Influenza viruses are remarkably adept at surviving in the human population over a long timescale. The human influenza A virus continues to thrive even among populations with widespread access to vaccines, and continues to be a major cause of morbidity and mortality^{1, 2}. The virus mutates from year to year, making the existing vaccines ineffective on a regular basis, and requiring that new strains be chosen for a new vaccine. Less-frequent major changes, known as antigenic shift, create new strains against which the human population has little protective immunity, thereby causing worldwide pandemics. The most recent pandemics include the 1918 'Spanish' flu, one of the most deadly outbreaks in recorded history, which killed 30–50 million people worldwide, the 1957 'Asian' flu, and the 1968 'Hong Kong' flu³. Motivated by the need for a better understanding of influenza evolution, we have developed flexible protocols that make it possible to apply large-scale sequencing techniques to the highly variable influenza genome. Here we report the results of sequencing 209 complete genomes of the human influenza A virus, encompassing a total of 2,821,103 nucleotides. In addition to increasing markedly the number of publicly available, complete influenza virus genomes, we have discovered several anomalies in these first 209 genomes that demonstrate the dynamic nature of influenza transmission and evolution. This new, large-scale sequencing effort promises to provide a more comprehensive picture of the evolution of influenza viruses and of their pattern of transmission through human and animal populations. All data from this project are being deposited, without delay, in public archives.

1. The Institute for Genomic Research, 9712 Medical Center Dr., Rockville, Maryland 20850, USA
2. National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA
3. Wadsworth Center, New York State Department of Health, Albany, New York 12201, USA
4. Department of Molecular Pathology, Armed Forces Institute of Pathology, Rockville, Maryland 20850, USA
5. Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, College Park, Maryland 20742, USA

Correspondence to: Steven L. Salzberg^1,5 Correspondence and requests for materials should be addressed to S.L.S. (Email: salzberg@umd.edu). GenBank accession numbers are provided in the Supplementary Data.

Received 7 July 2005; Accepted 16 September 2005

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