Clark A G, Weiss K M, Nickerson D A, Taylor S L, Buchanan A, Stengård J, Salomaa V, Vartiainen E, Perola M, Boerwinkle E, Sing C F
Institute of Molecular Evolutionary Genetics, Department of Biology, Pennsylvania State University, University Park, PA 16802, USA.
Am J Hum Genet. 1998 Aug;63(2):595-612. doi: 10.1086/301977.
Allelic variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase gene (LPL) was scored in 71 healthy individuals (142 chromosomes) from three populations: African Americans (24) from Jackson, MS; Finns (24) from North Karelia, Finland; and non-Hispanic Whites (23) from Rochester, MN. The sequences had a total of 88 variable sites, with a nucleotide diversity (site-specific heterozygosity) of .002+/-.001 across this 9.7-kb region. The frequency spectrum of nucleotide variation exhibited a slight excess of heterozygosity, but, in general, the data fit expectations of the infinite-sites model of mutation and genetic drift. Allele-specific PCR helped resolve linkage phases, and a total of 88 distinct haplotypes were identified. For 1,410 (64%) of the 2,211 site pairs, all four possible gametes were present in these haplotypes, reflecting a rich history of past recombination. Despite the strong evidence for recombination, extensive linkage disequilibrium was observed. The number of haplotypes generally is much greater than the number expected under the infinite-sites model, but there was sufficient multisite linkage disequilibrium to reveal two major clades, which appear to be very old. Variation in this region of LPL may depart from the variation expected under a simple, neutral model, owing to complex historical patterns of population founding, drift, selection, and recombination. These data suggest that the design and interpretation of disease-association studies may not be as straightforward as often is assumed.
在来自三个群体的71名健康个体（142条染色体）中，对人类脂蛋白脂肪酶基因（LPL）9.7 kb基因组DNA序列中的等位基因变异进行了评分：来自密西西比州杰克逊的非裔美国人（24名）；来自芬兰北卡累利阿的芬兰人（24名）；以及来自明尼苏达州罗切斯特的非西班牙裔白人（23名）。在这个9.7 kb区域内，这些序列共有88个可变位点，核苷酸多样性（位点特异性杂合性）为0.002±0.001。核苷酸变异的频率谱显示杂合性略有过剩，但总体而言，数据符合突变和遗传漂变的无限位点模型的预期。等位基因特异性PCR有助于解析连锁相位，共鉴定出88种不同的单倍型。在2211个位点对中的1410个（64%）中，所有四种可能的配子都存在于这些单倍型中，这反映了过去重组的丰富历史。尽管有强有力的重组证据，但仍观察到广泛的连锁不平衡。单倍型的数量通常远大于无限位点模型下预期的数量，但存在足够的多位点连锁不平衡以揭示两个主要分支，它们似乎非常古老。由于群体建立、漂变、选择和重组的复杂历史模式，LPL这个区域的变异可能偏离简单中性模型下预期的变异。这些数据表明，疾病关联研究的设计和解释可能不像通常假设的那么直接。
