Dynamic mutations in genome, like triplet repeat expansion

与包括亨廷顿病(HD)在内的严重神经退行性疾病相关的短片段三核苷酸重复序列的显著扩大，已成为人类遗传学中最引人入胜的现象之一。齿状核-苍白球萎缩症在西方国家几乎闻所未闻，但在日本更常见，我们的研究小组已将其确定为由三重重复扩增引起的疾病的第七位成员。为了确定流行的地理差异的分子基础，我们分析了几个不同种族群体中DRPLA重复序列周围的单倍型。两个基因内双等位基因多态性区分了三种单倍型，每一种单倍型都形成了在三个主要种族群体中发现的优势单倍型。所有被研究的日本人和高加索人DR解放军患者的扩增重复序列都共享一个特定的单倍型，否则该单倍型与亚洲人中常见的较长重复序列有关。这些结果支持重复扩增的多步骤模型，并表明扩大的DRPLA重复序列可能是从起源于亚洲的古代染色体单倍型进化而来的。然而，HRS患者的染色体与日本人和高加索人DR解放军患者的单倍型不同。这表明在非洲人口中存在第二种易感单倍型。我们还进行了CAG重复序列扩增揭示神经元死亡的分子机制的研究。

The remarkable expansion of short stretches of trinucleotide repeats associated with serious neurodegenerative disorders, including Huntington's disease (HD), has emerged as one of the most fascinating phenomena in human genetics. Dentatorubral-pallidoluysian atrophy (DRPLA), almost unheard of in Western countries but a little more common in Japan, has been identified by our group as the seventh member of diseases caused by triplet repeat expansion. To define the molecular basis for the geographic variation in prevalence, we have analyzed haplotypes around the DRPLA repeats in several different ethnic groups. Two intragenic biallelic polymorphisms distinguished three haplotypes, each of which formed a predominant haplotype found in the three major racial populations. All the expanded repeats of Japanese and Caucasian DRPLA patients studied shared a particular haplotype, which otherwise was associated with longer repeats commonly found in Asians. These results support a multi-step model for repeat expansion and suggest that expanded DRPLA repeats may have evolved from an ancient chromosomal haplotype of Asian origin. Chromosomes of the HRS patients, however, were associated with a different haplotype from those in Japanese and Caucasian DRPLA patients. This indicates that a second predisposing haplotype is present in the African population. We also conducted studies for reveal molecular mechanism of neuron death by CAG repeat expansion.