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Ontology highlight
ABSTRACT:
PROVIDER: PRJEB51941 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR9435463_1.fastq.gz | Fastqsanger.gz | |||
| ERR9435463_2.fastq.gz | Fastqsanger.gz | |||
| ERR9452020_1.fastq.gz | Fastqsanger.gz | |||
| ERR9452020_2.fastq.gz | Fastqsanger.gz | |||
| ERR9452040_1.fastq.gz | Fastqsanger.gz |
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Project description:Somatic copy number variant load in neurons of healthy controls and Alzheimer’s disease patients
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Project description:Interventions: Group 1: Blood and sputum samples as well as paraffin embedded tumour tissue from patients with microsatellite stable colorectal cancer shall be analysed before therapy and over time to establish and validate hotspot mutation and somatic copy number variant (SCNAs) analysis. We therefore need the following samples:
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- Two Cell-Free DNA BCT CE Streck tubes with 8 ml blood per sampling for preparation of plasma-DNA.
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Project description:Constitutional epimutations of tumor suppressor genes manifest as promoter methylation and transcriptional silencing of a single allele in normal somatic tissues, thereby predisposing to cancer. Constitutional MLH1 epimutations occur in individuals with young-onset cancer and demonstrate non-Mendelian inheritance through their reversal in the germline. We report a cancer-affected family showing dominant transmission of soma-wide highly mosaic MLH1 methylation and transcriptional repression linked to a particular genetic haplotype. The epimutation was erased in spermatozoa but reinstated in the somatic cells of the next generation. The affected haplotype harbored two single nucleotide substitutions in tandem: c.-27C>A located near the transcription initiation site and c.85G>T. The c.-27C>A variant significantly reduced transcriptional activity in reporter assays and is the probable cause of this epimutation. Five members of a three-generation Caucasian Lynch syndrome family with an autosomal dominant MLH1 epimutation linked to a single nucleotide variant (c.-27C>A) within the MLH1 5'UTR were examined for copy number variations and retention of heterozygosity on chromosome 3. These five carriers of constitutional MLH1 methylation and the c.-27C>A variant were compared with 300 healthy Caucasian controls from the Wellcome Trust Case Control Consortium using three algorithms (QuantiSNP, PennCNV, COKGEN) to detect any copy number variants. The five family members studied were female (the proband II5, her affected mother I1, and three asymptomatic relatives II2, II4 and III2) are labeled according to the pedigree in Figure 3 of the associated publication (Hitchins et al., Cancer Cell, 2011). The supplementary file 'GSE30348_gw6.lrr_baf.txt' contains log R ratio and B-allele frequency values in a tab-delimited format with one marker per row.
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Project description:Epilepsy is a heterogenous group of disorders defined by recurrent seizure activity due to abnormal synchronized activity of neurons. A growing number of epilepsy cases are believed to be caused by genetic factors and copy number variants (CNV) contribute to up to 5% of epilepsy cases. However, CNVs in epilepsy are usually large deletions or duplications involving multiple neurodevelopmental genes. Here we identify focal amplifications of regulatory regions of receptor tyrosine kinase genes as a genetic abnormality in epileptogenic brains. Whole genome DNA methylation profiling identified three main clusters of which one showed strong association with receptor tyrosine kinase genes. By copy number analysis, we identified focal copy number gains involving EGFR and PDGFRA in brain tissue of patients who underwent seizure focus resection for treatment-resistant epilepsy. The dysplastic neurons showed marked overexpression of pEGFR and pPDGFRA, while glial and endothelial cells were negative. Sequencing and DNA methylation analysis revealed that enhancer regions of EGFR and PDGFRA gene promoter were amplified, while coding regions did not show copy number abnormalities or somatic mutations. Our results identify somatic focal copy number gains of noncoding regulatory regions in the brain as a previously unrecognized genetic driver in epilepsy. Somatic copy number aberrations of regulatory regions represent a mechanism of abnormal activation of receptor tyrosine kinase genes in epilepsy. Upregulated receptor tyrosine kinases provide a potential avenue for therapy in seizure disorders.
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Project description:Late-onset Alzheimer’s disease (LOAD) is the most common form of AD. However, modeling sporadic LOAD, without clear genetic predispositions, to capture hallmark neuronal pathologies such as extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal loss, remains an unmet need. Here, we demonstrate that neurons generated by microRNA-based direct reprogramming of fibroblasts from patients affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional (3D) environment, effectively recapitulate key neuropathological features of AD without additional cellular or genetic insults. These LOAD neurons exhibit Aβ-dependent neurodegeneration, as treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover, inhibiting age-associated retrotransposable elements (RTEs) in LOAD neurons reduced both Ab deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency microRNA-based neuronal reprogramming.
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