Origin and evolution of influenza virus hemagglutinin genes

Mol Biol Evol. 2002 Apr;19(4):501-9. doi: 10.1093/oxfordjournals.molbev.a004105.


Influenza A, B, and C viruses are the etiological agents of influenza. Hemagglutinin (HA) is the major envelope glycoprotein of influenza A and B viruses, and hemagglutinin-esterase (HE) in influenza C viruses is a protein homologous to HA. Because influenza A virus pandemics in humans appear to occur when new subtypes of HA genes are introduced from aquatic birds that are known to be the natural reservoir of the viruses, an understanding of the origin and evolution of HA genes is of particular importance. We therefore conducted a phylogenetic analysis of HA and HE genes and showed that the influenza A and B virus HA genes diverged much earlier than the divergence between different subtypes of influenza A virus HA genes. The rate of amino acid substitution for A virus HAs from duck, a natural reservoir, was estimated to be 3.19 x 10(-4) per site per year, which was slower than that for human and swine A virus HAs but similar to that for influenza B and C virus HAs (HEs). Using this substitution rate from the duck, we estimated that the divergences between different subtypes of A virus HA genes occurred from several thousand to several hundred years ago. In particular, the earliest divergence time was estimated to be about 2,000 years ago. Also, the A virus HA gene diverged from the B virus HA gene about 4,000 years ago and from the C virus HE gene about 8,000 years ago. These time estimates are much earlier than the previous ones.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • DNA, Viral / analysis
  • Evolution, Molecular*
  • Genes, Viral
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics*
  • Humans
  • Influenza A virus / genetics*
  • Influenza B virus / genetics*
  • Influenzavirus C / genetics*
  • Molecular Sequence Data
  • Phylogeny
  • Sequence Homology, Amino Acid


  • DNA, Viral
  • Hemagglutinin Glycoproteins, Influenza Virus