Variabilität des Haupthistokompatibilitätskomplexes auf verschiedenen Ebenen - Eine evolutionäre Perspektive

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The human leukocyte antigen (HLA) represents an exceptionally gene-dense region in the human genome, containing some of the most polymorphic human genes known to date. These genes code for cell surface molecules that are key factors of the adaptive immune system and present pathogen-derived antigens to immune effector cells to initiate a pathogen-specific immune response. Due to the restricted allele-specific range of presented antigens, the HLA plays a key role in immunogenetic adaptation to local pathogens. This project will investigate signatures of pathogen-mediated selection in the HLA region with a focus on local adaptation in human populations at different levels. At the sequence level, the extent of potentially adaptive structural variation between haplotypes and signatures of balancing selection in different functional regions will be explored. At the allele/genotype level, allele-specific antigen-binding properties, non-random association of alleles and characteristics of potentially advantageous high-frequency alleles will be investigated. At the population level, the extent of adaptation in local HLA allele pools will be analyzed and eventually, the link between local signatures of selection and geographical differences in human epidemiology will be made to improve our understanding of potentially still ongoing immunogenetic adaptation in human populations. By bridging the fields of human genetics and evolutionary medicine, the proposed project addresses several fundamental aspects of human evolution, such as co-evolution between humans and their pathogens, maintenance of genetic diversity within and among human populations but also potential changes in the selection regime in modern societies. The acquired results will contribute to our understanding of individual differences in pathogen resistance and immunity, and therefore potentially contribute to the emerging field of individualized medicine.