title: The role of RNA folding free energy in the evolution of the polymerase genes of the influenza A virus.
abstract: BACKGROUND
  The influenza A virus genome is composed of eight single-stranded RNA segments of negative polarity. Although the hemagglutinin and neuraminidase genes are known to play a key role in host adaptation, the polymerase genes (which encode the polymerase segments PB2, PB1, PA) and the nucleoprotein gene are also important for the efficient propagation of the virus in the host and for its adaptation to new hosts. Current efforts to understand the host-specificity of the virus have largely focused on the amino acid differences between avian and human isolates.
  
  
  RESULTS
  Here we show that the folding free energy of the RNA segments may play an equally important role in the evolution and host adaptation of the influenza virus. Folding free energy may affect the stability of the viral RNA and influence the rate of viral protein translation. We found that there is a clear distinction between the avian and human folding free energy distributions for the polymerase and the nucleoprotein genes, with human viruses having substantially higher folding free energy values. This difference is independent of the amino acid composition and the codon bias. Furthermore, the folding free energy values of the commonly circulating human viruses tend to shift towards higher values over the years, after they entered the human population. Finally, our results indicate that the temperature in which the cells grow affects infection efficiency.
  
  
  CONCLUSIONS
  Our data suggest for the first time that RNA structure stability may play an important role in the emergence and host shift of influenza A virus. The fact that cell temperature affects virus propagation in mammalian cells could help identify those avian strains that pose a higher threat to humans.
authors.affiliation: Department of Computational Biology, School of Medicine, University of Pittsburgh, Fifth Avenue, Pittsburgh, PA 15260, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Brower-Sinning
authors.forename: Donald M
authors.initials: DM
authors.lastname: Carter
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Crevar
authors.forename: Elodie
authors.initials: E
authors.lastname: Ghedin
authors.forename: Ted M
authors.initials: TM
authors.lastname: Ross
authors.forename: Panayiotis V
authors.initials: PV
authors.lastname: Benos
mesh_terms: D000818:Animals; D001717:Birds; D019143:Evolution, Molecular; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D053121:Influenza A Virus, H2N2 Subtype; D053122:Influenza A Virus, H3N2 Subtype; D053124:Influenza A Virus, H5N1 Subtype; D009980:Influenza A virus / Q000201:enzymology* / Q000235:genetics; D009690:Nucleic Acid Conformation; D020871:RNA Stability; D012367:RNA, Viral / Q000737:chemistry / Q000502:physiology*; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D013696:Temperature; D013816:Thermodynamics; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication
chemical_list: C061290:PA protein, influenza viruses; C502893:PB2 protein, influenza virus; D012367:RNA, Viral; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D012324:RNA-Dependent RNA Polymerase