• Many regions of the genome (exons, introns, intergenic regions) normally contain trinucleotide sequences, or repeated sequences of one particular nucleotide, or sequences of 2, 4, 5 or 6 nucleotides. (wikipedia.org)
  • Short tandem repeats (STRs) compose approximately 3% of the genome, and mutations at STR loci have been linked to dozens of human diseases including amyotrophic lateral sclerosis, Friedreich ataxia, Huntington disease, and fragile X syndrome. (biomedcentral.com)
  • Improving our understanding of these mutations would increase our knowledge of the mutational dynamics of the genome and may uncover additional loci that contribute to disease. (biomedcentral.com)
  • To estimate the genome-wide pattern of mutations at STR loci, we analyze blood-derived whole-genome sequencing data for 544 individuals from 29 three-generation CEPH pedigrees. (biomedcentral.com)
  • Approximately 30% of new STR mutations occur within Alu elements, which compose only 11% of the genome, but only 10% are found in LINE-1 insertions, which compose 17% of the genome. (biomedcentral.com)
  • We estimate the average number of de novo genome-wide STR mutations per individual to be approximately 85, which is similar to the average number of observed de novo single nucleotide variants. (biomedcentral.com)
  • Some of these tools are designed to detect STR expansions at disease-related loci, while others detect expansions and contractions of STRs genome-wide but are constrained by sequencing read length and the STR motif size. (biomedcentral.com)
  • New technologies such as next-generation sequencing (including whole exome or whole genome sequencing) are expanding testing options, discovering new mutations, and creating challenges in counseling, interpreting, and reporting results to the patient. (medlink.com)
  • The advent of massively parallel sequencing technologies [ 8 ] allowed cheap and efficient evaluation of the somatic mutations in a cancer genome. (biomedcentral.com)
  • This provided an unprecedented opportunity to examine somatic mutational patterns by sequencing multiple cancer-associated genes, by sequencing all coding regions of the human genome (i.e., usually referred to as whole-exome sequencing), or even by interrogating the complete sequence of a cancer genome (i.e., an approach known as whole-genome sequencing). (biomedcentral.com)
  • Short tandem repeats (STRs), or microsatellites, are 1-6 base pair (bp) motifs of repeating units of DNA. (biomedcentral.com)
  • Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. (bvsalud.org)
  • Trinucleotide repeat disorders, also known as microsatellite expansion diseases, are a set of over 50 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides (trinucleotide repeats) increase in copy numbers until they cross a threshold above which they cause developmental, neurological or neuromuscular disorders. (wikipedia.org)
  • Genetic mutations that result in loss of RecQ helicase activity gives rise to disorders that are associated with CANCER predisposition and premature aging. (lookformedical.com)
  • Further studies are needed to determine if recovery from this perturbation through gradual mixing of diverged populations by migration and gene flow leads to the pre-climate event state, or whether the observed changes represent a new genetic equilibrium. (biomedcentral.com)
  • An abnormal congenital condition, associated with defects in the LAMIN TYPE A gene, which is characterized by premature aging in children, where all the changes of cell senescence occur. (lookformedical.com)
  • In recently bottlenecked populations not yet in mutation-drift equilibrium, a transient (lasting only a few generations) excess of heterozygosity can occur because allelic diversity is reduced faster than heterozygosity [ 11 - 13 ]. (biomedcentral.com)
  • However, the frequency of occurrence of any one particular repeat sequence disorder varies greatly by ethnic group and geographic location. (wikipedia.org)
  • Sometimes, a person may have more than the usual number of copies of a repeat sequence associated with a gene, but not enough to alter the function of that gene. (wikipedia.org)
  • An increase number of repeats of a genomic, tandemly repeated DNA sequence from one generation to the next. (uams.edu)
  • Trinucleotide repeat disorders and the related microsatellite repeat disorders affect about 1 in 3,000 people worldwide. (wikipedia.org)
  • Three categories of trinucleotide repeat disorders and related microsatellite (4, 5, or 6 repeats) disorders are described by Boivin and Charlet-Berguerand. (wikipedia.org)
  • The second main category of trinucleotide repeat disorders and related microsatellite disorders involves a toxic RNA gain of function mechanism. (wikipedia.org)
