Founder Haplotype for Machado-Joseph Disease in the Indian Population

Abstract

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. To trace the origin of expanded alleles of MJD in the Indian population. 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. 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. 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.