Viral Evolution in the Genomic Age

G enome sequence data will undoubtedly deliver much to the study of viral pathogens and their diseases. A prominent example of this new genomic perspective is infl uenza A virus, for which a large-scale genome sequencing project begun in the year 2005 has, to date, generated around 2,500 complete viral genomes [1]. While this alone is newsworthy, the rise of rapid, high-throughput genome " pyrosequencing " promises to take the production of viral genomes to a level once unimaginable [2]. Yet advances in genome sequencing also create a major intellectual challenge; rather than simply maintaining ever-larger genomic databases for relatively straightforward surveys of viral biodiversity and molecular epidemiology, it is crucial that we direct the power of genomics to help address questions of more fundamental biological importance. Genome sequence data has the potential to shed new light on many key questions in viral evolution and epidemiology, and here I outline three research avenues where the large-scale comparison of genome sequences will be of particular importance. Evolutionary studies of viral pathogens have, with few exceptions, tended to focus on individual species. If an attempt is made to place their evolution " in context, " this usually only relates to the different host species that a virus infects. For example, there is currently great interest in determining the viral and host determinants for the sustained transmission of H5N1 infl uenza A virus in birds as opposed to humans. Although such studies are an essential part of modern molecular epidemiology, an exploration of how the multiplicity of pathogens that co-circulate within a single host population might infl uence each other's evolution and etiology is strikingly absent. Similarly important questions include: What role does cross-protective immunity play in shaping microbial diversity? How widespread is ecological interference among pathogens? Existing data already hint at the importance of evolutionary interactions among pathogens. For example, the HIV pandemic has resulted in an abundance of people with pronounced immune defi ciency, stimulating a resurgence in opportunistic pathogens like Mycobacterium tuberculosis. It is also possible that widespread immunodefi ciency will assist the emergence of new pathogens [3], perhaps by extending the infectious period of normally acute viral infections. Similarly, the nature of the interactions among the four serotypes of dengue virus has been a subject of much debate, particularly whether immunological responses to different serotypes are usually cross-protective [4] or enhancing [5]. Not only might these interactions dictate underlying …