Association of genetic copy number variations at 11 q14.2 with brain regional volume differences in an alcohol use disorder population Journal Article ...
It has been suggested that a high EGFR gene copy number may be an indicator of good response to EGFR tyrosine kinase inhibitor therapy and a marker of poor prognosis in NSCLC. However, imaging features related to EGFR gene copy number status in adenocarcinoma are still unknown. We therefore retrospectively analyzed CT, FDG-PET, and histopathologic slides of surgical resected lung adenocarcinoma in 132 patients. Tumor characteristics on preoperative chest-CT, such as, GGO proportions, tumor diameters, and cavitation; FDG-PET SUV(max); and histopathologically determined differentiation degrees and tumor subtypes were evaluated. EGFR gene copy number status was categorized as FISH-positive or -negative. FISH-positivity was found in 53 patients (40.2%) and was significantly more frequent in tumors with a SUV(max),7.0 (P=0.007). Furthermore, FISH-negativity was found to be more frequent in tumors with a GGO,50% (P=0.023) and diameter ,15.5mm (P=0.006) on CT, or a well-differentiated histopathology ...
Deregulation of the EGFR signaling pathway is one of the most frequently observed genetic abnormalities that drives cancer development. Although mutations in the downstream components of the EGFR signaling pathway, including KRAS, BRAF and PIK3CA, have been reported in numerous cancers, extensive mutation and copy number analysis of these genes in clinical samples has not been performed for head and neck squamous cell carcinoma (HNSCC). We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients. We used DNA sequencing to detect mutations and the copy number changes were evaluated by qPCR and array comparative genomic hybridization (CGH) analysis. We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients. We identified 3 mutations (2.6%) in K-RAS and 3 mutations (2.6%) in PIK3CA. Copy number amplification was
The extent to which large duplications and deletions contribute to human genetic variation and diversity is unknown. Here, we show that large-scale copy number polymorphisms (CNPs) (about 100 kilobases and greater) contribute substantially to genomic variation between normal humans. Representational oligonucleotide microarray analysis of 20 individuals revealed a total of 221 copy number differences representing 76 unique CNPs. On average, individuals differed by 11 CNPs, and the average length of a CNP interval was 465 kilobases. We observed copy number variation of 70 different genes within CNP intervals, including genes involved in neurological function, regulation of cell growth, regulation of metabolism, and several genes known to be associated with disease.. ...
Changes in gene and chromosome copy number are widely observed in systems from cancer to drug resistance to genome evolution. Despite the importance of aneuploi...
Rasmussen M, Sundström M, Göransson Kultima H, Botling J, Micke P, Birgisson H, Glimelius B, Isaksson A Genome Biol. 12 (10) R108 [2011-10-24; online 2011-10-24] We describe a bioinformatic tool, Tumor Aberration Prediction Suite (TAPS), for the identification of allele-specific copy numbers in tumor samples using data from Affymetrix SNP arrays. It includes detailed visualization of genomic segment characteristics and iterative pattern recognition for copy number identification, and does not require patient-matched normal samples. TAPS can be used to identify chromosomal aberrations with high sensitivity even when the proportion of tumor cells is as low as 30%. Analysis of cancer samples indicates that TAPS is well suited to investigate samples with aneuploidy and tumor heterogeneity, which is commonly found in many types of solid tumors. Affiliated researcher QC bibliography QC xrefs PubMed 22023820. DOI 10.1186/gb-2011-12-10-r108. Crossref 10.1186/gb-2011-12-10-r108. ...
DNA copy number alterations in 146 bladder tumors.A) Whole genome heatmap representing relative copy number profiles of the samples. Segments of gains or deleti
TY - JOUR. T1 - A versatile statistical analysis algorithm to detect genome copy number variation. AU - Daruwala, Raoul Sam. AU - Rudra, Archisman. AU - Ostrer, Harry. AU - Lucito, Robert. AU - Wigler, Michael. AU - Mishra, Bud. PY - 2004/11/16. Y1 - 2004/11/16. N2 - We have developed a versatile statistical analysis algorithm for the detection of genomic aberrations in human cancer cell lines. The algorithm analyzes genomic data obtained from a variety of array technologies, such as oligonucleotide array, bacterial artificial chromosome array, or array-based comparative genomic hybridization, that operate by hybridizing with genomic material obtained from cancer and normal cells and allow detection of regions of the genome with altered copy number. The number of probes (i.e., resolution), the amount of uncharacterized noise per probe, and the severity of chromosomal aberrations per chromosomal region may vary with the underlying technology, biological sample, and sample preparation. Constrained ...
Complement component 4 (C4) gene copy number (GCN) affects the susceptibility to systemic lupus erythematosus (SLE) in different populations, however the possible phenotype significance remains to be determined. This study aimed to associate C4A, C4B and total C4 GCN and SLE, focusing on the clinical phenotype and disease progression. C4, C4A and C4B GCN were determined by real-time PCR in 427 SLE patients and 301 healthy controls, which underwent a detailed clinical evaluation according to a pre-established protocol. The risk of developing SLE was 2.62 times higher in subjects with low total C4 GCN (| 4 copies, OR = 2.62, CI = 1.77 to 3.87, p | 0.001) and 3.59 times higher in subjects with low C4A GCN (| 2 copies; OR = 3.59, CI = 2.15 to 5.99, p | 0.001) compared to those subjects with normal or high GCN of total C4 (≥4) and C4A (≥2), respectively. An increased risk was also observed regarding low C4B GCN, albeit to a lesser degree (OR = 1.46, CI = 1.03 to 2.08, p = 0.03). Furthermore, subjects
Diagnosing constitutional pathogenic copy number variants (CNVs) requires detecting submicroscopic segmental chromosomal imbalances
Sequencing technology is increasingly demonstrating the impact of genomic copy number variation (CNV) on phenotypes. Opposing variation in growth, head size, cognition and behaviour is known to result from deletions and reciprocal duplications of some genomic regions. We propose normative inversion of face shape, opposing difference from a matched norm, as a basis for investigating the effects of gene dosage on craniofacial development. We use dense surface modelling techniques to match any face (or part of a face) to a facial norm of unaffected individuals of matched age, sex and ethnicity and then we reverse the individuals face shape differences from the matched norm to produce the normative inversion. We demonstrate for five genomic regions, 4p16.3, 7q11.23, 11p15, 16p13.3 and 17p11.2, that such inversion for individuals with a duplication or (epi)-mutation produces facial forms remarkably similar to those associated with a deletion or opposite (epi-)mutation of the same region, and vice versa. The
Women more frequently than men have a type of gene mutation linked to schizophrenia and other neuropsychiatric illnesses, but that doesnt translate into increased risk for the condition.
We have developed ascatNgs to aid researchers in carrying out Allele-Specific Copy number Analysis of Tumours (ASCAT). ASCAT is capable of detecting DNA copy number changes affecting a tumor genome when comparing to a matched normal sample. Additionally, the algorithm estimates the amount of tumor DNA in the sample, known as Aberrant Cell Fraction (ACF). ASCAT itself is an R-package which requires the generation of many file types. Here, we present a suite of tools to help handle this for the user. Our code is available on our GitHub site (https://github.com/cancerit). This unit describes both one-shot execution and approaches more suitable for large-scale compute farms. © 2016 by John Wiley & Sons, Inc.
