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Abstract
The killer cell immunoglobulin-like receptor (KIR) region of human chromosome 19 contains up to 16 genes for natural killer (NK) cell receptors that recognize human leukocyte antigen (HLA)/peptide complexes and other ligands. The KIR proteins fulfill functional roles in infections, pregnancy, autoimmune diseases and transplantation. However, their characterization remains a constant challenge. Not only are the genes highly homologous due to their recent evolution by tandem duplications, but the region is structurally dynamic due to frequent transposon-mediated recombination. A sequencing approach that precisely captures the complexity of KIR haplotypes for functional annotation is desirable. We present a unique approach to haplotype the KIR loci using single-molecule, real-time (SMRT) sequencing. Using this method, we have—for the first time—comprehensively sequenced and phased sixteen KIR haplotypes from eight individuals without imputation. The information revealed four novel haplotype structures, a novel gene-fusion allele, novel and confirmed insertion/deletion events, a homozygous individual, and overall diversity for the structural haplotypes and their alleles. These KIR haplotypes augment our existing knowledge by providing high-quality references, evolutionary informers, and source material for imputation. The haplotype sequences and gene annotations provide alternative loci for the KIR region in the human genome reference GrCh38.p8.
Highlights
On human chromosome 19, a 150–250 000 bp region contains between four and 14 protein-encoding genes, and two pseudogenes of the killer cell immunoglobulin-like receptor (KIR) family.These genes encode proteins containing two or three extracellular immunoglobulin-like domains that recognize human leukocyte antigen (HLA) )/peptide complexes and other ligands.[1]
Sixteen haplotypes from eight individuals were completely and unambiguously sequenced except for two haplotypes whose KIR3DL3 genes were not captured in the fosmid and a small gap in one of the haplotypes, located in a repetitive insertion spanning over 100 000 bp
Our collective knowledge of the KIR locus, especially in a translational context, was to date limited by sequencing technologies, with the primary challenge being homology and variation at both large and small scales in the KIR locus
Summary
These genes encode proteins containing two or three extracellular immunoglobulin-like domains that recognize human leukocyte antigen (HLA) )/peptide complexes and other ligands.[1] This recognition helps initiate inhibitory or activating cytotoxic signaling in natural killer (NK) cells (and some T cells), utilizing an intracellular immunoreceptor tyrosine-based inhibitory or activation motif (ITIM or ITAM), respectively.[2,3] NKs and their KIR receptors are essential to human health and their genes impact infections (including HIV/AIDs), pregnancy, autoimmune diseases, transplantation and immunotherapy.[3,4,5,6] NK cells induce cytotoxicity against infected or abnormal cells and they release cyto- and chemo-kines as part of a larger immune reaction This reaction is mediated by competing lack of self antigen recognition and recognition of non-self antigen. The frequency of recombination is high in this system, and dozens of gene-content haplotypes are seen in Europeans alone.[10,11,12,13] It is a transposon-rich region, which provides the primary mechanism for recurrent meiotic recombination events.[13]
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