The Evolutionary Dynamics of Human Influenza B Virus

  • Rubing Chen
  • Edward C. Holmes


Despite their close phylogenetic relationship, type A and B influenza viruses exhibit major epidemiological differences in humans, with the latter both less common and less often associated with severe disease. However, it is unclear what processes determine the evolutionary dynamics of influenza B virus, and how influenza viruses A and B interact at the evolutionary scale. To address these questions we inferred the phylogenetic history of human influenza B virus using complete genome sequences for which the date (day) of isolation was available. By comparing the phylogenetic patterns of all eight viral segments we determined the occurrence of segment reassortment over a 30-year sampling period. An analysis of rates of nucleotide substitution and selection pressures revealed sporadic occurrences of adaptive evolution, most notably in the viral hemagglutinin and compatible with the action of antigenic drift, yet lower rates of overall and nonsynonymous nucleotide substitution compared to influenza A virus. Overall, these results led us to propose a model in which evolutionary changes within and between the antigenically distinct ‘Yam88’ and ‘Vic87’ lineages of influenza B virus are the result of changes in herd immunity, with reassortment continuously generating novel genetic variation. Additionally, we suggest that the interaction with influenza A virus may be central in shaping the evolutionary dynamics of influenza B virus, facilitating the shift of dominance between the Vic87 and the Yam88 lineages.


Influenza B virus Phylogeny Reassortment Coalescent Antigenic drift Epidemiology 



We thank Dr. J. K. Taubenberger for constructive comments on an earlier version of the manuscript and Dr. C. Viboud for assistance with the epidemiological data. We thank all those involved in the Influenza Genome Sequencing Project for contributing their viruses or obtaining genome sequence data. This work was supported in part by NIH Grant GM080533-01.

