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Quantitative evaluation of chromosomal rearrangements in primary gene-edited human stem cells by preclinical CAST-Seq

ABSTRACT: Quantitative evaluation of chromosomal rearrangements in primary gene-edited human stem cells by preclinical CAST-Seq

PROVIDER: PRJNA690516 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13377000_1.fastq.gz	Fastqsanger.gz
	SRR13377000_2.fastq.gz	Fastqsanger.gz
	SRR13377001_1.fastq.gz	Fastqsanger.gz
	SRR13377001_2.fastq.gz	Fastqsanger.gz
	SRR13377002_1.fastq.gz	Fastqsanger.gz

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Quantitative evaluation of chromosomal rearrangements in primary gene-edited human stem cells by preclinical CAST-Seq

Project description:Genome editing with programmable nucleases has shown great promise for clinical translation but also revealed the risk of genotoxicity caused by chromosomal translocations or the insertion of mutations at off-target sites. Here, we describe CAST-Seq, an innovative assay to identify and quantify chromosomal aberrations derived from on- and off-target activities of CRISPR-Cas nucleases or TALENs. CAST-Seq also detected novel types of chromosomal rearrangements, including homology-mediated translocations that are mediated by homologous recombination. Depending on the employed designer nuclease, translocations occurred in 0–0.5% of gene-edited human stem cells and some 20% of target loci harbored gross aberrations. In conclusion, CAST-Seq analyses are particularly relevant for therapeutic editing of stem cells to enable a thorough risk assessment before clinical application of gene editing products.

2021-02-14 | GSE164389 | GEO

Gene editing of colocalized NCF1 loci is associated with homologous recombination and chromosomal rearrangements - CAST-seq

Project description:Despite lingering genotoxicity concerns, CRISPR-based genome editing has progressively entered the gene therapy field. Here we report that interactions between nucleotide sequences that are localized on the same chromosome and exhibit a high degree of homology contribute substantially to post-editing chromosomal rearrangements. We successfully employed corrective editing strategies at the NCF1 gene, as well as at the colocalized pseudogenes, NCF1B and NCF1C, in a human cell line model of p47phox-deficient chronic granulomatous disease and in patient-derived human hematopoietic stem cells. Upon genetic manipulation, an improved droplet digital PCR-based method identified cells with altered copy numbers, spanning megabases from the edited loci. We attributed the high aberration frequency to the interaction between repetitive sequences and their predisposition to recombination events. Our findings emphasize the need for careful evaluation of the target-specific genomic context, such as the presence of homologous regions, whose genome instability can constitute a risk factor for chromosomal rearrangements upon genome editing.

2024-10-16 | GSE263692 | GEO

Gene editing of colocalized NCF1 loci is associated with homologous recombination and chromosomal rearrangements - CAST-seq

Project description:Gene editing of colocalized NCF1 loci is associated with homologous recombination and chromosomal rearrangements - CAST-seq

| PRJNA1098731 | ENA

Analysis of Gross Chromosomal Rearrangements in Budding Yeast

Project description:Determine changes in genomic copy across the entire genome for isolated strains with selected gross chromosomal rearrangements relative to the wild-type strain.

2014-03-15 | E-MTAB-2377 | biostudies-arrayexpress

PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA

Project description:Chromosomal rearrangements are essential events in the pathogenesis of both malignant and nonmalignant disorders, yet the factors affecting their formation are incompletely understood. We developed a zinc finger nuclease translocation reporter (ZITR) and screened for factors that modulate rearrangements in human cells. We identified UBC9 and RAD50 as suppressors and 53BP1, DDB1, and PARP3 as promoters of chromosomal rearrangements across human cell types. We focused on poly(ADP)ribose polymerase 3 (PARP3) as it is dispensable for murine viability and has druggable catalytic activity. We found that PARP3 regulated G quadruplex (G4) DNA in response to DNA damage, which suppressed repair by nonhomologous end-joining and homologous recombination. Chemical stabilization of G4 DNA in PARP3-/- cells led to widespread DNA double-strand breaks and synthetic lethality. We propose a model in which PARP3 suppresses G4 DNA and facilitates DNA repair by multiple pathways.

2017-03-01 | GSE94588 | GEO

Comparative genomic hybridization of Saccharomyces cerevisiae - analysis of gross chromosomal rearrangements

Project description:Determine changes in genomic copy across the entire genome for isolated strains with selected gross chromosomal rearrangements relative to the wild-type strain.

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Project description:We investigated the effects of the ploidy on cellular response in strains carrying various types of gross chromosomal rearrangements.

2011-06-17 | GSE28285 | GEO

Toxoplasma gondii CAST

Project description:Toxoplasma gondii CAST genome sequencing project

| PRJNA61553 | ENA

Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease

Project description:To determine the genome-wide spectrum and persistence of genomic rearrangements, we applied UniDirectional Targeted Sequencing (UDiTaS) in edited normal donor CD34+ HSPCs. At day 5 and 14 post-electroporation, no reproducible translocations or structural genomic re-arrangements were identified.

2024-09-14 | GSE277175 | GEO

CGH detection of chromosomal rearrangements in diploid yeast cells exposed to ionizing radiation

Project description:At the organismal level, genome rearrangements are usually deleterious and are often associated with disease. Yet, on an evolutionary scale, they can be beneficial as they provide for rapid genetic diversification. DNA lesions, particularly double-strand breaks (DSBs), are sources of genome instability that can be rectified by various repair processes. Homologous recombination (HR) is highly effective at protecting the genome from DSBs and provides for accurate repair between sister chromatids and homologous chromosomes. Here we show that although random DSBs induced by ionizing radiation in yeast chromosomes are repaired efficiently by HR in G-2 diploid cells, rearrangements are frequent. The chromosome aberrations (ABs) primarily resulted from recombination between Ty retrotransposable elements, the most abundant class of dispersed repetitive DNAs in the genome, while some rearrangements involved other classes of repetitive DNA. Few, if any, of the ABs could be attributed to nonhomologous end-joining (NHEJ). We conclude that only those few DSBs that fall at or near the 3-5% of the genome composed of repetitive DNA elements are effective at generating rearrangements, while other lesions that appear in unique (single copy) sequences are correctly repaired. Thus, by successfully competing with repair that normally occurs between large homologous chromosomal DNAs, the combination of repetitive elements and DSBs provides genome plasticity and a rich source of evolutionary opportunities. Keywords: CGH-array

2007-02-08 | GSE6984 | GEO

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