Copy number variation leads to considerable diversity for B but not A haplotypes of the human KIR genes encoding NK cell receptors

Abstract

The KIR complex appears to be evolving rapidly in humans, and more than 50 different haplotypes have been described, ranging from four to 14 KIR loci. Previously it has been suggested that most KIR haplotypes consist of framework genes, present in all individuals, which bracket a variable number of other genes. We used a new technique to type 793 families from the United Kingdom and United States for both the presence/absence of all individual KIR genes as well as copy number and found that KIR haplotypes are even more complex. It is striking that all KIR loci are subject to copy number variation (CNV), including the so-called framework genes, but CNV is much more frequent in KIR B haplotypes than KIR A haplotypes. These two basic KIR haplotype groups, A and B, appear to be following different evolutionary trajectories. Despite the great diversity, there are 11 common haplotypes, derived by reciprocal recombination near KIR2DL4, which collectively account for 94% of KIR haplotypes determined in Caucasian samples. These haplotypes could be derived from combinations of just three centromeic and two telomeric motifs, simplifying disease analysis for these haplotypes. The remaining 6% of haplotypes displayed novel examples of expansion and contraction of numbers of loci. Conventional KIR typing misses much of this additional complexity, with important implications for studying the genetics of disease association with KIR that can now be explored by CNV analysis.

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

“…To gain additional information on KIR in our population, we typed 185 patients who had undergone treatment with pegylated IFN and ribavirin with a high resolution KIR typing method (Table S3). This allowed both gene copy number and haplotype assignment to the cohort 25. Briefly KIR haplotypes can be categorized as centromeric and telomeric A and B haplotypes according to the classification of Cooley et al 30 As individual KIR genes are in strong linkage disequilibrium with each other, these haplotypes may be more strongly associated with disease outcome than individual genes.…”

“…Genotyping had previously been performed for KIR, IFN‐λ3/4 rs12979860, HLA and tapasin 9, 12, 14. Additional high resolution KIR genotyping was later performed on the patients with chronic HCV infection to accurately determine KIR copy number and impute KIR haplotype 25. Demographic data and primary end points [spontaneous and treatment‐induced viral clearance, the development of cirrhosis and hepatocellular carcinoma (HCC)] were collected retrospectively by the researchers using the patient's electronic medical records.…”

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…The distinction between alleles and genes is, therefore, sometimes blurred; for example KIR 2 DS 3 can be located in two different positions within the KIR locus. (a) The arrangements of genes in 12 common European haplotypes18 are shown. Typically, a person inherits between 14 and 24 KIR genes (between 7 and 12 KIR genes per haplotype).…”

Influence of KIR gene copy number on natural killer cell education

“…5,6 In addition, extensive CNV contributes to diversity of KIR genes. 7 At the protein level, KIR2DL3 (2DL3) and 3DS1 expression frequencies were shown to be higher in individuals with 2 copies of the respective KIR gene compared with those with only 1 copy, suggesting a gene dose effect on KIR expression. 3,5 However, the overarching impact of KIR CNV on human NK cell repertoires and functionality remains unknown.…”