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Identifying genetic cues of functional relevance is key to understanding the drivers of evolution and increasingly important for the conservation of biodiversity. This study introduces nuclear ribosomal DNA (nrDNA) to mitochondrial DNA (mtDNA) copy number ratios as a metric with which to screen for this functional genetic variation prior to more extensive omics analyses. To illustrate the metric, quantitative PCR was used to estimate nrDNA (18S) to mtDNA (16S) copy number ratios in muscle tissue from samples of two zooplankton species: Salpa thompsoni caught near Elephant Island (Southern Ocean) and S. fusiformis sampled off Gough Island (South Atlantic). Average 18S:16S ratios in these samples were 9:1 and 3:1, respectively. nrDNA 45S arrays and mitochondrial genomes were then deep sequenced to uncover the sources of intra-individual genetic variation underlying these 18S:16S copy number differences. The deep sequencing profiles obtained were consistent with genetic changes resulting from ...
Importantly, when creating the mimicked data sets we did not generate any simulated ratio values; rather, we formed different selections of values using real experimental data. We believe that this use of real experimental data is of significance for aCGH data. This belief is founded on that, in contrast to expression levels, copy number levels are restricted to a, by comparison, moderate dynamic range. Therefore, when a genomic region is subjected to gain or amplification, the increase of genomic material is relatively substantial. Thus, we reasoned that probes for regions of gain would yield comparably higher average intensities than those for regions of normal copy number and that this, in turn, would result in a correlation between M and A: probes measuring ratios of gain will have higher average intensities. The opposite relationship would apply for probes measuring ratios of loss. Consequently, utilizing normalization strategies based on Lowess would possibly correct for correlations ...
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inproceedings{8564264, author = {{Mus, Liselot and Denecker, Geertrui and Zeltner, Nadja and Ogando, Yudelca and Van Haver, Stéphane and Sanders, Ellen and Jacobs, Eva and Popovic, Mina and Van Neste, Christophe and Vanhauwaert, Suzanne and Durinck, Kaat and Menten, Björn and De Preter, Katleen and Heindryckx, Björn and Studer, Lorenz and Roberts, Stephen and Speleman, Franki}}, booktitle = {{Advances in Neuroblastoma Research, Congress abstracts}}, language = {{eng}}, location = {{San Fransisco, CA, USA}}, title = {{Exploring the contribution of gene dosage effects of 17q gain on ESC and neuroblastoma proliferation}}, year = {{2018 ...
A research team led by Associate Professor Jonathan Sebat, Ph.D., of Cold Spring Harbor Laboratory (CSHL) has developed a sensitive and accurate way of identifying gene copy number variations (CNVs). The method, which is ...
Accurate assignment of copy number at known copy number variant (CNV) loci is important for both increasing understanding of the structural evolution of genomes as well as for carrying out association studies of copy number with disease. As with calling SNP genotypes, the task can be framed as a clustering problem but for a number of reasons assigning copy number is much more challenging. CNV assays have lower signal-to-noise ratios than SNP assays, often display heavy tailed and asymmetric intensity distributions, contain outlying observations and may exhibit systematic technical differences among different cohorts. In addition, the number of copy-number classes at a CNV in the population may be unknown a priori. Due to these complications, automatic and robust assignment of copy number from array data remains a challenging problem. We have developed a copy number assignment algorithm, CNVCALL, for a targeted CNV array, such as that used by the Wellcome Trust Case Control Consortiums recent CNV
Large deletions encompassing the NF1 gene and its flanking regions belong to the group of genomic disorders caused by copy number changes that are mediated by the local genomic architecture. Although nonallelic homologous recombination (NAHR) is known to be a major mutational mechanism underlying such genomic copy number changes, the sequence determinants of NAHR location and frequency are still poorly understood since few high-resolution mapping studies of NAHR hotspots have been performed to date. Here, we have characterized two NAHR hotspots, PRS1 and PRS2, separated by 20 kb and located within the low-copy repeats NF1-REPa and NF1-REPc, which flank the human NF1 gene region. High-resolution mapping of the crossover sites identified in 78 type 1 NF1 deletions mediated by NAHR indicated that PRS2 is a much stronger NAHR hotspot than PRS1 since 80% of these deletions exhibited crossovers within PRS2, whereas 20% had crossovers within PRS1. The identification of the most common strand exchange ...
Purpose: As genome-scale technologies begin to unravel the complexity of the equivalent tumors in adults, we can attempt detailed characterization of high-grade gliomas in children, that have until recently been lacking. Toward this end, we sought to validate and extend investigations of the differences between pediatric and adult tumors.. Experimental Design: We carried out copy number profiling by array comparative genomic hybridization using a 32K bacterial artificial chromosome platform on 63 formalin-fixed paraffin-embedded cases of high-grade glioma arising in children and young people (,23 years).. Results: The genomic profiles of these tumors could be subclassified into four categories: those with stable genomes, which were associated with a better prognosis; those with aneuploid and those with highly rearranged genomes; and those with an amplifier genotype, which had a significantly worse clinical outcome. Independent of this was a clear segregation of cases with 1q gain (more common in ...
View article as PDF. In recent years, we have dramatically changed our view of human genome, from a collection of DNA base pairs that was largely quite stable to one whose very structure can change. Weve learned that higher-order structural features, such as specific configurations of repeated base pair sequences, can predispose for DNA rearrangements.1. One of the most intriguing types of DNA rearrangements is copy-number variants (CNVs), deletions or duplications of parts of the genome. While CNVs range in size from a few hundred base pairs to several mega-bases affecting the copy number of one to dozens of juxtaposed genes, they are not identifiable by conventional light microscopy. It was not until a few years ago that improved technology enabled us to perform high-resolution genome-wide surveys of CNVs in individual genomes. These surveys revealed a large amount of copy number variation (at least 12,000 CNVs overlapping more than 1,000 genes), most of which represent benign polymorphic ...
4468 Detecting the genetic changes associated with cancer development and progression is a major focus in current cancer research. We have developed a high-resolution technology to assess DNA copy number changes in cancer and other diseases. The method combines our whole genome sampling analysis (WGSA), which genotypes over 100,000 single nucleotide polymorphisms (SNPs) from nanogram quantities of human genomic DNA, and our chromosomal copy number tool (CCNT). CCNT can detect regions of chromosomal deletion, amplification, and loss of heterozygosity (LOH). Copy number changes are calculated based on SNP hybridization signal intensity data from the experimental sample relative to intensity distributions derived from a reference set containing over 100 individuals. CCNT also provides a statistical significance of this intensity difference. Several advantages of this technique include the simultaneous collection of genotype information and DNA copy number changes, no requirement of a reference ...
MYC copy gain, chromosomal instability and PI3K activation as potential markers of unfavourable outcome in trastuzumab-treated patients with metastatic breast cancer. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Purpose: The expression of HAGE as a novel prognostic and predictive tool was assessed in 1079 TNBCs. Experimental Design: HAGE protein expression was investigated in an early primary TNBC (EP-TNBC; n=520) cohort who received adjuvant chemotherapy (ACT) and in a locally advanced primary TNBC cohort who received anthracycline-combination Neo-ACT (n=110; AC-Neo-ACT). HAGE-mRNA expression was evaluated in the METABRIC-TNBC-cohort (n=311) who received ACT and in a cohort of patients with TNBC who received doxorubicin/cyclophosphamide Neo-ACT, followed by 1:1 randomisation to ixabepilone (n=68) or paclitaxel (n=64) as part of a phase II clinical trial. Furthermore, a cohort of 128 tumours with integrated HAGE gene copy number changes, mRNA and protein levels were analysed. Results: In patients with EP-TNBC, who were chemotherapy-naïve, high HAGE protein expression (HAGE+) was associated with a higher risk of death (HR: 1.3; 95% CI: 1.2-1.5; p=0.000005) when compared HAGE- cases. Patients who ...
