A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation
A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation
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DOI：
10.1086/510885
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发表时间：
2007-02-01
影响因子：
9.8
通讯作者：
Sturm, Richard A.
中科院分区：
文献类型：
--
作者：
Duffy, David L.;Montgomery, Grant W.;Sturm, Richard A.
我们之前已经证明，与15 q的OCA 2区域相关的数量性状基因座占人眼颜色变异的74%。我们进行了额外的基因分型，以阐明OCA 2基因座在遗传眼睛颜色和其他与白色人群皮肤癌风险相关的色素性状中的作用。在3,839名青少年双胞胎、他们的兄弟姐妹和他们的父母中，对58个同义和非同义外显子单核苷酸多态性（SNP）和标签SNP进行了分型。与蓝色/非蓝色眼睛颜色相关性最高的是OCA 2内含子1中的三个SNP：rs7495174 T/C、rs6497268 G/T和rs 11855019 T/C（P值分别为1.02 x 10（-61）、1.57 x 10（-96）和4.45 x 10（-54））。这三个SNP在一个主要的单倍型块中，TGT代表78.4%的等位基因。在62.2%的样本中发现的TGT/TGT二倍型是观察到的改变眼睛颜色的主要基因型，在蓝色或绿色中的频率为0.905，而在棕色眼睛颜色中的频率仅为0.095。这种基因型在浅棕色头发的受试者中频率最高，在白皙和中等皮肤类型中更常见，这与TGT单倍型作为较浅色素沉着表型的隐性修饰剂一致。rs 11855019 C/C的纯合子主要没有雀斑，并且具有较低的痣计数。与非蓝眼睛相关的非同义编码区多态性Arg 305 Trp和Arg 419 Gln的较小群体影响，以及OCA 2内含子1内的主要TGT单倍型与蓝眼睛颜色和较浅的头发和肤色的紧密连锁，表明OCA 2基因5'近端调控区内的差异改变了信使RNA的表达。转录水平，并可能负责这些协会。
We have previously shown that a quantitative-trait locus linked to the OCA2 region of 15q accounts for 74% of variation in human eye color. We conducted additional genotyping to clarify the role of the OCA2 locus in the inheritance of eye color and other pigmentary traits associated with skin-cancer risk in white populations. Fifty-eight synonymous and nonsynonymous exonic single-nucleotide polymorphisms (SNPs) and tagging SNPs were typed in a collection of 3,839 adolescent twins, their siblings, and their parents. The highest association for blue/nonblue eye color was found with three OCA2 SNPs: rs7495174 T/C, rs6497268 G/T, and rs11855019 T/C (P values of 1.02 x 10(-61), 1.57 x 10(-96), and 4.45 x 10(-54), respectively) in intron 1. These three SNPs are in one major haplotype block, with TGT representing 78.4% of alleles. The TGT/TGT diplotype found in 62.2% of samples was the major genotype seen to modify eye color, with a frequency of 0.905 in blue or green compared with only 0.095 in brown eye color. This genotype was also at highest frequency in subjects with light brown hair and was more frequent in fair and medium skin types, consistent with the TGT haplotype acting as a recessive modifier of lighter pigmentary phenotypes. Homozygotes for rs11855019 C/C were predominantly without freckles and had lower mole counts. The minor population impact of the nonsynonymous coding-region polymorphisms Arg305Trp and Arg419Gln associated with nonblue eyes and the tight linkage of the major TGT haplotype within the intron 1 of OCA2 with blue eye color and lighter hair and skin tones suggest that differences within the 5' proximal regulatory control region of the OCA2 gene alter expression or messenger RNA-transcript levels and may be responsible for these associations.