Apolipoprotein E variation at the sequence haplotype level:: Implications for the origin and maintenance of a major human polymorphism
Apolipoprotein E variation at the sequence haplotype level:: Implications for the origin and maintenance of a major human polymorphism
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DOI：
10.1086/303070
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发表时间：
2000-10-01
影响因子：
9.8
通讯作者：
Sing, CF
中科院分区：
文献类型：
--
作者：
Fullerton, SM;Clark, AG;Sing, CF
载脂蛋白E （apoE）的三种常见蛋白同工型，由apoE基因的（epsilon）2、（epsilon）3和（epsilon）4等位基因编码，它们与心血管和阿尔茨海默病风险的关系不同。为了更好地了解这一重要多态性背后的遗传变异，我们在四个种群的96个个体中鉴定了5.5 kb的基因组DNA序列单倍型变异，包括整个APOE位点和相邻的侧翼区域：来自密西西比州杰克逊的黑人（n = 48条染色体），来自墨西哥坎佩切的玛雅人（n = 48条染色体），来自芬兰北卡累利阿的芬兰人（n = 48条染色体），以及来自明尼苏达州罗切斯特的非西班牙裔白人（rt 48条染色体）。在测序的区域中，23个位点发生了变化（21个单核苷酸多态性，或snp， 1个双等位基因缺失和1个多等位基因缺失）。22个双等位位点在样本中定义了31个不同的单倍型。该位点的核苷酸多样性（位点特异性杂合性）估计为0.0005 +/- 0.0003。对黑猩猩APOE基因的序列分析表明，该基因与人类（epsilon）4型单倍型亲缘关系最为密切，但在67个同义位点（54个替换位点，13个缺失位点）和9个非同义固定位点上与人类的一致序列存在差异。人类等位基因分化的进化史是从单倍型关系的模式推断出来的。这一分析表明，定义（epsilon）3和（epsilon）2等位基因的单倍型来源于祖先（epsilon）4s，并且在过去的20万年中，（epsilon）3组单倍型的频率相对于（epsilon）4s有所增加。在所有三种序列单倍型中都存在大量异质性，并且在蛋白质同工型的序列变异中存在重要的种群间差异，这可能与解释与常见蛋白质同工型变异的表型关联的相互矛盾的报告有关。
Three common protein isoforms of apolipoprotein E (apoE), encoded by the (epsilon)2, (epsilon)3, and (epsilon)4 alleles of the APOE gene, differ in their association with cardiovascular and Alzheimer's disease risk. To gain a better understanding of the genetic variation underlying this important polymorphism, we identified sequence haplotype variation in 5.5 kb of genomic DNA encompassing the whole of the APOE locus and adjoining flanking regions in 96 individuals from four populations: blacks from Jackson, MS (n = 48 chromosomes), Mayans from Campeche, Mexico (n 48), Finns from North Karelia, Finland (n = 48), and non-Hispanic whites from Rochester, MN (rt 48). In the region sequenced, 23 sites varied (21 single nucleotide polymorphisms, or SNPs, 1 diallelic indel, and 1 multiallelic indel). The 22 diallelic sites defined 31 distinct haplotypes in the sample. The estimate of nucleotide diversity (site-specific heterozygosity) for the locus was 0.0005 +/- 0.0003. Sequence analysis of the chimpanzee APOE gene showed that it was most closely related to human (epsilon)4-type haplotypes, differing from the human consensus sequence at 67 synonymous (54 substitutions and 13 indels) and 9 nonsynonymous fixed positions. The evolutionary history of allelic divergence within humans was inferred from the pattern of haplotype relationships. This analysis suggests that haplotypes defining the (epsilon)3 and (epsilon)2 alleles are derived from the ancestral (epsilon)4s and that the (epsilon)3 group of haplotypes have increased in frequency, relative to (epsilon)4s, in the past 200,000 years. Substantial heterogeneity exists within all three classes of sequence haplotypes, and there are important interpopulation differences in the sequence variation underlying the protein isoforms that may be relevant to interpreting conflicting reports of phenotypic associations with variation in the common protein isoforms.