Intermediate repeat alleles at neurodegenerative loci in the indian population

One of the most abundant classes of variations in human genomes encompasses tandem repeats. Tandem repeats are widespread throughout the genome, polymorphic, multiallelic, highly mutable, and highly unstable in a length-dependent manner during vertical transmission. Several trinucleotide repeat-containing genes have been associated with Mendelian, monogenic neurodegenerative disorders. Such repeat sequences are inherently unstable and have a tendency to expand during vertical transmission. Many of these repeat expansion-linked diseases also manifest with psychiatric symptoms, either before or concurrent with neurological signs and symptoms. In addition, families with neurological disorders often have an increased occurrence of psychiatric diseases in their families. This suggests that the epidemiology of ‘intermediate’ alleles might provide clues to the ‘hidden’ heritability that is often encountered in neuropsychiatric illness. At-risk individuals and families who bear the intermediate size of repeats might have psychiatric presentations, including mood symptoms, and bipolar disorder. This relationship is also seen with other conditions, which often have a mix of psychotic symptoms and dementia. We checked for the prevalence of carriers of intermediate and pathological ranges of tandem DNA repeat alleles among individuals with a neuropsychiatric diagnosis, patients with a suspected polyglutamine disease diagnosis and population controls at five CAG repeat loci including SCA1, SCA2, SCA3, DRPLA, HD. An intermediate allele in ATXN1 was detected in 37 chromosomes of the 1002 persons at this locus. At the ATXN2 locus, we detected 1 chromosome with an intermediate allele in 940 persons. For ATXN3, 11 chromosomes of 881 persons had an intermediate allele. In HTT, 27 chromosomes of 1195 people tested were found to have an intermediate allele. The prevalence of intermediate alleles in ATXN1 and HTT genes in the non-ataxia sample was observed to be 2.49% and 2.16% respectively. The prevalence of intermediate alleles suggests that this may be a reservoir of expansion-prone alleles in the normal population. The additional aspect of somatic mosaicism in the brain might partly explain associated psychiatric symptoms in some individuals with intermediate alleles. DNA sequence variation is often associated with disease. The prevalence of intermediate alleles and the range of ‘high-normal’ alleles at these loci, and their biological effects, may provide clues to the risk of disease that they contribute to.