Browse
Submit Data
Databases
API
Help

Dataset Information

35 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Trinucleotide repeats: triggers for genomic disorders?

ABSTRACT: Among the various sequence repeats that shape the human genome, trinucleotide repeats have attracted special interest as a result of their involvement in a class of human genetic disorders known as triplet repeat expansion diseases. Recently, long TGG repeat tracts were shown to be implicated in a genomic disorder resulting from chromosome 14q32.2 deletion. Various different mechanisms might trigger this deletion, and looking at the problem from a structural biology perspective may help. Deeper insight into repeated sequences and their features may shed light on the mechanisms involved in this microdeletion and similar genomic rearrangements.

SUBMITTER: Kozlowski P

PROVIDER: S-EPMC2873807 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Trinucleotide repeats: triggers for genomic disorders?

Kozlowski Piotr P Sobczak Krzysztof K Krzyzosiak Wlodzimierz J WJ

Genome medicine 20100430 4

Among the various sequence repeats that shape the human genome, trinucleotide repeats have attracted special interest as a result of their involvement in a class of human genetic disorders known as triplet repeat expansion diseases. Recently, long TGG repeat tracts were shown to be implicated in a genomic disorder resulting from chromosome 14q32.2 deletion. Various different mechanisms might trigger this deletion, and looking at the problem from a structural biology perspective may help. Deeper ...[more]

PMID: 20441603

Similar Datasets

Trinucleotide repeats: a structural perspective.

Project description:Trinucleotide repeat (TNR) expansions are present in a wide range of genes involved in several neurological disorders, being directly involved in the molecular mechanisms underlying pathogenesis through modulation of gene expression and/or the function of the RNA or protein it encodes. Structural and functional information on the role of TNR sequences in RNA and protein is crucial to understand the effect of TNR expansions in neurodegeneration. Therefore, this review intends to provide to the reader a structural and functional view of TNR and encoded homopeptide expansions, with a particular emphasis on polyQ expansions and its role at inducing the self-assembly, aggregation and functional alterations of the carrier protein, which culminates in neuronal toxicity and cell death. Detail will be given to the Machado-Joseph Disease-causative and polyQ-containing protein, ataxin-3, providing clues for the impact of polyQ expansion and its flanking regions in the modulation of ataxin-3 molecular interactions, function, and aggregation.

| S-EPMC3687200 | biostudies-literature

Interrogating the "unsequenceable" genomic trinucleotide repeat disorders by long-read sequencing.

Project description:Microsatellite expansion, such as trinucleotide repeat expansion (TRE), is known to cause a number of genetic diseases. Sanger sequencing and next-generation short-read sequencing are unable to interrogate TRE reliably. We developed a novel algorithm called RepeatHMM to estimate repeat counts from long-read sequencing data. Evaluation on simulation data, real amplicon sequencing data on two repeat expansion disorders, and whole-genome sequencing data generated by PacBio and Oxford Nanopore technologies showed superior performance over competing approaches. We concluded that long-read sequencing coupled with RepeatHMM can estimate repeat counts on microsatellites and can interrogate the "unsequenceable" genomic trinucleotide repeat disorders.

| S-EPMC5514472 | biostudies-literature

Trinucleotide repeats in human genome and exome.

Project description:Trinucleotide repeats (TNRs) are of interest in genetics because they are used as markers for tracing genotype-phenotype relations and because they are directly involved in numerous human genetic diseases. In this study, we searched the human genome reference sequence and annotated exons (exome) for the presence of uninterrupted triplet repeat tracts composed of six or more repeated units. A list of 32 448 TNRs and 878 TNR-containing genes was generated and is provided herein. We found that some triplet repeats, specifically CNG, are overrepresented, while CTT, ATC, AAC and AAT are underrepresented in exons. This observation suggests that the occurrence of TNRs in exons is not random, but undergoes positive or negative selective pressure. Additionally, TNR types strongly determine their localization in mRNA sections (ORF, UTRs). Most genes containing exon-overrepresented TNRs are associated with gene ontology-defined functions. Surprisingly, many groups of genes that contain TNR types coding for different homo-amino acid tracts associate with the same transcription-related GO categories. We propose that TNRs have potential to be functional genetic elements and that their variation may be involved in the regulation of many common phenotypes; as such, TNR polymorphisms should be considered a priority in association studies.

| S-EPMC2896521 | biostudies-literature

Folate Deficiency Triggers the Abnormal Segregation of a Region With Large Cluster of CG-Rich Trinucleotide Repeats on Human Chromosome 2.