  • The third main category of trinucleotide repeat disorders and related microsatellite disorders is due to the translation of repeat sequenced into pathogenic proteins containing a stretch of repeated amino acids. (wikipedia.org)
  • Next-generation sequencing of the whole exome is useful for testing for multiple candidate genes simultaneously or for discovering new, rare disorders. (medlink.com)
  • Whole exome sequencing is not suitable for detecting polynucleotide repeat disorders or large insertion/deletions. (medlink.com)
  • In this second type of disorder, large repeat expansions in DNA are transcribed into pathogenic RNAs that form nuclear RNA foci. (wikipedia.org)
  • These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. (bvsalud.org)
  • To address the molecular and cellular events that lead to these pathological outcomes, we recently generated a mouse Dmpk CTG expansion knock-in model and identified choroid plexus epithelial cells as particularly affected by the expression of toxic CUG expansion RNAs. (bvsalud.org)
  • This results in, variously, a toxic gain of function, a loss of function, a dominant negative effect and/or a mix of these mechanisms for the protein hosting the expansion. (wikipedia.org)
  • Translation of these repeat expansions occurs mostly through two mechanisms. (wikipedia.org)
  • It is possible that each of these mechanisms contributes to the high mutation rate of STRs, but strand slippage is the mechanism proposed for generating most observed mutations in STR loci [ 19 ]. (biomedcentral.com)
  • Slatkin [ 4 ] argued that local extinction and re-colonisation dynamics imply ongoing gene flow, which will prevent local populations from becoming differentiated. (biomedcentral.com)
  • The discovery that trinucleotide repeats could expand during intergenerational transmission and could cause disease was the first evidence that not all disease-causing mutations are stably transmitted from parent to offspring. (wikipedia.org)
  • Phasing these mutations to the parent of origin shows that parental transmission biases vary among families. (biomedcentral.com)
  • We use HipSTR to identify de novo STR mutations in the 2nd generation of these pedigrees and require transmission to the third generation for validation. (biomedcentral.com)
  • Analyzing approximately 1.6 million STR loci, we estimate the empirical de novo STR mutation rate to be 5.24 × 10 −5 mutations per locus per generation. (biomedcentral.com)
  • The first main category these authors discuss is repeat expansions located within the promoter region of a gene or located close to, but upstream of, a promoter region of a gene. (wikipedia.org)
  • There is often increased methylation at CpG islands near the repeat region, resulting in a closed chromatin state, causing gene downregulation. (wikipedia.org)
  • We found that population turnover after 2003 led to a loss of allelic richness and gene diversity but not to significant changes in observed heterozygosity. (biomedcentral.com)
  • The second DNA-triplet repeat disease, fragile X-E syndrome, was also identified on the X chromosome, but was found to be the result of an expanded CCG repeat. (wikipedia.org)
  • Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. (lookformedical.com)
  • While the tool provides a comprehensive classification of mutations, SigProfilerMatrixGenerator is also faster and more memory efficient than existing tools that generate only a single matrix. (biomedcentral.com)
  • In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes. (wikipedia.org)
  • The epigenetic alterations and their effects are described more fully by Barbé and Finkbeiner These authors cite evidence that the age at which an individual begins to experience symptoms, as well as the severity of disease, is determined both by the size of the repeat and the epigenetic state within the repeat and around the repeat. (wikipedia.org)
  • This graph shows the total number of publications written about "DNA Repeat Expansion" by people in UAMS Profiles by year, and whether "DNA Repeat Expansion" was a major or minor topic of these publications. (uams.edu)
  • Below are the most recent publications written about "DNA Repeat Expansion" by people in Profiles over the past ten years. (uams.edu)
  • Some carriers, during the formation of eggs or sperm, may give rise to higher levels of repetition of the repeat they carry. (wikipedia.org)
  • Within all valleys, permanent and temporary streams in any given year were not differentiated, suggesting considerable gene flow and admixture between streams with differing hydroperiods. (biomedcentral.com)
