| The genetic diversity and evolutionary plasticity of the influenza A virus poses a continual, yet unpredictable threat to public health. The notorious 1918 pandemic of 'Spanish flu' was associated with 20-50 million deaths worldwide and is considered one of the most devastating single disease outbreaks in history. Despite intensive year-round sequencing and antigenic characterization of global influenza A viruses, major aspects of influenza A virus evolution and epidemiology remain poorly understood. In particular, the dominant model of influenza A virus evolution by long-term 'antigenic drift', while clearly of great importance for viral escape of host antibodies, inadequately explains important epidemic dynamics. Significantly, neither the distinct winter seasonality of the influenza A virus, nor the sudden emergence of major antigenic variants are fully accounted for on the basis of antigenic drift alone.;Through phylogenetic analysis of whole-genome influenza viruses sampled intensively over multiple discrete spatial-temporal scales, the studies in this thesis reveal evolutionary dynamics that have been previously obscured by spatially limited sampling and sequencing of the HA1 domain in isolation. Most notably, although strong immune selection periodically limits genetic diversity through antigenic drift, multiple diverse viral lineages typically co-circulate globally and are introduced into a given locality during an epidemic. This genetic diversity co-circulates over the course of an epidemic, allowing for frequent genomic 'reassortment' and greatly complicating patterns of spatial-temporal dissemination. The process of reassortment is capable of situating antigenic novelty within a more compatible viral genome, rapidly producing influenza viruses of greater overall fitness that occasionally are associated with major epidemics. In addition, extensive global migration results in complex global networks between viral populations from different geo-climatic regions, and these networks appear to be critical for the continual survival of the virus and 're-seeding' of local epidemics. Further understanding of this intricate global ecology is central to understanding the evolution of the influenza A virus, and will require surveillance to be substantially increased in important under-sampled regions such as South-East Asia. |
