Global patterns of KIR genotype diversity reflect human migration and regional differences

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Background: Killer-cell immunoglobulin-like receptors (KIR) are highly polymorphic receptors expressed by natural killer (NK) cells that regulate immune responses through interactions with HLA class I ligands. Variation in KIR gene content influences immunity, reproduction, transplantation outcomes, and susceptibility to disease, yet global patterns of KIR genotype diversity remain incompletely characterized. Methods: We assembled a curated dataset comprising 25,304 individuals from 192 populations worldwide, representing 662 distinct KIR genotypes. Genotypes were classified according to gene content and haplotype structure, including group A and B haplotype-associated motifs. Population diversity was assessed using Simpson's diversity index, while geographic distribution, pairwise statistical testing, and principal component analysis were used to evaluate population structure and patterns of genetic variation. Results: KIR genotype diversity was high overall but showed marked geographic heterogeneity. Populations of Northeast Asia, Southeast Asia and the Americas exhibited reduced diversity due to enrichment of specific genotype subsets, whereas South Asian populations displayed greater diversity and more balanced genotype distributions. Geographic mapping and statistical analyses identified regional differences characterized by distinct KIR genotype profiles. Principal component analysis further demonstrated strong population stratification associated with demographic history and regional differences. The observed distributions could be due to founder effects as well as selection acting on KIR-mediated immune and reproductive functions, maintaining diversity while favoring different genotype subsets in different populations. Conclusions: This study provides the most comprehensive assessment of global KIR genotype diversity to date and demonstrates how it is possible that human migration, demographic history, and selective pressures have shaped NK cell receptor variation worldwide. These findings advance our understanding of human immunogenetic diversity and have important implications for transplantation, disease association studies, immunotherapy, and the implementation of population-informed precision medicine.

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