The relationship between mutation frequency and replication strategy in positive-sense single-stranded RNA viruses

Thebaud, G., Chad uf, J., Morelli, M.J., McCauley, J.W. and Haydon, D.T. (2010) The relationship between mutation frequency and replication strategy in positive-sense single-stranded RNA viruses. Proceedings of the Royal Society of London Series B: Biological Sciences, 277(1682), pp. 809-817. (doi: 10.1098/rspb.2009.1247) (PMID:19906671) (PMCID:PMC2842737)

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Abstract

For positive-sense single-stranded RNA virus genomes, there is a trade-off between the mutually exclusive tasks of transcription, translation and encapsidation. The replication strategy that maximizes the intracellular growth rate of the virus requires iterative genome transcription from positive to negative, and back to positive sense. However, RNA viruses experience high mutation rates, and the proportion of genomes with lethal mutations increases with the number of replication cycles. Thus, intracellular mutant frequency will depend on the replication strategy. Introducing apparently realistic mutation rates into a model of viral replication demonstrates that strategies that maximize viral growth rate could result in an average of 26 mutations per genome by the time plausible numbers of positive strands have been generated, and that virus viability could be as low as 0.1 per cent. At high mutation rates or when a high proportion of mutations are deleterious, the optimal strategy shifts towards synthesizing more negative strands per positive strand, and in extremis towards a 'stamping-machine' replication mode where all the encapsidated genomes come from only two transcriptional steps. We conclude that if viral mutation rates are as high as current estimates suggest, either mutation frequency must be considerably higher than generally anticipated and the proportion of viable viruses produced extremely small, or replication strategies cannot be optimized to maximize viral growth rate. Mechanistic models linking mutation frequency to replication mechanisms coupled with data generated through new deep-sequencing technologies could play an important role in improving the estimates of viral mutation rate

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Morelli, Dr Marco and Haydon, Professor Daniel
Authors: Thebaud, G., Chad uf, J., Morelli, M.J., McCauley, J.W., and Haydon, D.T.
Subjects:Q Science > QR Microbiology > QR355 Virology
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:Proceedings of the Royal Society of London Series B: Biological Sciences
ISSN:0962-8452
ISSN (Online):1471-2954
Published Online:11 November 2009

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
461341A systems biology approach to integrating pathogen evolution and epidemiologyDaniel HaydonBiotechnology and Biological Sciences Research Council (BBSRC)BB/F005733/1Institute of Biodiversity Animal Health and Comparative Medicine