  • As with many other tandemly repeated microsatellite sequences, pathogenic TNRs are highly unstable in both the somatic and germ cell lineage, leading to expansions and contractions in the length of the repeats in successive cell or individual generations. (bmj.com)
  • An increase number of repeats of a genomic, tandemly repeated DNA sequence from one generation to the next. (nih.gov)
  • The chromosomal instability resulting from this trinucleotide expansion presents clinically as intellectual disability, distinctive facial features, and macroorchidism in males. (wikipedia.org)
  • 31 Therefore, we have hypothesised that mutagenic stress could result in an induction of instability of unexpanded TNR sequences, leading to an increase in the frequency of spontaneously occurring contractions/expansions in repeat number. (bmj.com)
  • Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. (org.ua)
  • However, pathogenic loci bear expanded alleles of up to several hundred or even thousand repeats in severe cases. (bmj.com)
  • Haplotype Analysis of DXS548 and FRAXAC1 Microsatellite Loci in Iranian Patients with Fragile X Syndrome. (cdc.gov)
  • Polymorphism of trinucleotide repeats at loci FRAXA and FRAXE in the population of Tomsk]. (cdc.gov)
  • The first trinucleotide repeat disease to be identified was fragile X syndrome, which has since been mapped to the long arm of the X chromosome. (wikipedia.org)
  • Patients carry from 230 to 4000 CGG repeats in the gene that causes fragile X syndrome, while unaffected individuals have up to 50 repeats and carriers of the disease have 60 to 230 repeats. (wikipedia.org)
  • The second DNA-triplet repeat disease, fragile X-E syndrome, was also identified on the X chromosome, but was found to be the result of an expanded CCG repeat. (wikipedia.org)
  • The number of trinucleotide repeats (TNRs) in most unaffected individuals is in the range of 5-35 repeats in DM1 and around 14-35 repeats in fragile X syndrome. (bmj.com)
  • Distribution of fragile X mental retardation 1 CGG repeat and flanking haplotypes in a large Chinese population. (cdc.gov)
  • Analysis of the Fragile X Trinucleotide Repeat in Basques: Association of Premutation and Intermediate Sizes, Anchoring AGGs and Linked Microsatellites with Unstable Alleles. (cdc.gov)
  • Differential epigenetic modifications in the FMR1 gene of the fragile X syndrome after reactivating pharmacological treatments. (cdc.gov)
  • Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. (org.ua)
  • Inheritance of the fragile X syndrome: size of the fragile X premutation is a major determinant of the transition to full mutation. (org.ua)
  • [12] Fisch GS, Snow K, Thibodeau SN, Chalifaux M, Holden JJ, Nelson DL, Howard-Peebles PN, Maddalena A. The fragile X premutation in carriers and its effect on mutation size in offspring. (org.ua)
  • The full mutation in the FMR-1 gene of male fragile X patients is absent in their sperm. (org.ua)
  • [16] Willems PJ, Van Roy B, De Boulle K, Vits L, Reyniers E, Beck O, Dumon JE, Verkerk A, Oostra B. Segregation of the fragile X mutation from an affected male to his normal daughter. (org.ua)
  • [18] W?hrle D, Hennig I, Vogel W, Steinbach P. Mitotic stability of fragile X mutations in differentiated cells indicates early post-conceptional trinucleotide repeat expansion. (org.ua)
  • Little is known, however, about the mechanism(s) that cause a stable, non-expanded allele to become unstable and pathogenic, probably because normal length alleles are thought to be stable compared with expanded pathogenic alleles. (bmj.com)
  • In addition, much of the evidence for the mechanisms that are thought to produce repeat expansion in pathological TNRs are dismissed as irrelevant for normal alleles. (bmj.com)
  • 2, 3 The full mutation appears in approximately 1 in 4000 males and 1 in 9000 females. (bmj.com)
  • Trinucleotide repeat disorders, also known as microsatellite expansion diseases, are a set of over 50 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides (trinucleotide repeats) increase in copy numbers until they cross a threshold above which they cause developmental, neurological or neuromuscular disorders. (wikipedia.org)
  • Comparative (computational) analysis of the DNA methylation status of trinucleotide repeat expansion diseases. (cdc.gov)
  • Is the 31 CAG repeat allele of the spinocerebellar ataxia 1 (SCA1) gene locus non-specifically associated with trinucleotide expansion diseases? (cdc.gov)
  • Developing text mining workflows that use natural language processing for identifying diseases, genes and variants, along with impact prediction algorithms and integrating with details on clinical phenotypes and functional assessments might be a promising approach to scale literature mining of variants and assigning correct pathogenicity. (bvsalud.org)