By using {\em E. coli} cells in which the unique origin of replication has been moved to a ectopic chromosome location distant from the native one, we probe how perturbation of gene order near the origin of replication impacts genome stability and survival under genomic attack. We find that when challenged with sub-inhibitory doses of ciprofloxacin, an antibiotic that generates replication fork stalling, cells with the ectopic origin show significant fitness loss. We show that genes functionally relevant to the cipro-induced stress response are largely located near the native origin, even in distantly related species. We show that while cipro induces increased copy number of genes proximal to the origin of replication as a direct consequence of replication fork stalling, gene copy number variation was reduced near the ectopic origin. Altered gene dosage in cells with an ectopic origin resulted in impaired replication fork repair and chromosome instability. We propose that gene distribution in ...
These results highlight the benefits of using CNstream, a method for whole-genome CNV discovery and genotyping for Illumina BeadChip arrays. The present method combined a single-locus scoring approach that takes advantage of the joint clustering analysis of all the intensity samples at each probe with the computational speed and analytical accuracy of estimating CNPs from segments of consecutive probes. Compared with PennCNV, CNstream has superior sensitivity in several common CNPs and it can identify different CNPs that are not detected by PennCNV. The CNP detected by CNstream was demonstrated to be the most significantly associated with RA susceptibility using available RT-PCR technology.. With regard to the single-locus scoring method, CNstream reduced the processing time by robustly initializing the GMM before the EM procedure. This allows a whole-genome analysis to be carried out without the need for previously defined CNP maps, which are required for the SCIMM method. In addition, in ...
Bioconductor version: Release (3.6) The CINdex package addresses important area of high-throughput genomic analysis. It allows the automated processing and analysis of the experimental DNA copy number data generated by Affymetrix SNP 6.0 arrays or similar high throughput technologies. It calculates the chromosome instability (CIN) index that allows to quantitatively characterize genome-wide DNA copy number alterations as a measure of chromosomal instability. This package calculates not only overall genomic instability, but also instability in terms of copy number gains and losses separately at the chromosome and cytoband level.. Author: Lei Song, Krithika Bhuvaneshwar, Yue Wang, Yuanjian Feng, Ie-Ming Shih, Subha Madhavan, Yuriy Gusev Maintainer: Yuriy Gusev ,yg63 at georgetown.edu, ...
Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number. Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with map …
Personalized drug therapy aims to optimize the efficacy of pharmacological treatments by considering genetic, pathophysiological, dietary, and environmental factors as well as comedications and compliance. A multitude of associations between the specific genetic constitution of the patient and drug pharmacokinetics and pharmacodynamics has been identified in the last decades that encompass mainly common single nucleotide variants (SNVs) and gene copy number variations (CNVs) of importance for the function of genes encoding drug-metabolizing enzymes and transporters involved in drug absorption, distribution, metabolism, and excretion (ADME). In addition, genetic variation in factors encoding the major histocompatibility complex have been helpful to predict immune-mediated drug toxicity. This knowledge has been translated into clinical applications through the implementation of pharmacogenomic biomarkers. Over 230 of such markers that can, to a certain extent, predict drug efficacy or the ...
FISH-positive criteria have been used according to the corresponding genes. FGFR1 high-level amplification is defined as copy number ≥ 9 or (1) an FGFR1/CEP8 ratio of ≥ 2.0, (2) the average number of FGFR1 signals per tumor cell nucleus ≥ 6, and (3) the percentage of tumor cells containing ≥ 15 FGFR1 signals or large clusters ≥ 10% [74,87]. According to previously published criteria, the EGFR gene copy number was classified into six FISH strata: disomy (two or fewer copies in more than 90% of cells), low trisomy (two or fewer copies in 40% or more of the cells, three copies in 10%-40% of cells, and four or more copies in less than 10% of cells), high trisomy (two or fewer copies in ≥ 40% of cells, three copies in ≥ 40% of cells, and four or more copies in less than 10% of cells), low polysomy (four or more copies in 10%-40% of cells), high polysomy (four or more copies in 40% of the cells or more), and gene amplification (defined by the presence of tight EGFR clusters and a ratio ...
TY - JOUR. T1 - Chromosome 18 gene dosage map 2.0. AU - Cody, Jannine D.. AU - Heard, Patricia. AU - Rupert, David. AU - Hasi-Zogaj, Minire. AU - Hill, Annice. AU - Sebold, Courtney. AU - Hale, Daniel. PY - 2018/12/1. Y1 - 2018/12/1. N2 - In 2009, we described the first generation of the chromosome 18 gene dosage maps. This tool included the annotation of each gene as well as each phenotype associated region. The goal of these annotated genetic maps is to provide clinicians with a tool to appreciate the potential clinical impact of a chromosome 18 deletion or duplication. These maps are continually updated with the most recent and relevant data regarding chromosome 18. Over the course of the past decade, there have also been advances in our understanding of the molecular mechanisms underpinning genetic disease. Therefore, we have updated the maps to more accurately reflect this knowledge. Our Gene Dosage Map 2.0 has expanded from the gene and phenotype maps to also include a pair of maps ...
Dr Liesbeth Lenaerts talks to ecancer at ESMO 2018 about a pre-existing pre-natal test which flagged up copy number alterations and cancer in the foetus'
AbstractLow FCGR3 copy numbers (CNs) has been associated with susceptibility to several systemic autoimmune diseases. However, inconsistent associations were reported and errors caused by shaky methods were suggested to be the major causes. In large scale case control association studies, robust copy number determination method is thus warranted, which was the main focus of the current study. In the present study, FCGR3 CNs of 90 HapMap Asians were firstly checked using four assays including paralogue ratio test combined with restriction enzyme digest variant ratio (PRT-REDVR), real-time quantitative (qPCR) using TaqMan assay, real-time qPCR using SYBR Green dye and short tenden repeat (STR). To improve the comparison precision reproductively, the results were compared with those from recently released sequencing data from 1000 genomes project as well as whole-genome tiling BAC array data. The tendencies of inconsistent samples by these methods were also characterized. Refined in-home TaqMan qPCR assay
Faster implementation of CRLMM specific to SNP 5.0 and 6.0 arrays, as well as a copy number tool specific to 5.0, 6.0, and Illumina platforms.
Pearson and Spearman correlation coefficients are commonly used to quantify the strength of bivariate associations of genomic variables. For example, correlations of gene-level DNA copy number and gene expression measurements may be used to assess the impact of DNA copy number changes on gene expression in tumor tissue. MVisAGe enables users to quickly compute and visualize the correlations in order to assess the effect of regional genomic events such as changes in DNA copy number or DNA methylation level. Please see Walter V, Du Y, Danilova L, Hayward MC, Hayes DN, 2018. Cancer Research ,doi:10.1158/0008-5472.CAN-17-3464,.. ...
