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

Julia R. Gog, Emmanuel Dos Santos Afonso, Rosa M. Dalton, India Leclercq, Laurence Tiley, Debra Elton, Johann C. von Kirchbach, Nadia Naffakh, Nicolas Escriou, Paul Digard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1897-1907
Number of pages11
JournalNucleic Acids Research
Volume35
Issue number6
DOIs
Publication statusPublished - 1 Mar 2007

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