Signatures of pathogen-driven selection and Austronesian gene flow of Papua New Guinea HLA alleles

Human leukocyte antigen (HLA) class I and II are cell surface proteins that display peptide antigens to immune cells, thereby mediating detection of infected cells and production of antibodies. Pathogen exposure and demographic events, including local adaptation and admixture, have driven and maintained exceptional polymorphism of HLA genes across human populations. Papua New Guinea has a complex demography, with geographically distinct populations in the highlands and lowlands and exceptional linguistic heterogeneity throughout the island. The lowland populations retain signatures of Austronesian expansion ∼3,000 years ago. Papua New Guinea populations are also differentially exposed to endemic malarial pathogens, with a greater burden in the lowlands. We analyzed genome-wide autosomal SNP data together with HLA allele sequences, linguistic, and geographical data from 337 Papuans. We find the substructure of HLA alleles to be highly correlated with altitude in Papua New Guinea, a signal that is distinct from the rest of the genome. In addition, specific HLA-B and HLA-DP alleles in lowland groups have a greater number of homozygous genotypes than expected under neutrality. Some of these HLA alleles are of Austronesian genetic ancestry. We find that the HLA-binding repertoires at candidate loci are significantly enriched for antigenic P. falciparum-derived peptides. Together, these results indicate that pathogen-driven selective pressures correlate with the observed HLA genetic substructure in Papua New Guinea, highlighting the critical importance of characterizing highly complex HLA variation in understanding differences in disease susceptibility across diverse human groups.