  • Many regions of the genome (exons, introns, intergenic regions) normally contain trinucleotide sequences, or repeated sequences of one particular nucleotide, or sequences of 2, 4, 5 or 6 nucleotides. (wikipedia.org)
  • To test this hypothesis, we analysed normal length TNR sequences at a single repeat resolution by radioactive PCR and denaturating polyacrylamide gels, using DNA from multiple single cell clones expanded in the presence or absence of mitomycin-C (MMC), a mutagenic agent able to induce interstrand DNA cross links, strand breaks, and replication blockage. (bmj.com)
  • [9] Richards RI, Sutherland GR. Heritable unstable DNA sequences. (org.ua)
  • These repeats are able to promote localized DNA epigenetic changes such as methylation of cytosines. (wikipedia.org)
  • There is often increased methylation at CpG islands near the repeat region, resulting in a closed chromatin state, causing gene downregulation. (wikipedia.org)
  • Its molecular basis is an expansion of a CTG repeat in the 3′ untranslated region (UTR) of the DMPK gene on chromosome 19. (bmj.com)
  • Myotonic dystrophy type 1 (DM1) is an autosomal dominant inherited disorder caused by expansion of a germline and somatically unstable CTG repeat in the DMPK gene. (nih.gov)
  • In this second type of disorder, large repeat expansions in DNA are transcribed into pathogenic RNAs that form nuclear RNA foci. (wikipedia.org)
  • The third main category of trinucleotide repeat disorders and related microsatellite disorders is due to the translation of repeat sequenced into pathogenic proteins containing a stretch of repeated amino acids. (wikipedia.org)
  • It is caused by an expansion of a CGG repeat in the 5′ UTR of the FMR1 gene. (bmj.com)
  • Distribution of CGG/GCC repeats at the FMR1 and FMR2 genes in an Indian population with mental retardation of unknown etiology. (cdc.gov)
  • In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes. (wikipedia.org)
  • 10 These factors are not mutually exclusive and include the purity and length of the repeated sequence, 7, 11 age of individuals, 6, 7 mitotic drive, 12 the relative position of the TNR with respect to adjacent origins of DNA replication, 13 and mutations in genes involved in DNA repair, replication, and recombination. (bmj.com)
  • To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. (nih.gov)
  • The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion. (nih.gov)
  • This results in, variously, a toxic gain of function, a loss of function, a dominant negative effect and/or a mix of these mechanisms for the protein hosting the expansion. (wikipedia.org)
  • Variants, symptoms, biochemical assay results, and protein function from literature on the SLC6A8 gene associated with X-linked Creatine Transporter Deficiency (CTD) were curated and reported as a highly annotated dataset of variants with clinical context and functional details. (bvsalud.org)
  • Mutations in KRIT1, a protein initially identified based on a yeast two-hybrid interaction with the RAS-family GTPase RAP1A, are responsible for the development of the inherited vascular disorder cerebral cavernous malformations (CCM1). (nih.gov)
  • Newly incorporated services include gene, variant and sample level reporting, literature and functional correlations among impacted genes, comparative analysis across samples and against data sources such as TCGA and ClinVar, and cohort building. (bvsalud.org)
  • The epigenetic alterations and their effects are described more fully by Barbé and Finkbeiner These authors cite evidence that the age at which an individual begins to experience symptoms, as well as the severity of disease, is determined both by the size of the repeat and the epigenetic state within the repeat and around the repeat. (wikipedia.org)
  • [1] Richards RI, Sutherland GR. Dynamic mutations: a new class of mutations causing human disease. (org.ua)
  • Some carriers, during the formation of eggs or sperm, may give rise to higher levels of repetition of the repeat they carry. (wikipedia.org)
  • We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. (bvsalud.org)
  • The higher level may then be at a "mutation" level and cause symptoms in their offspring. (wikipedia.org)
  • Previously, CTG repeat length at birth has been correlated to patient age at symptom onset. (nih.gov)
  • The second main category of trinucleotide repeat disorders and related microsatellite disorders involves a toxic RNA gain of function mechanism. (wikipedia.org)
  • The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. (nih.gov)