Department of Clinical Pharmacology, University of Oxford, Oxford, UK.
Eur J Hum Genet. 2010 Aug;18(8):924-32. doi: 10.1038/ejhg.2010.32. Epub 2010 Mar 31.
The HLA region on chromosome 6 is gene-rich and under selective pressure because of the high proportion of immunity-related genes. Linkage disequilibrium (LD) patterns and allele frequencies in this region are highly differentiated across broad geographical populations, making it a region of interest for population genetics and immunity-related disease studies. We examined LD in this important region of the genome in six European populations using 166 putatively neutral SNPs and the classical HLA-A, -B and -C gene alleles. We found that the pattern of association between classic HLA gene alleles and SNPs implied that most of the SNPs predated the origin of classic HLA gene alleles. The SNPs most strongly associated with HLA gene alleles were in some cases highly predictive of the HLA allele carrier status (misclassification rates ranged from <1 to 27%) in independent populations using five or fewer SNPs, a much smaller number than tagSNP panels previously proposed and often with similar accuracy, showing that our approach may be a viable solution to designing new HLA prediction panels. To describe the LD within this region, we developed a new haplotype clustering method/software based on r(2), which may be more appropriate for use within regions of strong LD. Haplotype blocks created using this proposed method, as well as classic HLA gene alleles and SNPs, were predictive of a northern versus southern European population membership (misclassification error rates ranged from 0 to 23%, depending on which independent population was used for prediction), indicating that this region may be a rich source of ancestry informative markers.
6 号染色体上的 HLA 区域富含基因，并受到选择压力的影响，因为其中有很高比例的免疫相关基因。该区域的连锁不平衡 (LD) 模式和等位基因频率在广泛的地理人群中存在高度差异，因此成为群体遗传学和免疫相关疾病研究的热点。我们使用 166 个假定的中性 SNPs 和经典的 HLA-A、-B 和 -C 基因等位基因，研究了该基因组重要区域的 LD。我们发现，经典 HLA 基因等位基因与 SNPs 之间的关联模式表明，大多数 SNPs 早于经典 HLA 基因等位基因的起源。与 HLA 基因等位基因关联最强烈的 SNPs 在某些情况下，使用 5 个或更少的 SNPs 可以高度预测独立人群中的 HLA 等位基因携带者状态（分类错误率从<1%到 27%不等），这比之前提出的标签 SNP 面板要少得多，而且通常具有相似的准确性，表明我们的方法可能是设计新的 HLA 预测面板的可行解决方案。为了描述该区域内的 LD，我们开发了一种基于 r(2)的新的单倍型聚类方法/软件，它可能更适合于强 LD 区域。使用该方法创建的单倍型块，以及经典的 HLA 基因等位基因和 SNPs，可以预测一个人群是北欧人还是南欧人（分类错误率从 0%到 23%不等，具体取决于用于预测的独立人群），表明该区域可能是一个丰富的祖先信息标记来源。
