Haplotype-based analysis of KIR-gene profiles in a south european population-distribution of standard and variant Haplotypes, and identification of novel recombinant structures

Cisneros, Elisa; Moraru, Manuela; Gómez-Lozano, Natalia; Muntasell i Castellví, Aura, 1972-; López-Botet, M. (Miguel); Vilches, Carlos

doi:http://dx.doi.org/10.3389/fimmu.2020.00440

Haplotype-based analysis of KIR-gene profiles in a south european population-distribution of standard and variant Haplotypes, and identification of novel recombinant structures

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Cisneros E, Moraru M, Gómez-Lozano N, Muntasell A, López-Botet M, Vilches C. Haplotype-based analysis of KIR-gene profiles in a south european population-distribution of standard and variant Haplotypes, and identification of novel recombinant structures. Front Immunol. 2020; 11:440. DOI: 10.3389/fimmu.2020.00440

Abstract

Inhibitory Killer-cell Immunoglobulin-like Receptors (KIR) specific for HLA class I molecules enable human natural killer cells to monitor altered antigen presentation in pathogen-infected and tumor cells. KIR genes display extensive copy-number variation and allelic polymorphism. They organize in a series of variable arrangements, designated KIR haplotypes, which derive from duplications of ancestral genes and sequence diversification through point mutation and unequal crossing-over events. Genomic studies have established the organization of multiple KIR haplotypes-many of them are fixed in most human populations, whereas variants of those have less certain distributions. Whilst KIR-gene diversity of many populations and ethnicities has been explored superficially (frequencies of individual genes and presence/absence profiles), less abundant are in-depth analyses of how such diversity emerges from KIR-haplotype structures. We characterize here the genetic diversity of KIR in a sample of 414 Spanish individuals. Using a parsimonious approach, we manage to explain all 38 observed KIR-gene profiles by homo- or heterozygous combinations of six fixed centromeric and telomeric motifs; of six variant gene arrangements characterized previously by us and others; and of two novel haplotypes never detected before in Caucasoids. Associated to the latter haplotypes, we also identified the novel transcribed KIR2DL5B * 0020202 allele, and a chimeric KIR2DS2/KIR2DL3 gene (designated KIR2DL3 * 033) that challenges current criteria for classification and nomenclature of KIR genes and haplotypes.