate estimates. Virology Journal. 2014; http://hdl.handle.net/11427/15380.en_ZA
dc.language.isoengen_ZA
dc.publisherBioMed Central Ltden_ZA
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Licenseen_ZA
dc.rights.holderCloete et al.; licensee BioMed Central Ltd. 2014en_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en_ZA
dc.sourceVirology Journalen_ZA
dc.source.urihttp://virologyj.biomedcentral.com/en_ZA
dc.subject.otherRubella virusen_ZA
dc.subject.otherCongenital rubella syndromeen_ZA
dc.subject.otherNucleotide substitution ratesen_ZA
dc.subject.otherSynonymous substitution ratesen_ZA
dc.subject.otherRecombination Nucleic acid secondary structureen_ZA
dc.subject.otherBayesian phylogenetic analysesen_ZA
dc.titleThe influence of secondary structure, selection and recombination on rubella virus nucleotide substitution rate estimatesen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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