title: Prediction of the next highly pathogenic avian influenza pandemic that can cause illness in humans.
abstract: BACKGROUND
  In recent years, avian influenza viruses (AIVs) have seriously threatened human health. Questions such as: why do AIVs infect humans?, how quickly can an AIV become pandemic?, and which virus is the most dangerous? cannot be sufficiently answered using current bioinformatic studies.
  
  
  METHODS
  Secondary structures and energies of representative 5'-untranslated region (UTR) of the HA gene were calculated. Then their secondary structures and energies were re-calculated after one or two nucleotide substitutions were introduced into the HA 5'-UTR. Phylogenetic trees on the basis of hemagglutinin (HA) and polymerase basic protein 2 (PB2) amino acid sequences and HA 5'-UTR nucleotide sequences were constructed. The connection between the energy and translation efficiency of 5'-UTR was confirmed by in vitro coupled transcription/translation assay.
  
  
  RESULTS
  The simplicity of the secondary structure of the 5'-UTR of the HA gene determines the overall virus replication rate and transmission potential. Point mutation assays show that the 5'-UTR sequences of the HA gene in the influenza subtypes H2N2, H3N2, and H7N9 have greater variation potentials than other virus subtypes.
  
  
  CONCLUSIONS
  Some high-virulent strains of avian influenza might emerge in the next two to three years. The H2N2 subtype, once disappeared in humans, may stage a comeback. The current outbreak of H7N9 may become pandemic and cause even more deaths, if one or two bases are substituted in the 5'-UTR sequence of the HA gene.
authors.affiliation: College of Resources Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China. zzwzhang@126.com.
authors.forename: Zhong-Wei
authors.initials: ZW
authors.lastname: Zhang
authors.affiliation: Sichuan Kelun Pharmaceutical Comp. Ltd., Chengdu, 610072, China. 191202430@q.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: College of Resources Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China. doplin@gmail.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Bioinformatic Study Centre, College of Life Sciences, Sichuan Agricultural University, Ya'an, 625014, China. anty9826@163.com.|Department of Plant Physiology, Umeå University, SE-901 87, Umeå, Sweden. anty9826@163.com.
authors.forename: Yang-Er
authors.initials: YE
authors.lastname: Chen
authors.affiliation: Bioinformatic Study Centre, College of Life Sciences, Sichuan Agricultural University, Ya'an, 625014, China. yuanmingsicau@126.com.|Boyce Thompson Institute, Cornell University, Ithaca, NY, 14850, USA. yuanmingsicau@126.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Yuan
authors.affiliation: College of Life Sciences, Sichuan University, Chengdu, 610064, China. yuanmiao1892@163.com.|Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 50011, USA. yuanmiao1892@163.com.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Sichuan University, Chengdu, 610064, China. zhufeng1361@163.com.|College of Horticulture and Plant Protection, Yangzhou University, Yangzhou, 225009, China. zhufeng1361@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: College of Resources Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China. roundtree318@hotmail.com.
authors.forename: Shu
authors.initials: S
authors.lastname: Yuan
mesh_terms: D020121:5' Untranslated Regions; D000595:Amino Acid Sequence; D000818:Animals; D019295:Computational Biology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics; D006801:Humans; D009980:Influenza A virus / Q000145:classification / Q000235:genetics* / Q000472:pathogenicity; D007251:Influenza, Human / Q000453:epidemiology* / Q000635:transmission / Q000821:virology*; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D058873:Pandemics; D010802:Phylogeny; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D012367:RNA, Viral; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics; D016415:Sequence Alignment; D014764:Viral Proteins / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; D019267:Hemagglutinin Glycoproteins, Influenza Virus; C057027:PB2 protein, Influenzavirus A; D012333:RNA, Messenger; D012367:RNA, Viral; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase