Disentangling the roles of adaptive and neutral evolution in shaping HLA immune gene diversity in humans

Human leukocyte antigen (HLA) molecules are crucial for immune responses against pathogens. High polymorphism observed in HLA genes is assumed to be maintained in response to diversity of pathogens infecting humans. This thesis analyzes both the diversity of pathogens at the peptide level and the effect of this diversity on HLA genes. Computational analysis reveals that most pathogen peptides are unique, providing the basis of pathogen mediated selection. Some HLA alleles specialize against particular pathogens, while others with large peptide repertoires offer broad protection. Diverse pathogen pressures result in increased HLA diversity in populations, as revealed by the population genetics analysis of several sub-Saharan African populations. This diversity is not only high within African populations, but also maintained by balancing selection in populations migrated out of Africa. Furthermore, HLA evolution appears driven by demography and balancing selection rather than adaptation to local pathogens. Analysis of Neolithic farmers' HLA diversity indicates changes in allele frequencies driven by admixture with local populations, with balancing selection and population history being the main drivers of recent HLA evolution. In conclusion, directional selection by pathogens has a minimal effect on HLA evolution compared to balancing selection and population history