ABSTRACT Human leukocyte antigens (HLA) and killer cell immunoglobulin-like receptors (KIR) are critical facets of the human immune system. Interactions of KIR, expressed by natural killer cells (NK cells), with HLA class I, expressed by most tissue cells, modulate immune cell functions. Variations in the highly polymorphic KIR and HLA genes are linked directly to NK cell functions and have profound impact on human health, including associations with autoimmunity and neurological disease, severity of infectious disease, pregnancy syndromes, and risk of cancer. Our ability to resolve the mechanisms of immune-mediated disease, to develop personalized medicines, including immunotherapies, and to match organ donors with recipients relies on our ability to accurately characterize KIR and HLA class I diversity. Despite this crucial importance, there is a lack of knowledge concerning the extent and nature of KIR and HLA class I diversity worldwide. This deficit includes the Eastern Hemisphere, which encompasses half the world's population, and multiple underrepresented groups in the USA. During this project we will fill these gaps in this knowledge through determining the characteristics and functional consequences of KIR and HLA class I diversity across the entire Eastern Hemisphere. We will examine 15,612 individuals representing 51 discrete populations, including indigenous populations from East Asia, South Asia, multiple Pacific Islands and Oceania. To overcome difficulties in analyzing these complex genomic regions, we developed a targeted sequencing and bioinformatics approach to analyze KIR and HLA class I genes at high throughput and resolution. To analyze an additional 22,905 individuals, we will develop an imputation algorithm to determine high-resolution KIR alleles from whole-genome SNP data. We will construct imputation panels specifically for these populations who have been neglected in previous analyses. This goal will be made possible through the extensive training data generated. We will then characterize the distribution of KIR and HLA haplotypes across the Eastern Hemisphere. We will examine how the geographic patterns of KIR and HLA diversity have been shaped by natural selection and investigate the impact of adaptive introgression and admixture specifically focused to the KIR and HLA loci in our study populations. We will determine the functional properties of those variants we have identified as targeted by natural selection. We will pursue these aims implementing innovative laboratory and analytical tools. These developments include CRISPR/cas9 targeting of long-read sequencing to examine KIR structural diversity, and methods both to identify alleles subject to natural selection, and the mode of selection acting on them. The expected outcome of this work is the genetic and functional characterization of HLA and KIR across multiple human populations, and a comprehensive understanding of how this variation is geographically distribu...