Founder haplotype for Machado-Joseph disease in the Indian population - Novel insights from history and polymorphism studies

Background: The ACA haplotype is associated with 72% of the expanded repeats in Machado-Joseph disease (MJD) worldwide and has been traced to a Portuguese ancestry. It is present in only 5% of the normal chromosomes in the Portuguese population. Objective: To trace the origin of expanded alleles of MJD in the Indian population. Methods: We performed CAG repeat size determination and haplotype analysis for 9 families with MJD and 263 unrelated chromosomes with unexpanded CAG sequences from the Indian population. Results: All the expanded alleles were exclusively associated with the ACA haplotype in the Indian population. Interestingly, this haplotype was very common in normal alleles (40%) as compared with the Portuguese population (5%) and was significantly associated with large normal alleles (Pearson chi(2)(1)=87.1, P <.001) in the Indian population. We also observed a rare intermediate allele of MJD with the ACA haplotype but with a CAG variant instead of CAA at the sixth position in the repeat tract. Conclusions: Overrepresentation of the ACA haplotype in large normal alleles in India as compared with the Portuguese population suggests that the expansion-prone large normal alleles with the ACA haplotype may have been introduced in the Portuguese population through admixture with South Asian populations. Detailed haplotype analysis of a CAG variant within the repeat tract in an intermediate allele of MJD suggests a mechanism of gene conversion. in the expansion.