Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

DNA polymerase stalling at structured DNA predicts the stability of short tandem repeats

ABSTRACT: Short tandem repeats (STRs) significantly contribute to de novo mutagenesis, driving phenotypic diversity and genetic disease. Although highly diverse, their low complexity and repetitive nature induces DNA polymerase slippage and stalling, leading to length variation and base substitutions. However, the characterisation of DNA synthesis through STR loci has been restricted to a handful of selected sequences, limiting our broader understanding of their evolutionary behaviour. In order to understand the interplay between the ability of a given STR to impair DNA synthesis and its genomic stability, we developed a high-throughput polymerase extension assay that allows monitoring the kinetics of DNA synthesis at all STR permutations in different lengths in parallel. We have used the assay to map at single-nucleotide resolution the movement of a prototypical A-family replicative DNA polymerase (T7 DNA polymerase) through the repeats over time. From this data we can infer the secondary structure adopted by a given STR from the precise manner in which it stalls polymerase and link this to slippage and point mutation during DNA synthesis.

ORGANISM(S): synthetic construct

PROVIDER: GSE144458 | GEO | 2020/07/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Short tandem repeats susceptible to pathogenic instability linked to chromatin domain disruption

Project description:More than 25 inherited human disorders are caused by the unstable expansion of repetitive DNA sequences termed short tandem repeats (STRs). A fundamental unresolved question is why some STRs are susceptible to pathologic expansion, whereas thousands of repeat tracts across the human genome are relatively stable. Here, we discover that nearly all disease-associated STRs (daSTRs) are located at boundaries demarcating 3D chromatin domains. We identify a subset of boundaries with markedly higher CpG island density compared to the rest of the genome. daSTRs specifically localize to ultra-high-density CpG island boundaries, suggesting they might be hotspots for epigenetic misregulation or topological disruption upon STR expansion. Fragile X Syndrome (FXS) patients exhibit severe boundary disruption in a manner that correlates with local loss of CTCF occupancy and the degree of FMR1 silencing. Our data uncover higher-order chromatin architecture as a new dimension in understanding repeat expansion disorders.

2018-08-29 | GSE111170 | GEO

Whole Genome Amplification – surveying yield, reproducibility and heterozygous balance, reported by MIPs targeting STRs

Project description:Whole Genome Amplification (WGA) is a crucial first step to nearly all single cell genomic analyses with following steps focusing solely on its products. Therefore, bias and variance caused by the WGA process add numerous challenges to the world of single cell genomics. Short Tandem Repeats (STRs) are sensitive genomic markers used widely in population genetics, forensics and retrospective lineage tracing. By extending a previous evaluation of common WGA kits(T, O et al. 2021) targeting ~1000 STR loci across the male X chromosome, to ~12,000 across the entire genome via a DuplexMIPS system, heterogeneous STR loci can be discovered in abundance, and better used to analyze the efficacy and effectiveness of various WGA kits. We show that while best overall yield is obtained using RepliG-SC, maximum uniformity between alleles and reproducibility across cells is maximized by Ampli1, rendering it as the best candidate for comparative heterozygous analysis of SC genomes.

2022-05-20 | E-MTAB-11711 | biostudies-arrayexpress

Cell-type specific dysregulation of RNA alternative splicing in short tandem repeat mouse knockin models of myotonic dystrophy

Project description:Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models that recapitulate the tissue specificity and developmental timing of an STR expansion gene, we used rolling circle amplification and CRISPR/Cas9-mediated genome editing to generate Dmpk CTG expansion (CTGexp) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts and brain choroid plexus epithelial cells are particularly susceptible to Dmpk CTGexp mutations and RNA mis-splicing. Our results implicate dysregulation of muscle regeneration and cerebrospinal fluid homeostasis as early pathogenic events in DM1.

2019-11-15 | GSE137494 | GEO

Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [Hi-C]

Project description:Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find Megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X-chromosome in induced pluripotent stem cell (iPSC)-derived neural progenitors, B-cells, and fibroblasts with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication stress-induced double strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the full-mutation CGG to premutation-length reverses H3K9me3 domains on the X-chromosome and multiple autosomes, refolds TADs, and restores expression. H3K9me3 domains also arise in a subset of normal-length iPSCs with increased STR instability burden. Our results reveal Mb-scale heterochromatinization and trans interactions among chromosomes susceptible to repeat genetic instability.

2023-12-21 | GSE218675 | GEO

Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [ChIP-seq]

2023-12-21 | GSE218674 | GEO

Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [Nanopore]

2023-12-21 | GSE218679 | GEO

Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [WGS]

2023-12-21 | GSE218678 | GEO

Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [CUT&RUN]

2023-12-21 | GSE218677 | GEO

Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome [RNA-seq]

2023-12-21 | GSE218676 | GEO

DNA polymerase η contributes to lagging strand synthesis