Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing
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ABSTRACT:
PROVIDER: EGAS00001001838 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm and the mitochondrial double membrane. Despite these physical barriers we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements and the features of the fusion fragments indicate that non-homologous end joining and/or replication-dependent DNA double strand break repair are the dominant mechanism involved. This study includes 12 pairs of whole-genome sequences (tumour and paired-normal), which present somatic mitochondrial DNA integrations in tumour genomes. Reference: Young Seok Ju et al., Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells, Genome Research (2015).
| EGAS00001001234 | EGA
Project description:Genome-directed oncology has the potential to revolutionize patient treatment, but is limited by an abundance of rare, uncharacterized and therapeutically uninformative somatic variants. To accelerate characterization of the “long tail” of rare somatic variants, we quantified the activity and drug responsiveness of virtually all possible (99.84%) missense variants in the Ser/Thr kinase MAPK1/ERK2. We identified recurrent and rare hypermorphic and loss-of-function alleles, revealing that variant activity is uncorrelated with mutational frequency. Somatic ERK2 variants displayed variable responses to RAF-, MEK- and ERK-directed therapies, potentially informing clinical treatment strategies for patients whose tumors harbor these alterations. A subset of recurrent and rare somatic variants co-localized on ERK2 protein-protein interfaces, yet engendered contrasting phenotypes based on their specific sub-domain localization. The approach presented here represents an allele-characterization framework that compliments existing computational efforts and supports current and future somatic variant discovery efforts, advancing the promise of genome-guided treatment strategies.
2017-12-01 | GSE79989 | GEO
Project description:ChIP-seq data characterizing the occupancy of TFAM over the mitochondrial and nuclear genomes in HeLa cells. Characterization of mitochondrial and nuclear genome-wide TFAM binding in HeLa cells
2013-09-21 | E-GEOD-48176 | biostudies-arrayexpress
Project description:Histone acetylation is sensitive to metabolic cues, however interplay between histone acetyl transferases and cellular metabolism remains poorly understood. Here we report the localization of a classical nuclear HAT- MOF and members of Non-Specific Lethal complex in mitochondria. MOF regulates expression of oxidative phosphorylation (OXPHOS) genes, residing in both nuclear and mitochondrial genomes, selectively in aerobically respiring cells. Furthermore, MOF/KANSL1 depletion causes impaired mitochondrial translation and reduced respiration. MOF loss is catastrophic for tissues with high-energy consumption. In mouse hearts, Mof knockout causes hypertrophic cardiomyopathy, compromised ventricular contractility/ stroke volume and ultimately leads to cardiac failure within three weeks of birth. RNA-seq analysis of the cardiomyocytes revealed deregulation of mitochondrial nutrient metabolism and OXPHOS pathways. Consistently, electron microscopy on affected tissues revealed mitochondrial deterioration with high tissue heterogeneity, commonly observed in mitochondrial diseases. Thus, we reveal a novel function of MOF in mitochondrial homeostasis and propose MOF as a sensor connecting epigenetic regulation to metabolism. We generated mRNA-seq profile of Mof depleted HeLa cells adapted in glucose or galactose media. We also present nuclear RNA seq profile from Mof deleted cardiomyocytes.
2016-10-21 | E-GEOD-77784 | biostudies-arrayexpress
Project description:Background: The presence of nuclear mitochondrial DNA (numtDNA) has been reported within several nuclear genomes. Next to mitochondrial protein coding genes, numtDNA sequences also encode for mitochondrial tRNA genes. However, the biological roles of numtDNA, remain elusive. Results: Employing in silico analysis we identify 281 mitochondrial tRNA homologs in the human genome, which we term nimtRNAs (nuclear intronic mitochondrial-derived tRNAs), being contained within introns of 76 nuclear host genes. Despite base changes in nimtRNAs when compared to their mtRNA homologs, a canonical tRNA cloverleaf structure is maintained. To address potential functions of intronic nimtRNAs, we insert them into introns of constitutive and alternative splicing reporters and demonstrate that nimtRNAs promote pre-mRNA splicing, dependent on number and positioning of nimtRNA genes and splice site recognition efficiency. A mutational analysis reveals that the nimtRNA cloverleaf structure is required for the observed splicing increase. Utilizing a CRISPR/Cas9 approach we show that a partial deletion of a single endogenous nimtRNALys within intron 28 of the PPFIBP1 gene decreases inclusion of the downstream located exon 29 of the PPFIBP1 mRNA. By employing a pull-down approach followed by mass spectrometry, a 3’-splice site associated protein network is identified, including KHDRBS1, which we show directly interacts with nimtRNATyr by an electrophoretic mobility shift assay. Conclusions: We propose that nimtRNAs, along with associated protein factors, can act as a novel class of intronic splicing regulatory elements in the human genome by participating in the regulation of splicing.
