Insights into the mutational history and prevalence of SCA1 in the Indian population through anchored polymorphisms

Abstract

There is a wide variation in prevalence of spinocerebellar ataxia type 1 (SCA1) in different populations. In the present study, we observed SCA1 in ∼22% (37/167 families) of the autosomal dominant cerebellar ataxias (ADCAs) in the Indian population. We investigated the role of various genetic factors like repeat length, interruption pattern and chromosomal background in predisposing the repeats to instability in these families. We analyzed 12 markers (9 SNPs and 3 microsatellite markers) and found 3 of them, spanning a region of ∼65 kbp to be linked with the disease locus in the Indian population. The haplotype C-4-C defined by rs1476464 (SNP9)-D6S288-rs2075974 (SNP1), which was extremely rare in nonaffected chromosomes (∼3%), was observed to be significantly (P<0.0000) associated with the expanded chromosomes in ∼44% of SCA1 families. This haplotype was found in all nonhuman primates. SNP1 (C/T), which showed a skewed allelic distribution between large (LN > 30 repeats) and small normal (SN ≤ 30 repeats) alleles (P<0.0000) had similar allelic distribution (P=0.3477) in LN and expanded alleles. Our study suggested that LN and expanded chromosomes linked with the ancestral C allele of SNP1 might have originated simultaneously during evolution by the lengthening of repeats. The LN alleles might have accumulated repeat stabilizing non-CAG interruptions during this process. Similar proportions of T allele in SN with single interruptions, LN and expanded chromosomes lend credence to the origin of expanded alleles from singly-interrupted chromosomes. Our analyses using markers linked (anchoring) to SCA1 suggest that prevalence of SCA1 is correlated to both repeat length and number of interruptions in the Indian population. The spectrum of these alleles also points toward the antiquity of SCA1 mutation in the Indian population.