February 6 2017

11:00 158 HH

Felix Breden
Department of Biological Sciences
Simon Fraser University

Variability in Germline and Expressed Immunoglobulin-gene Repertoires: Evolutionary Insights and Disease Associations


The vertebrate adaptive immune system has evolved to produce an immense diversity of immunoglobulin (Ig) and T-cell receptor (TcR) molecules to recognize and remove invasive pathogens and cancer cells, while tolerating commensal microbes and healthy cells. Diversity among Igs and TcRs is generated through a unique process of somatic recombination among sets of highly repeated and homologous germline-gene segments. This high copy number and diversity presents special challenges to describing the evolutionary forces shaping human population variability and relating this variability to disease susceptibility. My lab produced the first full-length sequences for the Ig loci, and based on this information, developed high-throughput genotyping assays for specific Ig genes. This allowed us to survey population-level structural variability in the Ig loci in humans, and show that this variability needs to be considered when developing vaccines and immunotherapies.

Variability among Ig germline-gene segments is expressed as the antibody repertoire, comprising hundreds of millions of unique B-cell clone sequences. On stimulation by a microbe or other foreign antigen, B-cell clones further diversify their recombined Ig genes by undergoing rounds of mutation and antigen-selection, following a model of Darwinian selection. In assessing this process in HIV-1 infection, our group was among the first to apply phylogenetic tools to reconstruct the evolutionary history of B-cell lineages. Since then, phylodynamic reconstructions of B-cell lineages have proved critical to understanding the selective forces controlling the development of the expressed immune repertoire in health and disease.

More recently, next-generation sequencing approaches have been applied to the rearranged Ig and TcR genes of thousands to millions of B and T cells. Yet, at present, there is no way to easily share and compare these huge repertoire databases across diseases, projects and/or institutions. We therefore developed the iReceptor data-integration platform, which searches federated data sets of Ig and TcR sequences, and sends these results for further analysis with software tools, such as the lineage-analysis and germline-gene prediction tools my group is developing based on evolutionary approaches. In conjunction with Dr. Jamie Scott at Simon Fraser University, we are also organizing the community that produces and uses these data, with the goal of developing common sets of protocols, best practices, and standard metadata in order to facilitate generating, storing and sharing Ig and TcR repertoire sequence data.

Thus, for the past several years, I have been applying my expertise in population and evolutionary genetics to understanding the adaptive immune system and its responses to environmental challenges and building resources for the immunogenetics community. In my seminar, I will emphasize how evolutionary approaches and phylogenetic tools have been, and will continue to be, of central importance to these efforts.











































































































































































































































































































































































































































































































































































































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