Molecular Cloning, also known as Maniatis, has served as the foundation of technical expertise in labs worldwide for 30 years. No other manual has been so popular, or so influential.
Over the past decade, utilization of microarray technology has flourished in biomedical research. It has evolved rapidly into a revolutionary tool that offers deeper insight into the molecular basis...
Are you proposing a thought experiment in which we subtract all the repeat derived sequences (minus the small proportion of bases that regulate gene expression), and most of the the non regulatory intergenic sequences, reducing intron and intergenic sizes by, say 90%, such that we end up with a small number of short chromosomes (say 50 Mb in size - since we know the current division processes can cope with such a size) but keeping the necessary telomeric and centromeric repeats. This would be done with all members of the human species such that all the current copy number polymorphisms and regulatory snps are maintained and all genes are allowed up to 2000bp of regulatory sequences (although we will allow a proportion of genes to have larger regulatory regions). The ultimate result is a human genome that is say, 90% smaller than the current one. You suggest that the current cellular machinery would be able to cope with this change, such that there would be no viability or evolutionary ...
Genome-wide analysis of copy number changes in breast and colorectal tumors used approaches that can reliably detect homozygous deletions and amplifications. The number of genes altered by major copy number changes-deletion of all copies or amplification of at least twelve copies per cell-averaged thirteen per tumor. These data were integrated with previous mutation analyses of the Reference Sequence genes in these same tumor types to identify genes and cellular pathways affected by both copy number changes and point alterations. Pathways enriched for genetic alterations include those controlling cell adhesion, intracellular signaling, DNA topological change, and cell cycle control. These analyses provide an integrated view of copy number and sequencing alterations on a genome-wide scale and identify genes and pathways that are useful for cancer diagnosis and therapy.
Integrative analysis of multiple layers of molecular profiles, such as somatic mutations, DNA copy-number alterations or mRNA expression, offers an unprecedented opportunity to obtain a comprehensive molecular portrait of an individuals tumor. By looking at the recurrence of the molecular alterations found in an individual and at the location of altered proteins in the human interactome, we can put molecular alterations into clinical and molecular context. This PanorOmic view of personal cancer genomes enables a better understanding and interpretation of the results and increases the diagnostic utility of high throughput methods. The current version of Cancer PanorOmics is 2020_01 ...
Heterokaryons provide a model system in which to examine how tissue-specific phenotypes arise and are maintained. When muscle cells are fused with nonmuscle cells, muscle gene expression is activated in the nonmuscle cell type. Gene expression was studied either at a single cell level with monoclonal antibodies or in mass cultures at a biochemical and molecular level. In all of the nonmuscle cell types tested, including representatives of different embryonic lineages, phenotypes, and developmental stages, muscle gene expression was induced. Differences among cell types in the kinetics, frequency, and gene dosage requirements for gene expression provide clues to the underlying regulatory mechanisms. These results show that the expression of genes in the nuclei of differentiated cells is remarkably plastic and susceptible to modulation by the cytoplasm. The isolation of the genes encoding the tissue-specific trans-acting regulators responsible for muscle gene activation should now be possible. ...
(A) Standard curve for quantitation of DNA copy number. The vertical axis shows copies of target DNA per reaction. The horizontal axis shows the ct values as de
Autor: Kramer, M. et al.; Genre: Zeitschriftenartikel; Im Druck veröffentlicht: 2010-05-01; Keywords: Paralogs; RAB-like; Gene expression; Paralog ratio test; Pyrosequencing; Titel: Analysis of relative gene dosage and expression differences of the paralogs RABL2A and RABL2B by Pyrosequencing.
Video created by The State University of New York for the course Big Data, Genes, and Medicine. After this module, you will be able to 1. List different types of gene alterations. 2. Compare and contrast methods for detecting gene mutations. 3. ...
Key to successful detoxification is to be on the QS Detox Cube protocol a minimum of 3 months and slowly titrate up doses. The Detox Cube includes all three months dosage requirements and additional suggestions for optimal health and safe detoxification.
Aims The clinical significance of TOP2A as a prognostic marker has not been clarified. The aims of this study were to investigate the frequency of TOP2A copy number change; to correlate TOP2A with HER2 status, hormone ...
Card is a stiff paper usually heavier than 200gsm (normal copy paper is usually around 60-80 gsm with heavier craft paper at between 100-160gsm) and comes in a range of finishes.
Deviation of gene expression from normal levels has been associated with diseases. Both under- and overexpression of genes could lead to deleterious biological consequences. Dosage balance has been proposed to be a key issue of determining gene expression phenotype. Gene deletion or overexpression of any component in a protein complex produces abnormal phenotypes. As a result, interacting partners should be co-expressed to avoid dosage imbalance effects. The strength of transcriptional co-regulation of interacting partners is supposed to reflect gene dosage sensitivity. Although many cases of dosage imbalance effects have been reported, the molecular attributes determining dosage sensitivity remain unknown. This thesis uses a protein structure analysis protocol to explore the molecular basis of gene dosage sensitivity, and studies the post-transcriptional regulation of dosage sensitive genes. Solvent-exposed backbone hydrogen bond (SEBH or called as dehydron) provides a structure marker for ...
Genomic aberrations in the form of subchromosomal DNA copy number changes are a hallmark of epithelial cancers, including breast cancer. The goal of the present study was to analyze such aberrations in breast cancer at high resolution. We employed high-resolution array comparative genomic hybridization with 4,134 bacterial artificial chromosomes that cover the genome at 0.9 megabase resolution to analyze 47 primary breast tumors and 18 breast cancer cell lines. Common amplicons included 8q24.3 (amplified in 79% of tumors, with 5/47 exhibiting high level amplification), 1q32.1 and 16p13.3 (amplified in 66% and 57% of tumors, respectively). Moreover, we found several positive correlations between specific amplicons from different chromosomes, suggesting the existence of cooperating genetic loci. Queried by gene, the most frequently amplified kinase was PTK2 (79% of tumors), whereas the most frequently lost kinase was PTK2B (hemizygous loss in 34% of tumors). Amplification of ERBB2 as measured by
The recent genome-wide allele-specific copy number variation data enable us to explore two types of genomic information including chromosomal genotype variations as well as DNA copy number variations. For a cancer study, it is common to collect data for paired normal and tumor samples. Then, two types of paired data can be obtained to study a disease subject. However, there is a lack of methods for a simultaneous analysis of these four sequences of data. In this study, we propose a statistical framework based on the change-point analysis approach. The validity and usefulness of our proposed statistical framework are demonstrated through the simulation studies and applications based on an experimental data set.
Copy number analysis usually refers to the process of analyzing data produced by a test for DNA copy number variation in patients sample. Such analysis helps detect chromosomal copy number variation that may cause or may increase risks of various critical disorders. Copy number variation can be detected with various types of tests such as fluorescent in situ hybridization, comparative genomic hybridization and with high-resolution array-based tests based on array comparative genomic hybridization (or aCGH), SNP array technologies and high resolution microarrays that include copy number probes as well an SNPs. Array-based methods have been accepted as the most efficient in terms of their resolution and high-throughput nature and the highest coverage (choose an array with over 2 million probes) and they are also referred to as Virtual Karyotype. Data analysis for an array-based DNA copy number test can be very challenging though due to very high volume of data that come out of an array platform. ...
