Letter | Published:

A synchronized global sweep of the internal genes of modern avian influenza virus

Nature volume 508, pages 254257 (10 April 2014) | Download Citation


Zoonotic infectious diseases such as influenza continue to pose a grave threat to human health1. However, the factors that mediate the emergence of RNA viruses such as influenza A virus (IAV) are still incompletely understood2,3. Phylogenetic inference is crucial to reconstructing the origins and tracing the flow of IAV within and between hosts3,4,5,6,7,8. Here we show that explicitly allowing IAV host lineages to have independent rates of molecular evolution is necessary for reliable phylogenetic inference of IAV and that methods that do not do so, including ‘relaxed’ molecular clock models9, can be positively misleading. A phylogenomic analysis using a host-specific local clock model recovers extremely consistent evolutionary histories across all genomic segments and demonstrates that the equine H7N7 lineage is a sister clade to strains from birds—as well as those from humans, swine and the equine H3N8 lineage—sharing an ancestor with them in the mid to late 1800s. Moreover, major western and eastern hemisphere avian influenza lineages inferred for each gene coalesce in the late 1800s. On the basis of these phylogenies and the synchrony of these key nodes, we infer that the internal genes of avian influenza virus (AIV) underwent a global selective sweep beginning in the late 1800s, a process that continued throughout the twentieth century and up to the present. The resulting western hemispheric AIV lineage subsequently contributed most of the genomic segments to the 1918 pandemic virus and, independently, the 1963 equine H3N8 panzootic lineage. This approach provides a clear resolution of evolutionary patterns and processes in IAV, including the flow of viral genes and genomes within and between host lineages.

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Data deposits

Sequences for A/equine/Detroit/3/1964(H7N7), A/chicken/Japan/1925(H7N7) and A/duck/Manitoba/1953(H10N7) have been deposited in the GenBank database under accession numbers KF435047KF435062 and KF619244KF619250.


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We thank J. Barnes, S. Meno, M. Shaw, R. Donis, S. Krauss, K. Friedman, R. Webster, Y. Muramoto and Y. Kawaoka for assistance in locating and sequencing A/equine/Detroit/3/1964(H7N7), A/chicken/Japan/1925(H7N7) and A/duck/Manitoba/1953(H10N7); M. Sanderson for comments on the HSLC model; S. Zohari for discussions of the NS1/2 A and B lineages; and M. Nachman, Y. Kawaoka, T. Watts, J. Cox, and D. Gill for comments. This work was supported by grants from the David and Lucile Packard Foundation to M.W., and the Wellcome Trust (grant no. 092807) to A.R. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 278433-PREDEMICS and European Research Council grant agreement no. 260864. The methodological approach was developed in part with support from a grant from the National Institutes of Health/National Institute of Allergy and Infectious Diseases. (R01AI084691).

Author information


  1. Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona 85721, USA

    • Michael Worobey
    •  & Guan-Zhu Han
  2. Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK

    • Andrew Rambaut
  3. Fogarty International Center, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Andrew Rambaut


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M.W., G.-Z.H. and A.R. designed the study. M.W. and A.R. conceived the analytical approach, and A.R. developed the software. G.-Z.H., M.W. and A.R. prepared the data sets. M.W., G.-Z.H. and A.R. performed the phylogenetic analyses. M.W. conducted the U content analyses. M.W. and A.R. wrote the paper. All authors discussed all the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Michael Worobey or Andrew Rambaut.

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