Haplotype diversity across 100 candidate genes for inflammation, lipid metabolism, and blood pressure regulation in two populations
Haplotype diversity across 100 candidate genes for inflammation, lipid metabolism, and blood pressure regulation in two populations
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DOI：
10.1086/382227
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发表时间：
2004-04-01
影响因子：
9.8
通讯作者：
Nickerson, DA
中科院分区：
文献类型：
--
作者：
Crawford, DC;Carlson, CS;Nickerson, DA
最近的研究表明，人类基因组的很大一部分包含在强连锁不平衡的片段中，长度从相似的5到100 kb不等，并且在这些片段中，一些常见的单倍型可能占观察到的单倍型的90%。此外，先前的研究表明，候选基因的共同单倍型通常在种群中共享，并代表每个种群中的大多数染色体。然而，从这些初步研究中得出的结论是基于对所检查区域的变化的不完全了解。为了弥补这方面的知识差距，我们对非洲人后裔和一个欧洲人后裔的100个候选基因进行了完全的重新测序。虽然这些基因由于其医学重要性而得到了很好的研究，但我们证明大量的序列变异尚未被描述。我们还报道，当使用完整的数据时，每个基因的推断单倍型的平均数量高于以前的报道，并且每个基因的普通单倍型所代表的所有单倍型的数量和比例是可变的。此外，我们证明了两个种群之间共有的单倍型仅占观察到的单倍型总数的一小部分，而且这些共有的单倍型所代表的非洲人后裔染色体的数量比以前的研究预期的要少。最后，我们表明，将变异发现限制在编码区域并不能充分描述所有常见的单倍型，或者当使用所有常见变异来推断单倍型时所观察到的真正的单倍型块结构。这些数据来源于对这些基因遗传变异的全面了解，表明人类基因组中候选基因的单倍型结构比以前认为的要复杂得多，这对候选基因和全基因组关联研究具有重要意义。
Recent studies have suggested that a significant fraction of the human genome is contained in blocks of strong linkage disequilibrium, ranging from similar to5 to >100 kb in length, and that within these blocks a few common haplotypes may account for >90% of the observed haplotypes. Furthermore, previous studies have suggested that common haplotypes in candidate genes are generally shared across populations and represent the majority of chromosomes in each population. The conclusions drawn from these preliminary studies, however, are based on an incomplete knowledge of the variation in the regions examined. To bridge this gap in knowledge, we have completely resequenced 100 candidate genes in a population of African descent and one of European descent. Although these genes have been well studied because of their medical importance, we demonstrate that a large amount of sequence variation has not yet been described. We also report that the average number of inferred haplotypes per gene, when complete data is used, is higher than in previous reports and that the number and proportion of all haplotypes represented by common haplotypes per gene is variable. Furthermore, we demonstrate that haplotypes shared between the two populations constitute only a fraction of the total number of haplotypes observed and that these shared haplotypes represent fewer of the African-descent chromosomes than was expected from previous studies. Finally, we show that restricting variation discovery to coding regions does not adequately describe all common haplotypes or the true haplotype block structure observed when all common variation is used to infer haplotypes. These data, derived from complete knowledge of genetic variation in these genes, suggest that the haplotype architecture of candidate genes across the human genome is more complex than previously suggested, with important implications for candidate gene and genomewide association studies.