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

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（natural killer cells）的免疫应答部分受杀伤细胞免疫球蛋白样受体（killer cell immunoglobulin-like receptors, KIR）调控。KIR基因系统中的16个高度同源基因经基因复制（gene duplication）与不等交换（unequal crossing over）发生演化，由此产生了基因拷贝数存在差异的单倍型（haplotype）；该基因复合体内的等位基因变异（allelic variation）同样进一步加剧了其多样性。本研究针对14个KIR基因座，估算了等位基因水平的单倍型频率及成对连锁不平衡（linkage disequilibrium）统计量。本次基因分型由四个实验室采用多种实验方法完成，确保每个等位基因至少获得2倍测序覆盖度；通过计算方法得到了等位基因水平单倍型的最大似然估计（maximum-likelihood estimates）值。研究结果显示，KIR框架基因以及定位于KIR A型单倍型端粒区域的基因，呈现出最为丰富的等位基因多样性。部分激活性基因座的特定等位基因在特定常见单倍型中近乎固定；而抑制性基因座的多数低频等位基因则可出现在多种单倍型中，其中部分单倍型具有共通的结构。本研究队列中，单倍型结构cA01和/或tA01占主导地位，这与全球多数人群中的已有观测结果一致。着丝粒区域与端粒区域内部的连锁不平衡程度较高，但二者之间并无显著连锁不平衡；其中着丝粒区域的KIR2DL5~KIR2DS3S5、KIR2DS3S5~KIR2DL1基因对，以及端粒区域的KIR3DL1~KIR2DS4基因对的连锁不平衡尤为显著。尽管93%的个体拥有独特的全长等位基因单倍型组合，但在最常见的单倍型中可观察到共享特定等位基因集合的大型基因组区块。这些高分辨率、高质量的单倍型拓展了我们对KIR基因系统的基础认知，可用于支持超越单基因分析范畴的临床研究。