Dynamic mutations in genome, like triplet repeat expansion

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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.