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Nucleic Acids Research Advance Access originally published online on March 1, 2007
Nucleic Acids Research 2007 35(6):1897-1907; doi:10.1093/nar/gkm087
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Nucleic Acids Research, 2007, Vol. 35, No. 6 1897-1907
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Computational Biology

Codon conservation in the influenza A virus genome defines RNA packaging signals

Julia R. Gog1, Emmanuel Dos Santos Afonso2, Rosa M. Dalton3, India Leclercq2, Laurence Tiley4, Debra Elton3, Johann C. von Kirchbach1, Nadia Naffakh2, Nicolas Escriou2 and Paul Digard3,*

1DAMTP, Centre for Mathematical Sciences, University of Cambridge, Wilberforce Road, Cambridge CB3 0WA, UK, 2Unité de Génétique Moléculaire des Virus Respiratoires, URA-CNRS 1966, Université Paris 7 EA302, Institut Pasteur, 25, rue du Dr Roux, 75724 Paris cedex 15, France, 3Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK and 4Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK

*To whom correspondence should be addressed. Tel: + 44 1223 336920; Fax: + 44 1223 336926; Email: pd1{at}mole.bio.cam.ac.uk

Received December 21, 2006. Revised January 29, 2007. Accepted January 30, 2007.

Genome segmentation facilitates reassortment and rapid evolution of influenza A virus. However, segmentation complicates particle assembly as virions must contain all eight vRNA species to be infectious. Specific packaging signals exist that extend into the coding regions of most if not all segments, but these RNA motifs are poorly defined. We measured codon variability in a large dataset of sequences to identify areas of low nucleotide sequence variation independent of amino acid conservation in each segment. Most clusters of codons showing very little synonymous variation were located at segment termini, consistent with previous experimental data mapping packaging signals. Certain internal regions of conservation, most notably in the PA gene, may however signify previously unidentified functions in the virus genome. To experimentally test the bioinformatics analysis, we introduced synonymous mutations into conserved codons within known packaging signals and measured incorporation of the mutant segment into virus particles. Surprisingly, in most cases, single nucleotide changes dramatically reduced segment packaging. Thus our analysis identifies cis-acting sequences in the influenza virus genome at the nucleotide level. Furthermore, we propose that strain-specific differences exist in certain packaging signals, most notably the haemagglutinin gene; this finding has major implications for the evolution of pandemic viruses.

Present address: Debra Elton, Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk, CB8 7UU, UK


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