Trinucleotide Repeat Loci Research Articles

Exclusion of expansion of 50 CAG/CTG trinucleotide repeats in bipolar disorder.

The purpose of this study was to identify the specific expanded CAG/CTG trinucleotide repeat associated with bipolar disorder. The study employed an efficient multistage approach for using a genomic CAG/CTG screening set. The authors found no evidence of expanded repeats at 43 polymorphic autosomal loci and seven X chromosomal loci. Secondary screening was pursued at the only locus that contained a large allele (37 repeats) in the primary screening. No association was found between allele size and diagnostic status. It is highly unlikely that expansions in repeat size at any of the 50 candidate trinucleotide repeat loci examined are responsible for the association between expanded CAG/ CTG repeats and bipolar disorder. However, although the authors prioritized the repeats that were a priori most likely to be involved, the study does not reject the more general hypothesis that expanded CAG/CTG repeats are implicated in the pathogenesis of bipolar disorder.

Exclusion of CAG/CTG trinucleotide repeat loci which map to chromosome 4 in bipolar disorder and schizophrenia

The hypothesis that expanded trinucleotide repeats contribute to the pathogenesis of schizophrenia and bipolar disorder has been recently supported by three independent studies which have shown that patients with either disorder tend to have larger CAG/CTG repeat expansion detection products than controls. In an attempt to identify the specific expanded CAG/CTG locus or loci which are associated with schizophrenia and bipolar disorder, we determined the repeat size at CAG/CTG loci mapping to candidate regions for psychosis. In this study we report our findings from eight loci which map to chromosome 4. We conclude that these loci are unlikely candidates for CAG/CTG repeat expansion in schizophrenia and bipolar disorder.

Exclusion of CAG/CTG trinucleotide repeat loci which map to chromosome 4 in bipolar disorder and schizophrenia

Exclusion of CAG/CTG trinucleotide repeat loci which map to chromosome 4 in bipolar disorder and schizophrenia

Analysis of thirteen trinucleotide repeat loci as candidate genes for schizophrenia and bipolar affective disorder

A group of diseases are due to abnormal expansions of trinucleotide repeats. These diseases all affect the nervous system. In addition, they manifest the phenomenon of anticipation, in which the disease tends to present at an earlier age or with greater severity in successive generations. Many additional genes with trinucleotide repeats are believed to be expressed in the human brain. As anticipation has been reported in schizophrenia and bipolar affective disorder, we have examined allele distributions of 13 trinucleotide repeat-containing genes, many novel and all expressed in the brain, in genomic DNA from schizophrenic (n = 20–97) and bipolar affective disorder patients (23–30) and controls (n = 43–146). No evidence was obtained to implicate expanded alleles in these 13 genes as causal factors in these diseases. © 1996 Wiley-Liss, Inc.

Analysis of thirteen trinucleotide repeat loci as candidate genes for schizophrenia and bipolar affective disorder.

A group of diseases are due to abnormal expansions of trinucleotide repeats. These diseases all affect the nervous system. In addition, they manifest the phenomenon of anticipation, in which the disease tends to present at an earlier age or with greater severity in successive generations. Many additional genes with trinucleotide repeats are believed to be expressed in the human brain. As anticipation has been reported in schizophrenia and bipolar affective disorder, we have examined allele distributions of 13 trinucleotide repeat-containing genes, many novel and all expressed in the brain, in genomic DNA from schizophrenic (n = 20-97) and bipolar affective disorder patients (23-30) and controls (n = 43-146). No evidence was obtained to implicate expanded alleles in these 13 genes as causal factors in these diseases.