In this chapter submicroscopic structural variation is described with a particular focus on copy number variation. There is a growing body of evidence to show that copy number variation is a common and important class of genetic variation. Recent technological advances for mapping the extent of copy number variation including microarray based comparative genomic hybridisation are described, together with the results of large scale surveys of copy number variation among healthy individuals. The consequences of such genetic diversity for gene expression are discussed. The important role of copy number variation in susceptibility to a variety of common multifactorial traits is described including infectious and autoimmune disease. Copy number variation is also discussed in relation to evidence for selection in relation to copy number of the gene encoding salivary amylase and a high starch diet, and in relation to drug metabolism with important consequences for pharmacogenomics.
Recent genome-wide microarray-based research investigations have revealed a high frequency of submicroscopic copy number alterations (CNAs) in the myelodysplastic syndromes (MDS), suggesting microarray-based comparative genomic hybridization (aCGH) has the potential to detect new clinically relevant genomic markers in a diagnostic laboratory. We performed an exploratory study on 30 cases of MDS, myeloproliferative neoplasia (MPN) or evolving acute myeloid leukemia (AML) (% bone marrow blasts ≤ 30%, range 0-30%, median, 8%) by aCGH, using a genome-wide bacterial artificial chromosome (BAC) microarray. The sample data were compared to corresponding cytogenetics, fluorescence in situ hybridization (FISH), and clinical-pathological findings. Previously unidentified imbalances, in particular those considered submicroscopic aberrations (| 10 Mb), were confirmed by FISH analysis. CNAs identified by aCGH were concordant with the cytogenetic/FISH results in 25/30 (83%) of the samples tested. aCGH revealed new
Introduction: Lung cancer, of which 85% is non-small cell (NSCLC), is the leading cause of cancer-related death in the United States. Copy number variations (CNVs) in lung adenocarcinoma do not occur randomly in the genome, but are positionally clustered. However, the functional significance of gene copy number changes remains unclear. We characterized genome-wide copy number profiles in non-small cell lung cancer both positionally and functionally. Methods: A series of 301 tumor samples was collected from NSCLC patients in the Massachusetts General Hospital (MGH), Boston, MA (N=202) and National Institute of Occupational Health in Norway (N=99). Copy numbers were evaluated in genomic DNA extracted from micro-dissected tumor tissue with at least 70% tumor cellularity using dense single nucleotide polymorphism arrays. Inferred copy numbers were obtained with dCHIP, and significance of CNVs for each locus was evaluated with binomial distribution. Gene set enrichment analysis algorithm was used to ...
|i|Background|/i|: C-Myc, a well-known oncogene located on 8q24.12–q24.23, is often amplified and over-expressed in both primary and metastasizing colorectal cancer. In addition, PRL-3 (also known as PTP4A3), a tyrosine phosphatase located on 8q24.3, is amplified in colorectal cancer metastasis. Beside PRL-3 and c-myc, other oncogenes located on the 8q23–24 region might be involved in this process. Therefore, the present study aims to correlate DNA copy number status of a series of genes at 8q23–24 in colorectal cancer at high resolution in correlation to metastatic disease. |i|Materials and Methods|/i|: Thirty-two cases of colorectal cancer, 10 stage B1, 10 B2 and 12 D (Astler–Coller) with their corresponding liver metastasis and one colorectal cell line (colo205, previously analyzed by array-CGH), were included in this study. A chromosome 8 specific MLPA probe mixture was used to analyze the presence of DNA copy number changes. The probe mixture contained 29 probes covering
Background: Congenital malformations are present in approximately 2-3% of liveborn babies and 20% of stillborn fetuses. The mechanisms underlying the majority of sporadic and isolated congenital malformations are poorly understood, although it is hypothesized that the accumulation of rare genetic, genomic and epigenetic variants converge to deregulate developmental networks. Methodology/Principal Findings: We selected samples from 95 fetuses with congenital malformations not ascribed to a specific syndrome (68 with isolated malformations, 27 with multiple malformations). Karyotyping and Multiplex Ligation-dependent Probe Amplification (MLPA) discarded recurrent genomic and cytogenetic rearrangements. DNA extracted from the affected tissue (46%) or from lung or liver (54%) was analyzed by molecular karyotyping. Validations and inheritance were obtained by MLPA. We identified 22 rare copy number variants (CNV) [,100 kb, either absent (n = 7) or very uncommon (n = 15, ,1/2,000) in the control ...
From a number of genome-wide association studies it was shown that de novo and/or rare copy number variants (CNVs) are found at an increased frequency in neuropsychiatric diseases. In this study we examined the prevalence of CNVs in six genomic regions (1q21.1, 2p16.3, 3q29, 15q11.2, 15q13.3, and 16p11.2) previously implicated in neuropsychiatric diseases. Hereto, a cohort of four neuropsychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, and intellectual disability) and control individuals from three different populations was used in combination with Multilpex Amplicon Quantifiaction (MAQ) assays, capable of high resolution (kb range) and custom-tailored CNV detection. Our results confirm the etiological candidacy of the six selected CNV regions for neuropsychiatric diseases. It is possible that CNVs in these regions can result in disturbed brain development and in this way lead to an increased susceptibility for different neuropsychiatric disorders, dependent on ...
Uveal melanomas (UM) are aggressive ocular tumours of adults that are typically characterized by chromosomal aberrations such as loss of 1p, 3, 6q, and gain 6p, and 8q. Of these monosomy 3 (M3) and 8q+ are powerful predictors of prognosis. The relationship of changes affecting chromosome 6 is however more ambivalent, having been linked to both good and poor prognosis, and yet both regions have not been well defined, which suggest the presence of one or more oncogenes in 6p and tumour suppressor gene in 6q. Therefore, different chromosome 6 alterations may have a variable impact on the prognosis of UM, and ultimately contain genes that contribute to the development and metastasis of this disease. It is likely that these changes can act as moderators to the tumour outcome. Although UM disseminates haematogenous with high propensity for the liver, and hepatic involvement reported in over 90% of patients, infrequently some patients will however initially present with metastases in sites other than ...
Mitochondrial dysfunction, generally characterized as a loss of efficiency in oxidative phosphorylation, is a hallmark of aging and a variety of chronic diseases. Mitochondrial dysfunction results in inefficient cellular energy production and in increased levels of reactive oxygen species (ROS) which may damage lipids, proteins, and nucleic acids. Mitochondrial dysfunction also affects the expression of nuclear genes involved in metabolism, growth, differentiation, and apoptosis. All these changes may explain the contribution of mitochondrial dysfunction to chronic and complex human diseases. A major limitation to the routine evaluation of mitochondrial dysfunction in clinical practice is the lack of reliable measures of mitochondrial dysfunction available for clinical use. Mitochondrial DNA copy number (mtDNA-CN) is a promising biomarker of mitochondrial dysfunction that has the potential to become widely available in clinical practice. Other measures of mitochondrial dysfunction, including ...
