Homologous Recombination Is Very Rare or Absent in Human Influenza A Virus

ABSTRACT To determine the extent of homologous recombination in human influenza A virus, we assembled a data set of 13,852 sequences representing all eight segments and both major circulating subtypes, H3N2 and H1N1. Using an exhaustive search and a nonparametric test for mosaic structure, we identified 315 sequences (∼2%) in five different RNA segments that, after a multiple-comparison correction, had statistically significant mosaic signals compatible with homologous recombination. Of these, only two contained recombinant regions of sufficient length (>100 nucleotides [nt]) that the occurrence of homologous recombination could be verified using phylogenetic methods, with the rest involving very short sequence regions (15 to 30 nt). Although this secondary analysis revealed patterns of phylogenetic incongruence compatible with the action of recombination, neither candidate recombinant was strongly supported. Given our inability to exclude the occurrence of mixed infection and template switching during amplification, laboratory artifacts provide an alternative and likely explanation for the occurrence of phylogenetic incongruence in these two cases. We therefore conclude that, if it occurs at all, homologous recombination plays only a very minor role in the evolution of human influenza A virus.

[1]  E. Holmes,et al.  Multiple recombinant dengue type 1 viruses in an isolate from a dengue patient , 2007, The Journal of general virology.

[2]  L. Real,et al.  Isolates of Zaire ebolavirus from wild apes reveal genetic lineage and recombinants , 2007, Proceedings of the National Academy of Sciences.

[3]  S. L. Murphy,et al.  Deaths: final data for 2004. , 2007, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[4]  N. Cox,et al.  Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. , 2007, The Journal of infectious diseases.

[5]  H. Niman.  Swine Influenza A Evolution via Recombination - Genetic Drift Reservoir , 2007 .

[6]  David Posada,et al.  An Exact Nonparametric Method for Inferring Mosaic Structure in Sequence Triplets , 2007, Genetics.

[7]  F. Aoki,et al.  Influenza Virus Susceptibility and Resistance to Oseltamivir , 2005, Antiviral therapy.

[8]  Cecile Viboud,et al.  Stochastic Processes Are Key Determinants of Short-Term Evolution in Influenza A Virus , 2006, PLoS pathogens.

[9]  J. Taubenberger,et al.  1918 Influenza: the Mother of All Pandemics , 2006, Emerging infectious diseases.

[10]  Bryan T Grenfell,et al.  Whole-Genome Analysis of Human Influenza A Virus Reveals Multiple Persistent Lineages and Reassortment among Recent H3N2 Viruses , 2005, PLoS biology.

[11]  A. Lapedes,et al.  Mapping the Antigenic and Genetic Evolution of Influenza Virus , 2004, Science.

[12]  I. Brown,et al.  Recombination Resulting in Virulence Shift in Avian Influenza Outbreak, Chile , 2004, Emerging infectious diseases.

[13]  Robert C. Edgar,et al.  MUSCLE: multiple sequence alignment with high accuracy and high throughput. , 2004, Nucleic acids research.

[14]  Edward C Holmes,et al.  Phylogenetic analysis reveals a low rate of homologous recombination in negative-sense RNA viruses. , 2003, The Journal of general virology.

[15]  N. Ferguson,et al.  Ecological and immunological determinants of influenza evolution , 2003, Nature.

[16]  Keiji Fukuda,et al.  Mortality associated with influenza and respiratory syncytial virus in the United States. , 2003, JAMA.

[17]  K. Strimmer,et al.  A novel exploratory method for visual recombination detection , 2003, Genome Biology.

[18]  O. Pybus,et al.  Questioning the evidence for genetic recombination in the 1918 "Spanish flu" virus. , 2002, Science.

[19]  Mark J. Gibbs,et al.  Recombination in the Hemagglutinin Gene of the 1918 "Spanish Flu" , 2001, Science.

[20]  M. P. Cummings,et al.  PAUP* Phylogenetic analysis using parsimony (*and other methods) Version 4 , 2000 .

[21]  W. Fitch,et al.  Positive selection on the H3 hemagglutinin gene of human influenza virus A. , 1999, Molecular biology and evolution.

[22]  David Posada,et al.  MODELTEST: testing the model of DNA substitution , 1998, Bioinform..

[23]  W. Fitch,et al.  Long term trends in the evolution of H(3) HA1 human influenza type A. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[24]  R. Rott,et al.  Nonhomologous recombination between the hemagglutinin gene and the nucleoprotein gene of an influenza virus. , 1994, Virology.

[25]  A. García-Sastre,et al.  Transfection-mediated recombination of influenza A virus , 1992, Journal of virology.

[26]  R. Webster,et al.  Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics , 1989, Journal of virology.

[27]  R. Rott,et al.  Increased viral pathogenicity after insertion of a 28S ribosomal RNA sequence into the haemagglutinin gene of an influenza virus , 1989, Nature.

[28]  N. Cox,et al.  Antigenic drift in influenza virus H3 hemagglutinin from 1968 to 1980: multiple evolutionary pathways and sequential amino acid changes at key antigenic sites , 1983, Journal of virology.

[29]  Kilbourne Ed.  Molecular epidemiology--influenza as archetype. , 1979 .

[30]  E. D. Kilbourne.  Molecular epidemiology--influenza as archetype. , 1979, Harvey lectures.

[31]  C. Scholtissek,et al.  On the origin of the human influenza virus subtypes H2N2 and H3N2. , 1978, Virology.

[32]  J. Taubenberger,et al.  Influenza : the Mother of All Pandemics , 2022 .