Supplementary material

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  1. Air GM, Gibbs AJ, Laver WG, Webster RG (1990) Evolutionary changes in influenza B are not primarily governed by antibody selection. Proc Natl Acad Sci USA 87:3884–3888PubMedCrossRefGoogle Scholar
  2. Anestad G (1987) Surveillance of respiratory viral infections by rapid immunofluorescence diagnosis, with emphasis on virus interference. Epidemiol Infect 99:523–531PubMedCrossRefGoogle Scholar
  3. Baigent SJ, McCauley JW (2003) Influenza type A in humans, mammals and birds: determinants of virus virulence, host-range and interspecies transmission. BioEssays 25:657–671PubMedCrossRefGoogle Scholar
  4. Chi XS, Bolar TV, Zhao P, Rappaport R, Cheng SM (2003) Cocirculation and evolution of two lineages of influenza B viruses in Europe and Israel in the 2001–2002 season. J Clin Microbiol 41:5770–5773PubMedCrossRefGoogle Scholar
  5. Drummond AJ, Nicholls GK, Rodrigo AG, Solomon W (2002) Estimating mutation parameters, population history and genealogy simultaneously from temporally spaced sequence data. Genetics 161:1307–1320PubMedGoogle Scholar
  6. Drummond AJ, Ho SY, Phillips MJ, Rambaut A (2006) Relaxed phylogenetics and dating with confidence. PLoS Biol 4:e88PubMedCrossRefGoogle Scholar
  7. Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32:1792–1797PubMedCrossRefGoogle Scholar
  8. Fitch WM, Leiter JME, Li X, Palese P (1991) Positive Darwinian evolution in human influenza A viruses. Proc Natl Acad Sci USA 88:4270–4274PubMedCrossRefGoogle Scholar
  9. Fitch WM, Bush RM, Bender CA, Cox NJ (1997) Long term trends in the evolution of H(3) HA1 human influenza type A. Proc Natl Acad Sci USA 94:7712–7718PubMedCrossRefGoogle Scholar
  10. Ghedin E, Sengamalay N, Shumway M, Zaborsky J, Feldblyum T, Subbu V, Spiro D, Sitz J, Koo H, Bolotov P, Dernovoy D, Tatusova T, Bao Y, St George K, Taylor J, Lipman D, Fraser C, Taubenberger J, Salzberg S (2005) Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution. Nature 437:1162–1166PubMedCrossRefGoogle Scholar
  11. Hanada K, Suzuki Y, Gojobori T (2004) A large variation in the rates of synonymous substitution for RNA viruses and its relationship to a diversity of viral infection and transmission modes. Mol Biol Evol 21:1074–1080PubMedCrossRefGoogle Scholar
  12. Hiromoto Y, Saito T, Lindstrom SE, Li Y, Nerome R, Sugita S, Shinjoh M, Nerome K (2000) Phylogenetic analysis of the three polymerase genes (PB1, PB2 and PA) of influenza B virus. J Gen Virol 81:929–937PubMedGoogle Scholar
  13. Holmes EC, Ghedin E, Miller N, Taylor J, Bao Y, St George K, Grenfell BT, Salzberg SL, Fraser CM, Lipman DJ, Taubenberger JK (2005) Whole-genome analysis of human influenza A virus reveals multiple persistent lineage and reassortment among recent H3N2 viruses. PLoS Biol 3:e300PubMedCrossRefGoogle Scholar
  14. Jenkins GM, Rambaut A, Pybus OG, Holmes EC (2002) Rates of molecular evolution in RNA viruses: a quantitative phylogenetic analysis. J Mol Evol 54:156–165PubMedCrossRefGoogle Scholar
  15. Kanegae Y, Sugita S, Endo A, Ishida M, Senya S, Osako K, Nerome K, Oya A (1990) Evolutionary pattern of the hemagglutinin gene of influenza B viruses isolated in Japan: cocirculating lineages in the same epidemic season. J Virol 64:2860–2865PubMedGoogle Scholar
  16. Lindstrom SE, Hiromoto Y, Nishimura H, Saito T, Nerome R, Nerome K (1999) Comparative analysis of evolutionary mechanisms of the hemagglutinin and three internal protein genes of influenza B virus: multiple cocirculating lineages and frequent reassortment of the NP, M, and NS genes. J Virol 73:4413–4426PubMedGoogle Scholar
  17. Maddison DR, Maddison WP (2001) MacClade 4: analysis of phylogeny and character evolution. Version 4.03. Sinauer Associates, Sunderland, MAGoogle Scholar
  18. Matsuzaki Y, Sugawara K, Takashita E, Muraki Y, Hongo S, Katsushima N, Mizuta K, Nishimura H (2004) Genetic diversity of influenza B virus: the frequent reassortment and cocirculation of the genetically distinct reassortant viruses in a community. J Med Virol 74:132–140PubMedCrossRefGoogle Scholar
  19. McCullers JA, Wang GC, He S, Webster RG (1999) Reassortment and insertion-deletion are strategies for the evolution of influenza B viruses in nature. J Virol 73:7374–7348Google Scholar
  20. McCullers JA, Saito T, Iverson AR (2004) Multiple genotypes of influenza B virus circulated between 1979 and 2003. J Virol 78:12817–12828PubMedCrossRefGoogle Scholar
  21. Mikheeva A, Ghendon YZ (1982) Intrinsic interference between influenza A and B viruses. Arch Virol 73:287–294PubMedCrossRefGoogle Scholar
  22. Nakagawa N, Kubota R, Okuno Y (2005) Variation of the conserved neutralizing epitope in influenza B virus Victoria group isolates in Japan. J Clin Microbiol 43:4212–4214PubMedCrossRefGoogle Scholar
  23. Nelson MI, Simonsen L, Viboud C, Miller MA, Taylor J, St. George K, Griesemer EG, Ghedin E, Sengamalay NA et al (2006) Stochastic processes are key determinants of short-term evolution in Influenza A virus. PLoS Pathog 2:e125Google Scholar
  24. Nobusawa E, Sato K (2006) Comparison of the mutation rates of human influenza A and B viruses. J Virol 80:3675–3678PubMedCrossRefGoogle Scholar
  25. Pond SL, Frost SDW (2005) Datamonkey: rapid detection of selective pressure on individual sites of codon alignments. Bioinformatics 21:2531–2533PubMedCrossRefGoogle Scholar
  26. Posada D, Crandall KA (1998) Modeltest: testing the model of DNA substitution. Bioinformatics 14:817–818PubMedCrossRefGoogle Scholar
  27. Pybus OG, Rambaut A, Freckleton RP, Belshaw R, Drummond AJ, Holmes EC (2007) Phylogenetic evidence for deleterious mutation load in RNA viruses and its contribution to viral evolution. Mol Biol Evol 24:845–852PubMedCrossRefGoogle Scholar
  28. Rambaut A (1996) Se–Al: Sequence Alignment Editor. Available at:
  29. Rota PA, Wallis TR, Harmon MW, Rota JS, Kendal AP, Nerome K (1990) Cocirculation of two distinct evolutionary lineages of influenza type B virus since 1983. Virology 175:59–68PubMedCrossRefGoogle Scholar
  30. Rota PA, Hemhill ML, Whistler T, Regnery HL, Kendal AP (1992) Antigenic and genetic characterization of the haemagglutinins of recent cocirculating strains of influenza B virus. J Gen Virol 73:2737–2742PubMedCrossRefGoogle Scholar
  31. Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, Osterhaus AD, Fouchier RA (2004) Mapping the antigenic and genetic evolution of influenza virus. Science 305:371–376PubMedCrossRefGoogle Scholar
  32. Swofford DL (2003) PAUP*. Phylogenetic analysis using parsimony (*and other methods). Version 4. Sinauer Associates, Sunderland, MAGoogle Scholar
  33. Viboud C, Alonso WJ, Simonsen L (2006a) Influenza in tropical regions. PLOS Med 3:461–471CrossRefGoogle Scholar
  34. Viboud C, Bjørnstad ON, Smith DL, Simonsen L, Miller MA, Grenfell BT (2006b) Synchrony, waves, and spatial hierarchies in the spread of influenza. Science 312:447–451PubMedCrossRefGoogle Scholar
  35. Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y (1992) Evolution and ecology of influenza A viruses. Microbiol Rev 56:152–179PubMedGoogle Scholar
  36. Yang Z (2007) PAML 4: phylogenetic analysis by maximum likelihood. Mol Biol Evol 24:1586–1591PubMedCrossRefGoogle Scholar
  37. Zou S, Prud’Homme I, Weber JM (1997) Evolution of the hemagglutinin gene of influenza B virus was driven by both positive and negative selection pressures. Virus Genes 14:181–185PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Center for Infectious Disease Dynamics, Department of BiologyThe Pennsylvania State University, Mueller LaboratoryUniversity ParkUSA
  2. 2.Fogarty International CenterNational Institutes of HealthBethesdaUSA

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