Project description:Folate deficiency is associated with a broad range of human disorders, including anemia, fetal neural tube defects, age-associated dementia and several types of cancer. It is well established that a subgroup of rare fragile sites (RFSs) containing expanded CGG trinucleotide repeat (TNR) sequences display instability when cells are deprived of folate. However, given that folate sensitive RFSs exist in a very small percentage of the population, they are unlikely to be the cause of the widespread health problems associated with folate deficiency. We hypothesized that folate deficiency could specifically affect DNA replication at regions containing CG-rich repeat sequences. For this, we identified a region on human chromosome 2 (Chr2) comprising more than 300 CG-rich TNRs (termed "FOLD1") by examining the human genome database. Via the analysis of chromosome shape and segregation in mitosis, we demonstrate that, when human cells are cultured under folate stress conditions, Chr2 is prone to display a "kink" or "bending" at FOLD1 in metaphase and nondisjunction in anaphase. Furthermore, long-term folate deprivation causes Chr2 aneuploidy. Our results provide new evidence on the abnormalities folate deficiency could cause in human cells. This could facilitate future studies on the deleterious health conditions associated with folate deficiency.

| S-EPMC8281231 | biostudies-literature

Genomic deletions and point mutations induced in Saccharomyces cerevisiae by the trinucleotide repeats (GAA·TTC) associated with Friedreich's ataxia.

Project description:Expansion of certain trinucleotide repeats causes several types of human diseases, and such tracts are associated with the formation of deletions and other types of genetic rearrangements in Escherichia coli, yeast, and mammalian cells. Below, we show that long (230 repeats) tracts of the trinucleotide associated with Friedreich's ataxia (GAA·TTC) stimulate both large (>50 bp) deletions and point mutations in a reporter gene located more than 1 kb from the repetitive tract. Sequence analysis of deletion breakpoints indicates that the deletions reflect non-homologous end joining of double-stranded DNA breaks (DSBs) initiated in the tract. The tract-induced point mutations appear to reflect a different mechanism involving single-strand annealing of DNA molecules generated by DSBs within the tract, followed by filling-in of single-stranded gaps by the error-prone DNA polymerase zeta.

| S-EPMC3534863 | biostudies-literature

Effect of Trinucleotide Repeats in the Huntington's Gene on Intelligence.

Project description:BACKGROUND:Huntington's Disease (HD) is caused by an abnormality in the HTT gene. This gene includes trinucleotide repeats ranging from 10 to 35, and when expanded beyond 39, causes HD. We previously reported that CAG repeats in the normal range had a direct and beneficial effect on brain development with higher repeats being associated with higher cognitive function. The current study now expands this line of inquiry to evaluate the effects of CAG repeat throughout the entire spectrum of repeats from 15 to 58. METHODS:We evaluated brain function in children ages 6-18?years old. DNA samples were processed to quantify the number of CAG repeats within HTT. Linear regression was used to determine if number of CAG repeats predicted measures of brain function. FINDINGS:The number of repeats in HTT, had a non-linear effect on a measure of general intelligence with an inverted U shape pattern. Increasing repeat length was associated with higher GAI scores up until roughly 40-41 repeats. After this peak, increasing repeat length was associated with declining GAI scores. INTERPRETATION:HTT may confer an advantage or a disadvantage depending upon the repeat length, playing a key role in the determination of intelligence, or causing a uniquely human brain disease.

| S-EPMC6013750 | biostudies-literature

Development of novel macrocyclic small molecules that target CTG trinucleotide repeats.

Project description:We describe the molecular design, synthesis, and investigation of a series of acridine-triaminotriazine macrocycles that selectively bind to CTG trinucleotide repeats in DNA with minimal nonspecific binding. The limited conformational flexibility enforces the stacking of the triaminotriazine and acridine units. Isothermal titration calorimetry studies and Job plot analyses revealed that the ligands bound to d(CTG) mismatched sites. The acridine and triaminotriazine units were shown to intramolecularly π-stack in aqueous solutions. Compared to a noncyclic analog, the macrocycles showed an almost 10-fold lower cytotoxicity in HeLa cells and up to 4-fold higher transcription inhibition of d(CTG·CAG)74.

| S-EPMC6592636 | biostudies-literature

Structures of trinucleotide repeats in human transcripts and their functional implications.

