A UNIQUE ORIGIN AND MULTISTEP PROCESS FOR THE GENERATION OF EXPANDED DRPLA TRIPLET REPEATS

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal domin ant neurodegenerative disorder associated with the expansion of a CAG repeat at chromosome band 12p13, Epidemiological studies have demonstr ated an increased prevalence of DRPLA in Japan, although several DRPLA kindreds of non-Japanese ancestry have been identified. To define the molecular basis for this geographic variation in prevalence, we have analyzed haplotypes around the repeat in several different ethnic grou ps. Two intragenic biallelic polymorphisms distinguished three haploty pes, each of which formed a predominant haplotype found in the three m ajor racial populations, All the expanded repeats of Japanese and Cauc asian patients studied were associated with a particular haplotype, wh ich otherwise was associated with longer repeats commonly found in Asi ans, Our results support a multi-step model for repeat expansion, and suggest that expanded DRPLA repeats may have evolved from an ancient c hromosomal haplotype of Asian origin, We also propose that a combinati on of a highly polymorphic microsatellite marker with relatively stabl e biallelic markers in a range of PCR amplification is a powerful tool for studies on human genome diversity, which may reveal the ancient h uman migration and the formation of ethnic groups.