Haplotype-Based Analysis of KIR-Gene Profiles in a South European Population-Distribution of Standard and Variant Haplotypes, and Identification of Novel Recombinant Structures.

Elisa Cisneros,Carlos Vilches,Miguel López-Botet,Natalia Gómez-Lozano,Manuela Moraru,Aura Muntasell

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.

Highlights

Human killer-cell immunoglobulin-like receptors (KIR) are a diverse and polymorphic family of glycoproteins that convey inhibitory or activating signals to subpopulations of NK and T lymphocytes upon recognition of their ligands, mainly HLA class I allotypes [1]
In-depth genomic studies have established the variable organization of the human KIR complex, defining gene motifs and extended haplotypes fixed in our species, and a series of variations from those, mostly generated by asymmetric homologous recombination [4, 6,7,8,9,10, 26, 28, 29]
Sequence analyses based on Sanger and, more recently, second generation methods, have revealed the diversity of alleles commonly found in each of those KIR haplotypes [23, 24, 30,31,32, 34,35,36,37,38,39]

Summary

Introduction

Human killer-cell immunoglobulin-like receptors (KIR) are a diverse and polymorphic family of glycoproteins that convey inhibitory or activating signals to subpopulations of NK and T lymphocytes upon recognition of their ligands, mainly HLA class I allotypes [1]. KIR are encoded in a ∼100–250 Kbp complex on chromosome 19q13.4, where variable combinations of 15 KIR genes and 2 pseudogenes arrange in a head-to-tail orientation, separated by intergenic regions of only ∼2.5 Kbp [4]. Three “framework” regions of the KIR complex are relatively well-conserved in their gene content: the genes at the 5′ and 3′ ends (KIR 3DL3 and 3DL2, respectively), and a central cluster formed by KIR 3DP1 and 2DL4 These framework KIR genes define the limits of two intervals, centromeric (5′) and telomeric (3′), containing variable combinations of the other genes [4, 6,7,8,9,10]. Certain gene arrangements or “motifs” are common within each of those intervals (Figure 1); in turn, the different centromeric and telomeric gene motifs are seen in any combinatorial association, possibly owing to a recombination hot-spot between KIR 3DP1 and 2DL4

Methods

Results

Conclusion