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The Journal of Immunology, 2002, 169: 5118-5129.
Copyright © 2002 by The American Association of Immunologists

Killer Ig-Like Receptor Haplotype Analysis by Gene Content: Evidence for Genomic Diversity with a Minimum of Six Basic Framework Haplotypes, Each with Multiple Subsets1

Katharine C. Hsu*,{dagger}, Xiao-Rong Liu*, Annamalai Selvakumar*, Eric Mickelson{ddagger}, Richard J. O’Reilly*,{dagger} and Bo Dupont2,*,{dagger}

* Immunology Program, Sloan-Kettering Institute for Cancer Research and {dagger} Allogeneic Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and {ddagger} Human Immunogenetics Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

Killer Ig-like receptor (KIR) genes constitute a multigene family whose genomic diversity is achieved through differences in gene content and allelic polymorphism. KIR haplotypes containing a single activating KIR gene (A-haplotypes), and KIR haplotypes with multiple activating receptor genes (B-haplotypes) have been described. We report the evaluation of KIR gene content in extended families, sibling pairs, and an unrelated Caucasian panel through identification of the presence or absence of 14 KIR genes and 2 pseudogenes. Haplotype definition included subtyping for the expressed and nonexpressed KIR2DL5 variants, for two alleles of pseudogene 3DP1, and for two alleles of 2DS4, including a novel 2DS4 allele, KIR1D. KIR1D appears functionally homologous to the rhesus monkey KIR1D and likely arose as a consequence of a 22 nucleotide deletion in the coding sequence of 2DS4, leading to disruption of Ig-domain 2D and a premature termination codon following the first amino acid in the putative transmembrane domain. Our investigations identified 11 haplotypes within 12 families. From 49 sibling pairs and 17 consanguineous DNA samples, an additional 12 haplotypes were predicted. Our studies support a model for KIR haplotype diversity based on six basic gene compositions. We suggest that the centromeric half of the KIR genomic region is comprised of three major combinations, while the telomeric half can assume a short form with either 2DS4 or KIR1D or a long form with multiple combinations of several stimulatory KIR genes. Additional rare haplotypes can be identified, and may have arisen by gene duplication, intergenic recombination, or deletions.




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