Allelic Polymorphism Synergizes with Variable Gene Content to Individualize Human KIR Genotype

Abstract

Killer Ig-like receptor (KIR) genes are a multigene family on human chromosome 19. KIR genes occur in various combinations on different haplotypes. Additionally, KIR genes are polymorphic. To examine how allelic polymorphism diversifies KIR haplotypes with similar or identical combinations of KIR genes, we devised methods for discriminating alleles of KIR2DL1, -2DL3, -3DL1, and -3DL2. These methods were applied to 143 individuals from 34 families to define 98 independent KIR haplotypes at the allele level. Three novel 3DL2 alleles and a chimeric 3DL1/3DL2 sequence were also identified. Among the A group haplotypes were 22 different combinations of 2DL1, 2DL3, 3DL1, and 3DL2 alleles. Among the B group haplotypes that were unambiguously determined were 15 distinct haplotypes involving 9 different combinations of KIR genes. A and B haplotypes both exhibit strong linkage disequilibrium (LD) between 2DL1 and 2DL3 alleles, and between 3DL1 and 3DL2 alleles. In contrast, there was little LD between the 2DL1/2DL3 and 3DL1/3DL2 pairs that define the two halves of the KIR gene complex. The synergistic combination of allelic polymorphism and variable gene content individualize KIR genotype to an extent where unrelated individuals almost always have different KIR types. This level of diversity likely reflects strong pressure from pathogens on the human NK cell response.

Genomic Organization of the Chicken CD8 Locus Reveals a Novel Family of Immunoreceptor Genes

“…20). In contrast with RHACD8 genes, KIR genes contain more than one V ectodomain and also include inhibiting members with ITIMs in the CY region (31)(32)(33)(34). Therefore, future functional studies to determine whether the products of RHACD8 genes, siblings of the CD8␣, could recognize classical/nonclassical MHC class I, class I-related molecules, or even perhaps the decoy ligands encoded by viruses as those described for NK receptors in humans and mice (reviewed in Refs.…”

Receptor systems controlling natural killer cell function are genetically stratified in Europe

“…25,26 In addition, several KIR genes are highly polymorphic. 14,27,28 This diversity results in variegated KIR expression in individuals, which influences the innate immune responses of NK cells. 4,14,27,29 Significant progress has been made over the last 15 years in defining the nature and extent of KIR gene diversity across human populations.…”

Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals

“…41 The number and type of KIR genes vary substantially between haplotypes 41,42 and display sequence polymorphism. 43,44 Patterns of linkage disequilibrium divide the KIR haplotype between 3DP1 and 2DL4 into two halves. 44,45 For genes within each half there is significant linkage disequilibrium, but it is much less for genes in the two different halves.…”

“…43,44 Patterns of linkage disequilibrium divide the KIR haplotype between 3DP1 and 2DL4 into two halves. 44,45 For genes within each half there is significant linkage disequilibrium, but it is much less for genes in the two different halves. Based on the gene content, the centromeric (C) and telomeric (T) halves can be subdivided into small motif groups such as C1, C2, C3, Cx, T1, T2 and Tx.…”