Dynamics of viral host range evolution

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 DESCRIPTION (provided by applicant) The emergence of new viruses impacting human health represents an important threat, with HIV, SARS and Ebola as recent examples. New viruses do not spontaneously generate, but arise from the extant viral population by acquisition of preferences for new hosts. However, the mechanisms by which this occurs remain poorly understood, and changes in the host preferences of viruses are not readily predictable. Bacteriophages represent a powerful model system for addressing questions of viral host range evolution. The phage population is vast, dynamic, and old, and they play key roles in environmental carbon turnover and bacterial pathogenicity. Phage studies provide a multitude of benefits, ranging biotechnology tools, diagnostics for bacterial infections, phage therapy, synthetic biology, microbial computers, and microbial batteries. The great genetic diversity of the phage population, the ease with which novel phages can be isolated, their host range manipulated, and their phage genes analyzed, presents a tractable experimental system. Phage genomes are typically small compared to their bacterial hosts, and yet the definition of phage genome sequences lags far behind that of their larger host genomes. Moreover, the abundance of novel genes within phage genomes shows they represent the largest unexplored reservoir of sequences in the biosphere, which we have been slow to tap. The diversity of phage genomes and genes is likely driven by 3-4 billion years of warfare between the hosts and their infecting viruses, with constant pressure for resistant hosts, and phage co- evolution to access new hosts. Thus, understanding the role of host preferences and the demands for specific genes to growth in specific hosts, will provide critical clues as to how new viruses emerge, and a context to interpreting both phage and bacterial genomes. A large collection of 800 completely sequenced phage genomes infecting a common host strain, Mycobacterium smegmatis mc2155 shows them to be highly diverse. Not only are there many types of unrelated genomes, but great variation among related genomes, and the GC% ranges from 50-70%. We propose that this diversity is generated by the availability of a diverse range of possible bacterial hosts, together with the ability of the phages to switch host preferences, and we predict that phages of other hosts that are isolated from similar environments will show similar degrees of diversity. To explore the dynamics of viral host range evolution we will characterize the phages of hosts within the Order Actinomycetales. Individual phages will be isolated and sequenced, and the genome diversity of these phages explored more broadly using targeted metagenomic strategies. The host ranges of these phages will be determined and host range variants evolved across several hosts. The genetic requirements for viral growth in different bacterial hosts will be established, and bioinformatic analyses will characterize genes under positive selection, recombination rates, the barriers to genetic exchange, and the contributions of host preferences.