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Abnormal Dosage of Ultraconserved Elements Is Highly Disfavored in Healthy Cells but Not Cancer Cells
Ultraconserved elements (UCEs) display a level of sequence conservation that has defied explanation. They are also dosage sensitive, being depleted from copy number variants (CNVs) in healthy cells. Here we address the process underlying this dosage sensitivity in order to gain insights into the way that UCE dosage affects cells. Our studies demonstrate that, in contrast to CNVs inherited by healthy individuals, cancer-specific CNVs are, as a rule, not depleted for UCEs and may even be enriched. Furthermore, by discovering that CNVs arising anew in the healthy, as opposed to diseased, body are depleted of UCEs, we obtain evidence that healthy cells may be responsive to changes in UCE dosage in a way that is disrupted in cancer cells. After examining CNVs over time in cell culture, we postulate that selection against UCE-disrupting CNVs in healthy cells acts rapidly, raising the surprising possibility of exploring in cell culture how UCE dosage sensitivity may explain ultraconservation. Our observations suggest that an understanding of the different responses of healthy and cancer cells to changes in UCE dosage could be harnessed to address genomic instabilities in cancer.
Vyšlo v časopise: Abnormal Dosage of Ultraconserved Elements Is Highly Disfavored in Healthy Cells but Not Cancer Cells. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004646
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004646Souhrn
Ultraconserved elements (UCEs) display a level of sequence conservation that has defied explanation. They are also dosage sensitive, being depleted from copy number variants (CNVs) in healthy cells. Here we address the process underlying this dosage sensitivity in order to gain insights into the way that UCE dosage affects cells. Our studies demonstrate that, in contrast to CNVs inherited by healthy individuals, cancer-specific CNVs are, as a rule, not depleted for UCEs and may even be enriched. Furthermore, by discovering that CNVs arising anew in the healthy, as opposed to diseased, body are depleted of UCEs, we obtain evidence that healthy cells may be responsive to changes in UCE dosage in a way that is disrupted in cancer cells. After examining CNVs over time in cell culture, we postulate that selection against UCE-disrupting CNVs in healthy cells acts rapidly, raising the surprising possibility of exploring in cell culture how UCE dosage sensitivity may explain ultraconservation. Our observations suggest that an understanding of the different responses of healthy and cancer cells to changes in UCE dosage could be harnessed to address genomic instabilities in cancer.
Zdroje
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Štítky
Genetika Reprodukčná medicína
Článek Oligoasthenoteratozoospermia and Infertility in Mice Deficient for miR-34b/c and miR-449 LociČlánek The Kinesin AtPSS1 Promotes Synapsis and is Required for Proper Crossover Distribution in MeiosisČlánek Payoffs, Not Tradeoffs, in the Adaptation of a Virus to Ostensibly Conflicting Selective PressuresČlánek Examination of Prokaryotic Multipartite Genome Evolution through Experimental Genome ReductionČlánek BMP-FGF Signaling Axis Mediates Wnt-Induced Epidermal Stratification in Developing Mammalian SkinČlánek Role of STN1 and DNA Polymerase α in Telomere Stability and Genome-Wide Replication in ArabidopsisČlánek RNA-Processing Protein TDP-43 Regulates FOXO-Dependent Protein Quality Control in Stress ResponseČlánek Integrating Functional Data to Prioritize Causal Variants in Statistical Fine-Mapping StudiesČlánek Salt-Induced Stabilization of EIN3/EIL1 Confers Salinity Tolerance by Deterring ROS Accumulation inČlánek Ethylene-Induced Inhibition of Root Growth Requires Abscisic Acid Function in Rice ( L.) SeedlingsČlánek Metabolic Respiration Induces AMPK- and Ire1p-Dependent Activation of the p38-Type HOG MAPK PathwayČlánek Signature Gene Expression Reveals Novel Clues to the Molecular Mechanisms of Dimorphic Transition inČlánek A Mouse Model Uncovers LKB1 as an UVB-Induced DNA Damage Sensor Mediating CDKN1A (p21) DegradationČlánek Dominant Sequences of Human Major Histocompatibility Complex Conserved Extended Haplotypes from to
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