Molecular characterisation of KIR2DS2*005, a fusion gene associated with a shortened KIR haplotype

Abstract

KIR2DS2 is an activating homologue of KIR2DL2, an inhibitory killer-cell immunoglobulin-like receptor (KIR) that surveys expression of major histocompatibility complex-C allotypes bearing a C1 epitope. We have studied here its allele KIR2DS2 *005, which shows a hybrid structure-it is identical to other KIR2DS2 alleles in the ectodomain, but has transmembrane and cytoplasmic regions identical to those of KIR2DS3*001, a short-tailed KIR of uncertain expression and function. Our results reveal that KIR2DS2 *005 is a fusion gene-the product of an unequal crossing over by which the genes KIR2DS2 and KIR2DS3 recombined within a 400 base pair region of complete identity in intron 6. Also resulting from that recombination was a shortened KIR haplotype of the B group, in which three genes commonly linked to KIR2DS2 (KIR2DL2, KIR2DL5B and KIR2DS3) are deleted. Population studies indicate that KIR2DS2 *005 is still associated to such haplotype, and it can be found in approximately 1.2% of Caucasoids. Using a combination of two monoclonal antibodies, we also demonstrate that KIR2DS2 *005 encodes a molecule expressed on the surface of natural killer-and T-lymphocytes.

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

“…The reason for this is that without determining copy number or defining alleles, ascertainment of the gene arrangements on these haplotypes can be obscured by variation in KIR gene content of the partnering chromosome, even with pedigrees to track gene transmission . Six of the uncommon gene combinations (haplotypes 12, 13, 14, 15, 18, and 33) appeared to match recombinant haplotypes reported previously by us and others (Gomez-Lozano et al 2003, 2005Martin et al 2003;Ordonez et al 2008Ordonez et al , 2011Traherne et al 2010). Using published methods for detecting hybrid genes (e.g., 2DL5/3DP1 [3DP1*004], 2DS2/2DS3 [2DS2*005], and 2DL3/2DP1) and specific alleles associated with these recombinant haplotypes, we were able to Gene copy number varies from zero to three copies on a single haplotype.…”

Recombinant structures expand and contract inter and intragenic diversification at the KIR locus

“…Conversely, the precise recombination point is arbitrary within the gene inter region (over 1100 bp) in both 3DL3-2DS2 and 2DS2-2DL2 because of the 99% sequence homology between groups of transposable elements (MER2B-AluSg-MER2-L1ME_ORF2-AluS) in the parent cB01 motif. The deletion that led to the del10 submotif of cB01 and the 2DS2/S3 hybrid gene (2DS2*005) [38,39] appears to be focused on a 357 bp MER70B repeat shared between the 2DS2 and 2DS3 intron 6 sequences (98% sequence homology) flanked by what is otherwise relatively highly divergent sequence. As a general statement, perhaps not surprisingly, it appears that repeat elements not only have been active in shaping the KIR region over long spans of primate evolution [40], but also continue to do so in more recent times within the human population.…”

Allele-Level Haplotype Frequencies and Pairwise Linkage Disequilibrium for 14 KIR Loci in 506 European-American Individuals

“…Pseudogenes are omitted except when they occur in a duplicated region or as a fusion gene. All but one haplotype (cA03∼tB07) have been previously reported [8], [13], [15], [19], [21], [22], [23], [24], [50].…”

“…Structural haplotype estimation was repeated with 15 reference haplotype structures, including 14 haplotypes consisting of previously reported centromeric and telomeric regions [8], [13], [15], [19], [21], [22], [23], [24], [50] and 1 novel haplotype (cA03∼tB07) identified through molecular characterization of the haplotype as described above. KIR2DS3 and KIR2DS5 were treated as a single gene ( KIR2DS3S5 ) based on previous reports of their alternative and invariant linkage with KIR2DL5 [15], [16].…”