Zhou Youyou, Tang Kun, Law Hai-Yang, Ng Ivy S L, Lee Caroline G L, Chong Samuel S
Departments of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074, Singapore.
Ann Hum Genet. 2006 Nov;70(Pt 6):784-96. doi: 10.1111/j.1469-1809.2006.00265.x.
Hyper-expansion of a CGG repeat in the 5' untranslated region of the FMR1 gene followed by methylation and silencing is the predominant cause of Fragile X syndrome, the most common inherited mental retardation disorder. Most detailed studies of the FMR1 gene have focused on Caucasian populations and patients. We performed a detailed haplotype and linkage disequilibrium analysis of the FMR1 gene in a total of 454 unselected normal X chromosomes from three Asian populations, Chinese, Malay and Indian. Compared to Caucasians and African Americans, the diversity of normal FMR1 CGG repeat lengths, patterns and flanking haplotypes were lower in Asians. Strong linkage disequilibrium was observed between the CGG repeat and flanking FMR1 markers in all three Asian populations, with strong association between specific CGG repeat alleles and flanking marker alleles observed only in the Chinese and Malays. A test for randomness of distribution between FRAXA CGG repeat patterns and flanking FMR1 marker haplotypes also revealed a highly significant non-random distribution between CGG repeat patterns and flanking haplotypes in all three ethnic groups (P < 0.001). Extending previous findings in Caucasians and African Americans we present a novel statistical approach, using data from unselected population samples alone, to show an association between absence of at least one AGG interruption in any position (5', 3', or middle) and increased CGG repeat instability.
FMR1基因5'非翻译区的CGG重复序列过度扩增，随后发生甲基化和沉默，是脆性X综合征（最常见的遗传性智力障碍疾病）的主要病因。大多数关于FMR1基因的详细研究都集中在白种人群体和患者身上。我们对来自三个亚洲人群（中国人、马来人和印度人）的总共454条未经选择的正常X染色体进行了FMR1基因的详细单倍型和连锁不平衡分析。与白种人和非裔美国人相比，亚洲人正常FMR1 CGG重复序列长度、模式和侧翼单倍型的多样性较低。在所有三个亚洲人群中均观察到CGG重复序列与FMR1侧翼标记之间存在强连锁不平衡，仅在中国人群和马来人群中观察到特定CGG重复等位基因与侧翼标记等位基因之间存在强关联。对FRAXA CGG重复模式与FMR1侧翼标记单倍型之间分布随机性的检验还显示，在所有三个种族群体中，CGG重复模式与侧翼单倍型之间均存在高度显著的非随机分布（P < 0.001）。扩展先前在白种人和非裔美国人中的研究结果，我们提出了一种新颖的统计方法，仅使用来自未经选择的人群样本的数据，以显示在任何位置（5'、3'或中间）至少没有一个AGG中断与CGG重复序列不稳定性增加之间的关联。
