Evolutionary genomics of an optimal adaptive immune response

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This project investigates the different evolutionary factors and genetic mechanisms that contribute to the delicate task of mounting an optimal adaptive immune response. The vertebrate adaptive immune system allows for initiating a highly targeted immune response against infectious pathogens and parasites. However, such a targeted response requires a number of complex and sophisticated mechanisms to maximize efficiency in fighting invading pathogens while at the same time minimize damage to own tissue through the activated immune machinery. This balance is reflected in the exceptionally complex genomic organisation of the major histocompatibility complex (MHC), a region in the genome that contains genetic information for key components of the adaptive immune system. Here we are using molecular, computational and theoretical approaches to elucidate the different factors and mechanisms that contribute to the evolution of this complex genomic region and thus the evolution of the adaptive immune system in general. Our approaches include the sequence analysis of ancient DNA samples from Native American populations, evolutionary and functional evaluation of extended haplotypes in the human MHC region, and theoretical modelling and simulations to explore the relative contribution of different factors for the evolution of the complex genomic organisation of the MHC. Furthermore, we are analysing genotype data from large human disease cohorts and antigen binding information for human MHC molecules to provide a functional explanation for the strong statistical association between genetic variation in the MHC region and many autoimmune diseases. Combining empirical sequence data from the three-spined stickleback as a vertebrate model system and theoretical models of induced peripheral self-tolerance, we eventually investigate different potential MHC-dependent mechanisms that may have evolved to prevent autoimmunity. The insights gained from this research project will further our understanding of human evolution and how evolutionary processes shape the vertebrate genome. Additionally, our results will contribute to the emerging field of evolutionary medicine, which incorporates the knowledge about evolutionary processes and individual genetic differences in disease predisposition into personalized medical prevention and therapy.