Abstract: Resistance to chemotherapeutic agents and radiotherapy has kept surgery the primary treatment of uterine leiomyosarcoma (ULMS). In search of leads for potential therapeutic targets, array CGH (aCGH) was used to obtain a genomewide pattern of ULMS-specific genetic imbalances and to define the affected biological processes. Fine-resolution genomewide aCGH analysis was performed using customised 16K cDNA microarrays on 18 primary ULMS cases. Furthermore, patterns of DNA copy number changes were assessed for associations with clinical parameters, i.e., tumour grade, tumour size and patient status at last follow-up. Our aCGH results demonstrated extensive DNA copy number changes in all chromosomes. Of the 10,590 gene loci included in the analysis, 4,387 were found to be affected by DNA copy number gains and 4,518 by DNA copy number losses in at least one case. Further analyses revealed that 231 of these were commonly gained, and 265 lost in at least 20% of the cases. The gains affected loci ...
We have used a new method of genomic microarray to investigate amplification of oncogenes throughout the genome of glioblastoma multiforme (GBM). Array-based comparative genomic hybridization (array CGH) allows for simultaneous examination of 58 oncogenes/amplicons that are commonly amplified in var …
© 2019, The Author(s). Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in |0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic
DNA copy number variants represent the greatest source of genetic variability in humans [1] and are the underlying cause of many human diseases. Array CGH is recognized as a first-tier test for DNA copy number variants (CNV) [2] and accordingly, many laboratories have already established their pipelines for pre-processing of array CGH data and CNV calling. In many cases these pipelines are based on software packages provided by the companies selling DNA microarrays or scanners such as BlueFuse [3], CytoSure [4] or CytoGenomics [5]. Yet, the scope of these tools is focused on the identification of CNVs and their evaluation in the context of gene content and frequency of a given variant in the healthy population. Comparative analysis, which integrates data obtained from multiple patients, or other experiment types are hardly supported, in particular when they are based on different array platforms or NGS technology.. Such kind of meta-analysis needs the implementation of additional commercial or ...
Oncogenic point mutations in KIT or PDGFRA are recognized as the primary events responsible for the pathogenesis of most gastrointestinal stromal tumors (GIST), but additional genomic alterations are frequent and presumably required for tumor progression. The relative contribution of such alterations for the biology and clinical behavior of GIST, however, remains elusive. In the present study, somatic mutations in KIT and PDGFRA were evaluated by direct sequencing analysis in a consecutive series of 80 GIST patients. For a subset of 29 tumors, comparative genomic hybridization was additionally used to screen for chromosome copy number aberrations. Genotype and genomic findings were cross-tabulated and compared with available clinical and follow-up data. We report an overall mutation frequency of 87.5%, with 76.25% of the tumors showing alterations in KIT and 11.25% in PDGFRA. Secondary KIT mutations were additionally found in two of four samples obtained after imatinib treatment. Chromosomal imbalances
About a decade ago the first large catalogs of copy number variants (CNVs) in the human genome were presented [1, 2]. Numerous studies later, CNVs are known to contribute to the genomic variation to a larger extent than single nucleotide polymorphisms (SNPs) in terms of number of nucleotide differences [3, 4]. CNVs are defined as DNA segments of variable length, up to several megabases (Mb), that varies in copy numbers in comparison to a reference genome [5]. The different types of CNVs include deletions and duplications, while consequences of CNVs include e.g. altered gene dosage and regulation, changed gene structure and unmasking of recessive alleles [5]. The effect of CNVs varies from being benign or neutral, to having subtle effects on disease predisposition or directly causing disease. The contribution and importance of CNVs for phenotypic diversity and disease susceptibility has been repeatedly shown in human and several complex diseases such as psoriasis, Crohns disease, type 2 ...
Arabidopsis thaliana is the model plant and is grown worldwide by plant biologists seeking to dissect the molecular underpinning of plant growth and development. Gene copy number variation (CNV) is a common form of genome natural diversity that is currently poorly studied in plants and may have broad implications for model organism research, evolutionary biology, and crop science. Herein, comparative genomic hybridization (CGH) was used to identify and interrogate regions of gene CNV across the A. thaliana genome. A common temperature condition used for growth of A. thaliana in our laboratory and many around the globe is 22 degrees C. The current study sought to test whether A. thaliana, grown under different temperature (16 and 28 degrees C) and stress regimes (salicylic acid spray) for five generations, selecting for fecundity at each generation, displayed any differences in CNV relative to a plant lineage growing under normal conditions. Three siblings from each alternative temperature or stress
The treatment strategy usually depends on the disease state in the individual patient. However, it is difficult to estimate the disease state before treatment in many patients. The purpose of this study was to develop a BAC (bacterial artificial chromosome) mini-array allowing for the estimation of node metastasis, liver metastasis, peritoneal dissemination and the depth of tumor invasion in gastric cancers. Initially, the DNA copy number aberrations (DCNAs) were analyzed by array-based comparative genomic hybridization (aCGH) in 83 gastric adenocarcinomas as a training-sample set. Next, two independent analytical methods were applied to the aCGH data to identify the BAC clones with DNA copy number aberrations that were linked with the disease states. One of the methods, a decision-tree model classifier, identified 6, 4, 4, 4, and 7 clones for estimating lymph node metastasis, liver metastasis, peritoneal dissemination, depth of tumor invasion, and histological type, respectively. In the other method, a
article{39c3420c-566c-4f24-879b-c3929d10ccd7, abstract = {It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed, significant increased risks of CLL (n=102) with increasing mtDNA ...
Genomic copy number changes are frequently found in cancers and they have been demonstrated to contribute to carcinogenesis; and it is widely accepted that tumors with microsatellite instability (MSI) are genetically stable and mostly diploid. In the present study we compared the copy number alterations and the gene-expression profiles of microsatellite stable (MSS) and MSI colorectal tumors. A total number of 31 fresh-frozen primary tumors (16 MSS and 15 MSI) were used. Twenty-eight samples (15 MSS and 13 MSI) were analyzed with metaphase comparative genomic hybridization (CGH), nine of which plus one additional sample (4 MSS and 6 MSI) were further analyzed by cDNA-based array-CGH. Gene expression analysis was performed with six samples [3 MSS and 3 MSI, four of these used in metaphase CGH (mCGH) analysis] to identify differentially expressed genes possibly located in the lost or amplified regions found by CGH, stressing the biological significance of copy number changes. Metaphase and ...
We conducted a genome-wide scan for large CNVs (≥100 kb) in a case-control dataset of Caribbean Hispanic origin that was previously investigated in a SNP-based GWAS (Lee JH et al. 2010). To generate results with high confidence, we focused on CNVs that were identified by at least two algorithms. We detected 1774 stringent CNVs (Table S4). First, we tested the hypothesis that rare CNVs (≤1%) with a potentially strong impact on AD risk in individual patients might contribute to the overall disease risk, as was previously observed in other common neuropsychiatric disorders (Kirov et al. 2009; Zhang et al. 2009; Glessner et al. 2010). However, the burden analyses of rare CNVs did not find significant differences between cases and controls in CNV rate, total or average CNV size, or the number of genes affected by CNVs.. In addition, we conducted a case-control analysis of large genic CNVs, including common variants, using PLINK regional analysis. The only nominally significant result that ...
