Computational Approaches to Virus Phylogenetics

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DBI 9974525, Goldstein, Richard, University of Michigan. Computational Approaches to Virus phylogeneticsProject SummaryViruses are important agents affecting the health and genomic evolution of almost all life forms, in addition to providing experimental models in many areas of basic and applied research. An important aspect of understanding the origin, transmission, and evolution of these viruses is dependent on our ability to understand their phylogenetic history. Unfortunately, our knowledge of this history has been hampered by a lack of understanding of how to model viral genomic evolution. While much work has been done by analyzing the evolution of viral DNA sequences, there are many advantages in modeling evolutionary change of the expressed proteins at the amino acid level. Generating accurate models for amino acid substitutions has, however, proven problematic. One of the challenges in developing an accurate model is dealing with the problem of "site heterogeneity", the qualitative and quantitative variation in substitution rates at different locations in a protein and in different proteins. In recent work, the PIs have developed a theoretical framework for modeling the substitution process in a way that takes into account the context-dependence of selective pressure while actually reducing the number of adjustable parameters to be determined. In this project the PIs will continue to develop these methods, and apply these methods to address basic questions in viral evolution.Specific projects will include:Continued development and refinement of models of the substitution process in protein evolution.Development of more efficient optimization methods for adapting these models to specific proteins and protein types.Validation of these models through analysis of simulated data as well as analysis of proteins from organisms with a known phylogenetic history.Applying these methods to a set of questions including the phylogeny of HIV1 subtypes and lentivirus genera.Interpretation of the results to better understand the process of molecular evolution in viruses.