Project description:Among the goals of RNA structural and functional genomics is determining structures and establishing the functions of a rich repertoire of simple sequence repeats in transcripts. These repeats are present in transcripts from their 'birth' in the nucleus to their 'death' in cytoplasm and have the potential of being involved in many steps of RNA regulation. The knowledge of their structural features and functional roles will also shed more light on the postulated mechanisms of RNA pathogenesis in a growing list of neurological diseases caused by simple sequence repeat expansions. Here, we discuss several different lines of research to support the hypothesis that the mechanism of RNA pathogenesis may be a more common phenomenon triggered or modulated also by abundant long normal repeats. We propose structures of the repeat regions in transcripts of genes involved in Triplet Repeat Expansion Diseases. We have classified the polymorphic repeat alleles of these genes according to their ability to form hairpin structures in transcripts, and describe the distribution of different structural forms of the repeats in the human population. We have also reported the results of a systematic survey of the human transcriptome to identify mRNAs containing triplet repeats and to classify them according to structural and functional criteria. Based on this knowledge, we discuss the putative wider role of triplet repeat RNA hairpins in human diseases. A hypothetical model is proposed in which long normal RNA hairpins formed by the repeats may also be involved in pathogenesis.

| S-EPMC206467 | biostudies-literature

Determinants of R-loop formation at convergent bidirectionally transcribed trinucleotide repeats.

Project description:R-loops have been described at immunoglobulin class switch sequences, prokaryotic and mitochondrial replication origins, and disease-associated (CAG)n and (GAA)n trinucleotide repeats. The determinants of trinucleotide R-loop formation are unclear. Trinucleotide repeat expansions cause diseases including DM1 (CTG)n, SCA1 (CAG)n, FRAXA (CGG)n, FRAXE (CCG)n and FRDA (GAA)n. Bidirectional convergent transcription across these disease repeats can occur. We find R-loops formed when CTG or CGG and their complementary strands CAG or CCG were transcribed; GAA transcription, but not TTC, yielded R-loops. R-loop formation was sensitive to DNA supercoiling, repeat length, insensitive to repeat interruptions, and formed by extension of RNA:DNA hybrids in the RNA polymerase. R-loops arose by transcription in one direction followed by transcription in the opposite direction, and during simultaneous convergent bidirectional transcription of the same repeat forming double R-loop structures. Since each transcribed disease repeat formed R-loops suggests they may have biological functions.

| S-EPMC3061079 | biostudies-literature

Length-dependent energetics of (CTG)n and (CAG)n trinucleotide repeats.

Project description:Trinucleotide repeats are involved in a number of debilitating diseases such as myotonic dystrophy. Twelve to seventy-five base-long (CTG)n oligodeoxynucleotides were analysed using a combination of biophysical [UV-absorbance, circular dichroism and differential scanning calorimetry (DSC)] and biochemical methods (non-denaturing gel electrophoresis and enzymatic footprinting). All oligomers formed stable intramolecular structures under near physiological conditions with a melting temperature that was only weakly dependent on oligomer length. Thermodynamic analysis of the denaturation process by UV-melting and calorimetric experiments revealed an unprecedented length-dependent discrepancy between the enthalpy values deduced from model-dependent (UV-melting) and model-independent (calorimetry) experiments. Evidence for non-zero molar heat capacity changes was also derived from the analysis of the Arrhenius plots and DSC profiles. Such behaviour is analysed in the framework of an intramolecular 'branched-hairpin' model, in which long CTG oligomers do not fold into a simple long hairpin-stem intramolecular structure, but allow the formation of several independent folding units of unequal stability. We demonstrate that, for sequences ranging from 12 to 25 CTG repeats, an intramolecular structure with two loops is formed which we will call 'bis-hairpin'. Similar results were also found for CAG oligomers, suggesting that this observation may be extended to various trinucleotide repeats-containing sequences.

| S-EPMC1179733 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data