|jats:title|Abstract|/jats:title||jats:p|Long regarded as an epicenter of drug-resistant malaria, Southeast Asia continues to provide new challenges to the control of |jats:italic|Plasmodium falciparum|/jats:italic| malaria. Recently, resistance to the artemisinin combination therapy partner drug piperaquine has been observed in multiple locations across Southeast Asia. Genetic studies have identified a single nucleotide polymorphism as well as a copy number variation molecular marker that associate with clinical and |jats:italic|in vitro|/jats:italic| resistance. The copy number polymorphism is a duplication of a region containing members of the plasmepsin multi-gene family of proteases. To accurately and quickly determine the presence of copy number variation in the |jats:italic|plasmepsin 2/3|/jats:italic| duplication in field isolates, we developed a quantitative PCR assay using TaqMan probes. We validated copy number estimates using a separate SYBR green-based quantitative PCR assay as well as a
Figure Novel compound heterozygous mutation in the COLQ gene causes congenital myasthenic syndrome. (A) Pedigree of the proband (II-1). Point mutation (IVS16+3A→G) in the COLQ gene was inherited from the father (I-1), and multiexon deletion from the mother (I-2). (B) Gene list of 21 known congenital myasthenic syndrome (CMS) genes included in the targeted CMS panel. (C) Genome view of PatternCNV analysis shows decreased copy number variation (CNV) log2 ratio for the COLQ gene in chromosome 3. (D) Exon-level CNV summary table shows the start and end position of deletion (984 base pairs) in the COLQ gene, which indicates 1 copy deletion of exons 14 and 15. SNR.db: signal noise ratio expressed in decibels; CNV.ratio: copy number ratio converted from CNV.log2ratio. CNV.ratio of 1 indicates no copy number change. (E) TaqMan Copy Number Assay results confirm exon deletions in the COLQ gene in the proband, which is also found in her mother (data not shown). Longer PCR cycle number (X-axis) denotes 1 ...
TY - JOUR. T1 - Identification of genes involved in squamous cell carcinoma of the lung using synchronized data from DNA copy number and transcript expression profiling analysis. AU - Lo, Ken C.. AU - Stein, Leighton C.. AU - Panzarella, Jenniffer A.. AU - Cowell, John Kenneth. AU - Hawthorn, Lesleyann. PY - 2008/3/1. Y1 - 2008/3/1. N2 - Lung cancer is the leading cause of cancer deaths in the world and squamous cell carcinoma (SqCC) is the second most common in this group. Genomic DNA copy number alterations are fundamental genetic events in the development and progression of SqCC as well as other epithelial-derived cancers. The ability to identify tumor suppressor genes (TSGs) and oncogenes that are affected during tumor initiation and progression could facilitate the identification of novel molecular targets for therapeutic intervention and provide diagnostic biomarkers. Despite the association of many genetic alterations in lung cancer the molecular mechanisms of tumor progression remain ...
BACKGROUND: Illumina Infinium whole genome genotyping (WGG) arrays are increasingly being applied in cancer genomics to study gene copy number alterations and allele-specific aberrations such as loss-of-heterozygosity (LOH). Methods developed for normalization of WGG arrays have mostly focused on diploid, normal samples. However, for cancer samples genomic aberrations may confound normalization and data interpretation. Therefore, we examined the effects of the conventionally used normalization method for Illumina Infinium arrays when applied to cancer samples. RESULTS: We demonstrate an asymmetry in the detection of the two alleles for each SNP, which deleteriously influences both allelic proportions and copy number estimates. The asymmetry is caused by a remaining bias between the two dyes used in the Infinium II assay after using the normalization method in Illuminas proprietary software (BeadStudio). We propose a quantile normalization strategy for correction of this dye bias. We tested the ...
Richard-Carpentier G, Kantarjian HM, Short NJ, Ravandi F, Ferrajoli A, Schroeder HM, et al. Yang J, Bhojwani D, Yang W. Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia. E. Jabbour has research grants with Amgen, AbbVie, Spectrum, BMS, Takeda Oncology, Pfizer, and Adaptive. Seizures 3. The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, et al. Pui CH, Crist WM, Look AT. PubMed Central Google Scholar. Blood. Additional tables. Neumann M, Vosberg S, Schlee C, Heesch S, Schwartz S, Gökbuget N, et al. However, a better understanding of the disease biology has generated important knowledge on the prognostic and predictive value of MRD, which has helped guide our treatment strategies, such as intensification or referral to HSCT, the use of MRD-directed novel agents or even treatment de-escalation. 2016;172(3):392-400. There ...
To select parameters for calling CNVs (that is, the statistical threshold of the ADM2 algorithm, the minimum +/- log2 ratio and the minimum number of consecutive probes in a CNV interval), we calculated the sensitivity and positive predictive value based on the comparison of aCGH-based CNV calls (using our high-resolution Agilent 24M platform) with read-depth sequence data for two samples from Korean individuals (AK1 and AK2). We attempted to obtain `absolute copy number status of the sample from NA10851, which was used as the reference sample for aCGH experiments in this study. For this, we used read-depth data for NA10851 obtained from massively parallel sequencing by the Illumina GA II data. The read-depth data represent the copy number status of NA10851 as compared to the human reference genome (hg18) because the short read sequences were aligned to hg18 ...
Thousands of genomic segments appear to be present in widely varying copy numbers in different human genomes. We developed ways to use increasingly abundant whole-genome sequence data to identify the copy numbers, alleles and haplotypes present at most large multiallelic CNVs (mCNVs). We analyzed 849 genomes sequenced by the 1000 Genomes Project to identify most large (,5-kb) mCNVs, including 3878 duplications, of which 1356 appear to have 3 or more segregating alleles. We find that mCNVs give rise to most human variation in gene dosage-seven times the combined contribution of deletions and biallelic duplications- and that this variation in gene dosage generates abundant variation in gene expression. We describe runaway duplication haplotypes in which genes, including HPR and ORM1, have mutated to high copy number on specific haplotypes. We also describe partially successful initial strategies for analyzing mCNVs via imputation and provide an initial data resource to support such analyses ...
The first estimation of how genomic copy number variation (CNV) can influence anesthetic sensitivity and the magnitude of this influence can be gauged by a new study
A fixed gene copy number is important for the in silico construction of engineered synthetic networks. However, the copy number of integrated genes depends on their genomic location. This gene dosage effect is rarely addressed in synthetic biology. Two studies in Escherichia colipresented conflicting data on the impact of gene dosage. Here, we investigate how genome location and gene orientation influences expression in Bacillus subtilis. An important difference with the E. coli studies is that we used an unbiased genome integration approach mediated by random transposon insertion. We found that there is a strong gene dosage effect in fast growing B. subtilis cells, which can amount to a 5-fold difference in gene expression. In contrast, gene orientation with respect to DNA replication direction does not influence gene expression. Our study shows that gene dosage should be taken into account when designing synthetic circuits in B. subtilis and presumably other bacteria.. ...
Copy number variation can contribute to the variation observed in susceptibility to complex diseases. Here we present the first study to investigate copy number variation of the chemokine gene CCL3L1 with susceptibility to malaria. We present a family-based genetic analysis of a Tanzanian population (n = 922), using parasite load, mean number of clinical infections of malaria and haemoglobin levels as phenotypes. Copy number of CCL3L1 was measured using the paralogue ratio test (PRT) and the dataset exhibited copy numbers ranging between 1 and 10 copies per diploid genome (pdg). Association between copy number and phenotypes was assessed. Furthermore, we were able to identify copy number haplotypes in some families, using microsatellites within the copy variable region, for transmission disequilibrium testing. We identified a high level of copy number haplotype diversity and find some evidence for an association of low CCL3L1 copy number with protection from anaemia.. ...
