Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota, USA.
PLoS One. 2012;7(11):e47491. doi: 10.1371/journal.pone.0047491. Epub 2012 Nov 5.
The immune responses of natural killer cells are regulated, in part, by killer cell immunoglobulin-like receptors (KIR). The 16 closely-related genes in the KIR gene system have been diversified by gene duplication and unequal crossing over, thereby generating haplotypes with variation in gene copy number. Allelic variation also contributes to diversity within the complex. In this study, we estimated allele-level haplotype frequencies and pairwise linkage disequilibrium statistics for 14 KIR loci. The typing utilized multiple methodologies by four laboratories to provide at least 2x coverage for each allele. The computational methods generated maximum-likelihood estimates of allele-level haplotypes. Our results indicate the most extensive allele diversity was observed for the KIR framework genes and for the genes localized to the telomeric region of the KIR A haplotype. Particular alleles of the stimulatory loci appear to be nearly fixed on specific, common haplotypes while many of the less frequent alleles of the inhibitory loci appeared on multiple haplotypes, some with common haplotype structures. Haplotype structures cA01 and/or tA01 predominate in this cohort, as has been observed in most populations worldwide. Linkage disequilibrium is high within the centromeric and telomeric haplotype regions but not between them and is particularly strong between centromeric gene pairs KIR2DL5∼KIR2DS3S5 and KIR2DS3S5∼KIR2DL1, and telomeric KIR3DL1∼KIR2DS4. Although 93% of the individuals have unique pairs of full-length allelic haplotypes, large genomic blocks sharing specific sets of alleles are seen in the most frequent haplotypes. These high-resolution, high-quality haplotypes extend our basic knowledge of the KIR gene system and may be used to support clinical studies beyond single gene analysis.
自然杀伤细胞的免疫反应部分受杀伤细胞免疫球蛋白样受体（KIR）调节。KIR 基因系统中的 16 个密切相关的基因通过基因复制和不等交换而多样化，从而产生基因拷贝数变异的单倍型。等位基因变异也为该复合体的多样性做出了贡献。在这项研究中，我们估计了 14 个 KIR 基因座的等位基因水平单倍型频率和成对连锁不平衡统计数据。该分型利用了来自四个实验室的多种方法，为每个等位基因提供至少 2 倍的覆盖度。计算方法生成了等位基因水平单倍型的最大似然估计。我们的结果表明，KIR 框架基因和位于 KIR A 单倍型端粒区域的基因观察到最广泛的等位基因多样性。刺激基因座的特定等位基因似乎几乎固定在特定的常见单倍型上，而抑制基因座的许多较少见的等位基因则出现在多个单倍型上，其中一些具有常见的单倍型结构。在这个队列中，cA01 和/或 tA01 单倍型结构占主导地位，这在世界上大多数人群中都有观察到。在着丝粒和端粒单倍型区域内，连锁不平衡程度较高，但在它们之间以及着丝粒基因对 KIR2DL5∼KIR2DS3S5 和 KIR2DS3S5∼KIR2DL1 以及端粒 KIR3DL1∼KIR2DS4 之间并不高。尽管 93%的个体具有独特的全长等位基因单倍型对，但在最常见的单倍型中可以看到共享特定等位基因集的大基因组块。这些高分辨率、高质量的单倍型扩展了我们对 KIR 基因系统的基本知识，并可用于支持超越单个基因分析的临床研究。
