Leveraging phylogenetic approaches to investigate the evolution of gene expression

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SUMMARY Across the biomedical sciences there has been an increased recognition that many key questions in these fields require phylogenetic thinking and approaches. My group has a very strong track record of making fundamental methodological contributions that have changed how biologists think about and analyze phylogenetically structured data and of finding new applications for these methods. My group’s current research is focused on two main themes, both related to the evolution of genomic function. First, we will use phylogenetic comparative approaches to investigate the dynamics of gene expression evolution across species. We will first assess the appropriateness of adopting phylogenetic models of phenotypic evolution for describing changes in gene expression using an approach we have previously developed. This will enable us to assess the robustness of findings regarding the relative importance of different evolutionary processes in generating interspecific diversity and help us develop the next-generation of models, specifically tailored to functional genomic data. We will then build a mechanistic model that will allow us and other researchers to test for associations between gene expression evolution and sequence evolution in the promoter regions. Second, we will study the evolution of Immunoglobulin genes, which encode the unique antigen recognition sequences of B cells, which produce antibodies. We will investigate this at two nested levels: the evolution of the B cell repertoire over time and in response to pathogens and the evolution of the germline Immunoglobulin genes. To examine changes in the B cell repertoire, we will adopt approaches that our research group has pioneered in the context of macroevolution, to characterize the dynamics of the system. We are specifically interested in estimating the rate of somatic mutation and the number of distinct clonal lineages that are expanding in response to an infectious disease. There is accumulating evidence that variation in the evolved response of B cells is associated with inter-individual variation in the germline Immunoglobulin genes. However, the underpinning mechanism remains unclear as do the reasons there appears to be so much diversity at these loci across individuals. We will derive an evolutionary model, and parameterize it using comparative genomic data, to evaluate the plausibility of alternative hypotheses for explaining both of these observations.