Copy number variants (CNVs) on the Breakpoint 1 to Breakpoint 2 region Ki8751 at 15q11. of publically obtainable expression data identified a relationship between expression of mRNA and FOXP2 in mind. We suggest that changed medication dosage through aberrant patterning from the lh.SMG may donate to language-related Mouse monoclonal to CD11b.4AM216 reacts with CD11b, a member of the integrin a chain family with 165 kDa MW. which is expressed on NK cells, monocytes, granulocytes and subsets of T and B cells. It associates with CD18 to form CD11b/CD18 complex.The cellular function of CD11b is on neutrophil and monocyte interactions with stimulated endothelium; Phagocytosis of iC3b or IgG coated particles as a receptor; Chemotaxis and apoptosis. Ki8751 issues connected with BP1-2 CNVs. Even more generally this process may be useful in clarifying the contribution Ki8751 of individual genes at CNV risk loci. Introduction Rare multi-gene copy number variants (CNVs) are well established to increase ...
Scientists reported the development of a robust procedure for whole-genome copy number profiling of circulating tumor cells (CTCs) from a blood test. In contrast to existing methods that are complex and costly, the single-tube, single-step protocol detect absolute copy number alterations (CNA) in single cells and maintain accuracy at a lower cost than conventional genomic analysis procedure, opening up to the possibility for genome-driven targeted therapy selection and monitoring of disease progression in liquid biopsy.
The authors profiled either unselected [3-5], triple-negative [1], or estrogen-receptor positive breast cancer [2] utilizing various technical approaches, including whole-genome sequencing, whole-exome sequencing, copy number profiling, and transcriptome analysis. Curtis and colleagues [5] integrate expression and copy number to identify ten subtypes of breast cancers and reveal aberration hotspots responsible for these groups. These hotspots contain known (ERBB2, MYC) and candidate driver loci that can impact patient prognosis. Stephens and colleagues [4] combined copy-number and sequencing to identify a number of novel driver genes (MAP3K1, MAP2K4, MAP3K13, and AKT2), albeit each at relatively low frequency. Together, however, these mutations all impact JUN signaling activation and encompass approximately 50% of all breast tumors, thus identifying a major recurrent pathway alteration in breast cancer. Banerji and colleagues [3] similarly utilize sequencing to identify driver mutations and copy ...
Complex focal chromosomal rearrangements in cancer genomes, also called firestorms, can be scored from DNA copy number data. The complex arm-wise aberration index (CAAI) is a score that captures DNA copy number alterations that appear as focal complex events in tumors, and has potential prognostic value in breast cancer. This study aimed to validate this DNA-based prognostic index in breast cancer and test for the first time its potential prognostic value in ovarian cancer. Copy number alteration (CNA) data from 1950 breast carcinomas (METABRIC cohort) and 508 high-grade serous ovarian carcinomas (TCGA dataset) were analyzed. Cases were classified as CAAI positive if at least one complex focal event was scored. Complex alterations were frequently localized on chromosome 8p (n = 159), 17q (n = 176) and 11q (n = 251). CAAI events on 11q were most frequent in estrogen receptor positive (ER+) cases and on 17q in estrogen receptor negative (ER-) cases. We found only a modest correlation between ...
Author Summary Mutations in noncoding sequence can cause disease but are very difficult to recognize. Here, we present two approaches intended to help identify noncoding regions of the genome that may carry mutations influencing disease. The first approach is based on comparing observed and predicted levels of standing human variation in the noncoding exome sequence of a gene. The second approach is based on the phylogenetic conservation of a genes noncoding exome sequence using GERP++. We find that both approaches can predict genes known to cause disease through changes in expression level, genes depleted of loss-of-function alleles in the general population, and genes permissive of copy number variants in the general population. We find that both scores aid in interpreting loss-of-function mutations and in defining regions of noncoding sequence that are more likely to harbor mutations that influence risk of disease.
BACKGROUND: Tandem repeat variation in protein-coding regions will alter protein length and may introduce frameshifts. Tandem repeat variants are associated with variation in pathogenicity in bacteria and with human disease. We characterized tandem repeat polymorphism in human proteins, using the UniGene database, and tested whether these were associated with host defense roles.. RESULTS: Protein-coding tandem repeat copy-number polymorphisms were detected in 249 tandem repeats found in 218 UniGene clusters; observed length differences ranged from 2 to 144 nucleotides, with unit copy lengths ranging from 2 to 57. This corresponded to 1.59% (218/13,749) of proteins investigated carrying detectable polymorphisms in the copy-number of protein-coding tandem repeats. We found no evidence that tandem repeat copy-number polymorphism was significantly elevated in defense-response proteins (p = 0.882). An association with the Gene Ontology term protein-binding remained significant after covariate ...
Environmental risk factors have been shown to alter DNA copy number variations (CNVs). Recently, CNVs have been described to arise after low-dose ionizing radiation in vitro and in vivo. Development of cost- and size-effective laser-driven electron accelerators (LDEAs), capable to deliver high energy beams in pico- or femtosecond durations requires examination of their biological effects. Here we studied in vitro impact of LDEAs radiation on known CNV hotspots in human peripheral blood lymphocytes on single cell level. Here CNVs in chromosomal regions 1p31.1, 7q11.22, 9q21.3, 10q21.1 and 16q23.1 earlier reported to be sensitive to ionizing radiation were analyzed using molecular cytogenetics. Irradiation of cells with 0.5, 1.5 and 3.0 Gy significantly increased signal intensities in all analyzed chromosomal regions compared to controls. The latter is suggested to be due to radiation-induced duplication or amplification of CNV stretches. As significantly lower gains in mean fluorescence intensities were
Most behavioral, physiological and cellular effects of theneurotransmitter dopamine require concomitant activation of both D1 and D2 receptors, a phenomenon referred to as D1/D2 synergism. Since D1 and D2 receptors are located mostly on separate neurons, and since D1/D2 synergism occurs in the absence of action potentials, we have suggested that electrotonic coupling via gap junctions plays an important role in this phenomenon. A major constituent of gap junctions is connexin36 (Cx36), a protein that is abundant in neurons. The role Cx36 in D1/D2 synergism, as manifested behaviorally, was studied here in mice genetically engineered to express normal, reduced, or undetectable amounts of this protein. The results show that D1/D2 synergism and its breakdown were not affected by the presence or absence of Cx36. Unexpectedly, it was observed that the absence of Cx36 leads to resistance to the cataleptic effects of reserpine in a gene dosage-dependent manner.
Reciprocal chromosomal rearrangements at the 22q11.2 locus are associated with elevated risk of neurodevelopmental disorders. The 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population. Here we conducted the first study of 22q11.2 gene dosage effects on brain structure in a sample of 143 human subjects: 66 with 22q11.2 deletions (22q-del; 32 males), 21 with 22q11.2 duplications (22q-dup; 14 males), and 56 age- and sex-matched controls (31 males). 22q11.2 gene dosage varied positively with intracranial volume, gray and white matter volume, and cortical surface area (deletion , control, duplication). In contrast, gene dosage varied negatively with mean cortical thickness (deletion , control , duplication). Widespread differences were observed for cortical surface area with more localized effects on cortical thickness. These diametric ...