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Genomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles.

ABSTRACT: Copy-number changes generate phenotypic variability in health and disease. Whether organisms protect against copy-number changes is largely unknown. Here, we show that Saccharomyces cerevisiae monitors the copy number of its ribosomal DNA (rDNA) and rapidly responds to copy-number loss with the clonal amplification of extrachromosomal rDNA circles (ERCs) from chromosomal repeats. ERC formation is replicative, separable from repeat loss, and reaches a dynamic steady state that responds to the addition of exogenous rDNA copies. ERC levels are also modulated by RNAPI activity and diet, suggesting that rDNA copy number is calibrated against the cellular demand for rRNA. Last, we show that ERCs reinsert into the genome in a dosage-dependent manner, indicating that they provide a reservoir for ultimately increasing rDNA array length. Our results reveal a DNA-based mechanism for rapidly restoring copy number in response to catastrophic gene loss that shares fundamental features with unscheduled copy-number amplifications in cancer cells.

SUBMITTER: Mansisidor A

PROVIDER: S-EPMC6214758 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Genomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles.

Mansisidor Andrés A Molinar Temistocles T Srivastava Priyanka P Dartis Demetri D DD Pino Delgado Adriana A Blitzblau Hannah G HG Klein Hannah H Hochwagen Andreas A

Molecular cell 20181004 3

Copy-number changes generate phenotypic variability in health and disease. Whether organisms protect against copy-number changes is largely unknown. Here, we show that Saccharomyces cerevisiae monitors the copy number of its ribosomal DNA (rDNA) and rapidly responds to copy-number loss with the clonal amplification of extrachromosomal rDNA circles (ERCs) from chromosomal repeats. ERC formation is replicative, separable from repeat loss, and reaches a dynamic steady state that responds to the add ...[more]

PMID: 30293780

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Project description:Somatic mosaicism denotes the presence of genetically distinct populations of somatic cells in one individual who has developed from a single fertilised oocyte. Mosaicism may result from a mutation that occurs during postzygotic development and is propagated to only a subset of the adult cells. Our aim was to investigate both somatic mosaicism for copy-neutral loss of heterozygosity (cn-LOH) events and DNA copy number variations (CNVs) in fully differentiated tissues.We studied panels of tissue samples (11-12 tissues per individual) from four autopsy subjects using high-resolution Illumina HumanOmniExpress-12 BeadChips to reveal the presence of possible intra-individual tissue-specific cn-LOH and CNV patterns. We detected five mosaic cn-LOH regions >5 Mb in some tissue samples in three out of four individuals. We also detected three CNVs that affected only a portion of the tissues studied in one out of four individuals. These three somatic CNVs range from 123 to 796 kb and are also found in the general population. An attempt was made to explain the succession of genomic events that led to the observed somatic genetic mosaicism under the assumption that the specific mosaic patterns of CNV and cn-LOH changes reflect their formation during the postzygotic embryonic development of germinal layers and organ systems.Our results give further support to the idea that somatic mosaicism for CNVs, and also cn-LOHs, is a common phenomenon in phenotypically normal humans. Thus, the examination of only a single tissue might not provide enough information to diagnose potentially deleterious CNVs within an individual. During routine CNV and cn-LOH analysis, DNA derived from a buccal swab can be used in addition to blood DNA to get information about the CNV/cn-LOH content in tissues of both mesodermal and ectodermal origin. Currently, the real frequency and possible phenotypic consequences of both CNVs and cn-LOHs that display somatic mosaicism remain largely unknown. To answer these questions, future studies should involve larger cohorts of individuals and a range of tissues.

Project description:BACKGROUND: Some diseases, like tumors, can be related to chromosomal aberrations, leading to changes of DNA copy number. The copy number of an aberrant genome can be represented as a piecewise constant function, since it can exhibit regions of deletions or gains. Instead, in a healthy cell the copy number is two because we inherit one copy of each chromosome from each our parents. Bayesian Piecewise Constant Regression (BPCR) is a Bayesian regression method for data that are noisy observations of a piecewise constant function. The method estimates the unknown segment number, the endpoints of the segments and the value of the segment levels of the underlying piecewise constant function. The Bayesian Regression Curve (BRC) estimates the same data with a smoothing curve. However, in the original formulation, some estimators failed to properly determine the corresponding parameters. For example, the boundary estimator did not take into account the dependency among the boundaries and succeeded in estimating more than one breakpoint at the same position, losing segments. RESULTS: We derived an improved version of the BPCR (called mBPCR) and BRC, changing the segment number estimator and the boundary estimator to enhance the fitting procedure. We also proposed an alternative estimator of the variance of the segment levels, which is useful in case of data with high noise. Using artificial data, we compared the original and the modified version of BPCR and BRC with other regression methods, showing that our improved version of BPCR generally outperformed all the others. Similar results were also observed on real data. CONCLUSION: We propose an improved method for DNA copy number estimation, mBPCR, which performed very well compared to previously published algorithms. In particular, mBPCR was more powerful in the detection of the true position of the breakpoints and of small aberrations in very noisy data. Hence, from a biological point of view, our method can be very useful, for example, to find targets of genomic aberrations in clinical cancer samples.

Dataset Information

Genomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles.

Publications

Genomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles.

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