2020-10-28 | PXD022204 | Pride
Project description:<p>International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not been identified by conventional epidemiology yet potentially make a substantial contribution to cancer burden1. This pertains to clear cell renal cell carcinoma (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence2. Some carcinogens generate somatic mutations and a complementary strategy for detecting past exposures is to sequence the genomes of cancers from populations with different incidence rates and infer underlying causes from differences in patterns of somatic mutations. Here, we sequenced 962 ccRCC from 11 countries of varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures likely caused by extracts of Aristolochia plants were present in most cases and rare elsewhere. In Japan, a mutational signature of unknown cause was found in >70% cases and <2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher kidney cancer incidence rates (p-value <6 × 10−18). Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension suggesting non-mutagenic mechanisms of action underlying these risk factors. The results indicate the existence of multiple, geographically variable, mutagenic exposures potentially affecting 10s of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.</p><p><br></p><p><strong>Linked cross omic data sets:</strong></p><p>Geographic variation of mutagenic exposures in kidney cancer genomes – patient metadata files (<strong>Mutographs</strong>) associated with this study are available in the <strong>European Genome-Phenome Archive</strong>: https://ega-archive.org/datasets/EGAD00001012223.</p>
2024-03-26 | MTBLS9394 | MetaboLights
Project description:In this work, we quantified mRNA flow rates between subcellular compartments in mouse embryonic stem cells. Combining metabolic RNA labeling, biochemical cell fractionation and RNA sequencing with mathematical modeling we were able to determine the kinetic rates of nuclear pre-, nuclear mature, cytosolic and membrane mRNA derived from more than 9000 protein-coding genes. For more than 5000 genes, we additionally estimated the transcript elongation rate. For most of the transcripts, mature nuclear half-lives are the longest, suggesting nuclear retention to be the rate-limiting step in the mRNA life cycle. Genes encoding transcription factors and immediate early genes possess fast kinetic rates, specifically a short nuclear half-life. Differentially localized mRNAs exhibit distinct combinations of rate constants, suggesting modular control within subcellular compartments. We show that membrane stability is high for membrane-localized mRNA and that cytosolic stability is high for cytosol-localized mRNA. Genes encoding target signals, such as signal peptides or transmembrane domains, have low cytosolic and high membrane half-lives with only slight differences between target signals. Nuclear-encoded mitochondrial proteins show long nuclear mature half-lives and otherwise similar features of cytoplasmic kinetics that do not resemble co-translational targeting to the mitochondria.
2024-09-17 | GSE252199 | GEO
Project description:In this work, we quantified mRNA flow rates between subcellular compartments in mouse embryonic stem cells. Combining metabolic RNA labeling, biochemical cell fractionation and RNA sequencing with mathematical modeling we were able to determine the kinetic rates of nuclear pre-, nuclear mature, cytosolic and membrane mRNA derived from more than 9000 protein-coding genes. For more than 5000 genes, we additionally estimated the transcript elongation rate. For most of the transcripts, mature nuclear half-lives are the longest, suggesting nuclear retention to be the rate-limiting step in the mRNA life cycle. Genes encoding transcription factors and immediate early genes possess fast kinetic rates, specifically a short nuclear half-life. Differentially localized mRNAs exhibit distinct combinations of rate constants, suggesting modular control within subcellular compartments. We show that membrane stability is high for membrane-localized mRNA and that cytosolic stability is high for cytosol-localized mRNA. Genes encoding target signals, such as signal peptides or transmembrane domains, have low cytosolic and high membrane half-lives with only slight differences between target signals. Nuclear-encoded mitochondrial proteins show long nuclear mature half-lives and otherwise similar features of cytoplasmic kinetics that do not resemble co-translational targeting to the mitochondria.
2024-09-17 | GSE256335 | GEO
Project description:Nuclear and mitochondrial organelles must maintain a communication system. Loci on the mitochondrial genome were recently reported to interact with nuclear loci. To determine whether this is part of a DNA based communication system we used genome conformation capture to map the global network of DNA-DNA interactions between the mitochondrial and nuclear genomes (Mito-nDNA) in Saccharomyces cerevisiae cells grown under three different metabolic conditions. The interactions that form between mitochondrial and nuclear loci are dependent on the metabolic state of the yeast. Moreover, the frequency of specific mitochondrial - nuclear interactions (i.e. COX1-MSY1 and Q0182-RSM7) showed significant reductions in the absence of mitochondrial encoded reverse transcriptase machinery. Furthermore, these reductions correlated with increases in the transcript levels of the nuclear loci (MSY1 and RSM7). We propose that these interactions represent an inter-organelle DNA mediated communication system and that reverse transcription of mitochondrial RNA plays a role in this process. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series.
2013-01-17 | E-GEOD-34132 | biostudies-arrayexpress
Project description:Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in normal eukaryotic cellular function. Here, we characterized the metabolic and transcriptional properties of A549 lung cancer cells and their isogenic mitochondrial DNA (mtDNA)-depleted rho zero counterparts grown in cell culture and as tumor xenografts in immune-deficient mice. A manuscript summarizing our conclusions is under review. Keywords: genetic modification and culture conditions
2008-04-18 | GSE10957 | GEO