Analysis of thirteen trinucleotide repeat loci as candidate genes for schizophrenia and bipolar disorder

S: 1996 World Congress on Psychiatric Genetics: IV. (A) THE RELEVANCE OF UNSTABLE TRINUCLEOTIDE REPEATS: PDF Only

Analysis of CAG/CTG triplet repeats in the human genome: Implication in transcription factor gene regulation

Instability and polymorphism at several CAG/CTG trinucleotide repeat loci have been associated with human genetic disorders. In an attempt to identify novel sites that may be possible loci for expansion of CAG/CTG repeats, we searched all human sequences in the EMBL nucleotide sequence database for (CAG)5 and (CTG)5 repeats. We have identified 121 human DNA sequences of known and unknown functions that contain stretches of five or more CAG or CTG repeats. Many repeat stretches were interrupted by variant triplets, a significant number of which differ from the repeat triplet only by a single base, suggesting that these evolved from the parent triplet by point mutations. A large number of human transcription factor genes were found to contain CAG repeats within their coding sequences. Analysis of the EMBL transcription factors database showed that many transcription factor genes of other eukaryotes, including genes involved inDrosophila embryo development, possess these repeats. Interestingly, CAG repeats are absent from prokaryotic transcription factors. Different sequence entries for the human TATA box binding protein showed a polymorphism in the length of the CAG repeat in this gene, suggesting that loci other than those already known to be associated with genetic diseases may be possible sites for repeat instability related disorders. On the basis of our findings in this database analysis, we propose a role for CAG repeats as cisacting regulatory elements involved in fine-tuning gene expression.

Human minisatellite loci composed of interspersed GGA-GGT triplet repeats

We have isolated two tandemly repeated loci from human DNA which contain long blocks of GGA and GGT trinucleotide repeats. These two repeat unit types, together with other less common variants, are apparently irregularly interspersed along each repeat array. Genotyping methods have been developed for these highly polymorphic loci, including typing by polymerase chain reaction followed by Southern blot hybridization. Linkage analysis in Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees has been used to map the loci to chromosomes 15 and 22. In normal individuals, alleles at these loci can contain thousands of repeats, greatly exceeding repeat copy number at most trinucleotide and other simple repeat loci. No evidence for longer, higher-order repeats was observed among the limited number of repeats sequenced. These loci may represent a transitional state between simple repeat loci and some minisatellites.

Population genetics of trinucleotide repeat polymorphisms.

Trinucleotide repeats at five disease loci (DM, DRPLA, HD, SBMA and SCA1) were surveyed in phenotypically normal individuals from three continental populations. This is the first analysis to examine the population dynamics of these five disease-related trinucleotide repeats in the same individuals from worldwide populations. Roughly half of all alleles observed at each locus are shared between all continental groups. For three loci, disease prevalence in each population corresponds with the number of alleles in the upper tail of the allele-size distribution. The allele-size distributions of African, Asian and Caucasian groups show a high degree of variation, and gene diversity estimates for trinucleotide repeat loci exceed estimates derived from dinucleotide or tetranucleotide repeats. Analyses that compared infinite alleles and stepwise mutation models suggest that normal variation at trinucleotide loci is not generated by stepwise mutation alone. Trees constructed for subpopulations using trinucleotide repeat loci show accurate continental clustering. Interpopulation genetic distance estimates show remarkable similarity to distance estimates produced from tetranucleotide repeats or nuclear restriction site polymorphisms. This finding is especially noteworthy in light of the fact that trinucleotide repeat polymorphisms at these loci can cause disease, while restriction site and tetranucleotide polymorphisms appear to be selectively neutral. In contrast, genetic distance estimates from trinucleotide loci are poorly correlated with genetic distance estimates from mitochondrial sequence data.

Distribution of Trinucleotide Microsatellites in Different Categories of Mammalian Genomic Sequence: Implications for Human Genetic Diseases

The distribution of all trinucleotide microsatellite sequences in the GenBank database was surveyed to provide insight into human genetic disease syndromes that result from expansion of microsatellites. The microsatellite motif (CAG) n is one of the most abundant microsatellite motifs in human GenBank DNA sequences and is the most abundant microsatellite found in exons. This fact may explain why (CAG) n repeats are thus far the predominant microsatellites expanded in human genetic diseases. Surprisingly, (CAG) n microsatellites are excluded from intronic regions in a strand-specific fashion, possibly because of similarity to the 3′ consensus splice site, CAGG. A comparison of the positions of microsatellites in human vs rodent homologous sequences indicates that some arrays are not extensively conserved for long periods of time, even when they form parts of protein coding sequences. The general lack of conservation of trinucleotide repeat loci in diverse mammals indicates that animal models for some human microsatellite expansion syndromes may be difficult to find.