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作者： Song, Lei Virginia Tech | University

DNA copy number change is an important form of structural variation in human genome. Somatic copy number alterations (CNAs) can cause over expression of oncogenes and loss of tumor suppressor genes in tumorigenesis. Recent development of SNP array technology has facilitated studies on copy number changes at a genome-wide scale, with high resolution. Quantitative analysis of somatic CNAs on genes has found broad applications in cancer research. Most tumors exhibit genomic instability at chromosome scale as a result of dynamically accumulated genomic mutations during the course of tumor progression. Such higher level cancer genomic characteristics cannot be effectively captured by the analysis of individual genes. We introduced two definitions of chromosome instability (CIN) index to mathematically and quantitatively characterize genome-wide genomic instability. The proposed CIN indices are derived from detected CNAs using circular binary segmentation and wavelet transform, which calculates a score based on both the amplitude and frequency of the copy number changes. We generated CIN indices on ovarian cancer subtypesâ copy number data and used them as features to train a SVM classifier. The experimental results show promising and high classification accuracy estimated through cross-validations. Additional survival analysis is constructed on the extracted CIN scores from TCGA ovarian cancer dataset and showed considerable correlation between CIN scores and various events and severity in ovarian cancer development. Currently our methods have been integrated into G-DOC. We expect these newly defined CINs to be predictors in tumors subtype diagnosis and to be a useful tool in cancer research.

关键词： DNA Copy Number Changes circular binary segmentation Haar Wavelet Transform Chromosome Instability Index Georgetown Database of Cancer Thesis

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A fast and accurate method to detect allelic genomic imbalances underlying mosaic rearrangements using SNP array data

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BMC BIOINFORMATICS 2011年第1期12卷 1-11页

作者： Gonzalez, Juan R. Rodriguez-Santiago, Benjamin Caceres, Alejandro Pique-Regi, Roger Rothman, Nathaniel Chanock, Stephen J. Armengol, Lluis Perez-Jurado, Luis A. Ctr Res Environm Epidemiol CREAL Barcelona 08003 Spain IMIM Barcelona 08003 Spain UPF Dept Ciencies Expt & Salut Barcelona 08003 Spain Univ Chicago Dept Human Genet Chicago IL 60637 USA NCI Div Canc Epidemiol & Genet Rockville MD 20852 USA SAIC Frederick Core Genotyping Facil Frederick MD 21702 USA Quantitat Genom Med Labs Ltd qGenom Barcelona 08003 Spain

Background: Mosaicism for copy number and copy neutral chromosomal rearrangements has been recently identified as a relatively common source of genetic variation in the normal population. However its prevalence is poorly defined since it has been only studied systematically in one large-scale study and by using non optimal adhoc SNP array data analysis tools, uncovering rather large alterations (> 1 Mb) and affecting a high proportion of cells. Here we propose a novel methodology, Mosaic Alteration Detection-MAD, by providing a software tool that is effective for capturing previously described alterations as wells as new variants that are smaller in size and/or affecting a low percentage of cells. Results: The developed method identified all previously known mosaic abnormalities reported in SNP array data obtained from controls, bladder cancer and HapMap individuals. In addition MAD tool was able to detect new mosaic variants not reported before that were smaller in size and with lower percentage of cells affected. The performance of the tool was analysed by studying simulated data for different scenarios. Our method showed high sensitivity and specificity for all assessed scenarios. Conclusions: The tool presented here has the ability to identify mosaic abnormalities with high sensitivity and specificity. Our results confirm the lack of sensitivity of former methods by identifying new mosaic variants not reported in previously utilised datasets. Our work suggests that the prevalence of mosaic alterations could be higher than initially thought. The use of appropriate SNP array data analysis methods would help in defining the human genome mosaic map.

关键词： False Discovery Rate Allelic Imbalance Single Nucleotide Polymorphism Array circular binary segmentation High False Discovery Rate

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Wavelet-based identification of DNA focal genomic aberrations from single nucleotide polymorphism arrays

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BMC BIOINFORMATICS 2011年第1期12卷 1-14页

作者： Hur, Youngmi Lee, Hyunju Gwangju Inst Sci & Technol Dept Informat & Commun Kwangju South Korea Johns Hopkins Univ Dept Appl Math & Stat Baltimore MD USA

Background: Copy number aberrations (CNAs) are an important molecular signature in cancer initiation, development, and progression. However, these aberrations span a wide range of chromosomes, making it hard to distinguish cancer related genes from other genes that are not closely related to cancer but are located in broadly aberrant regions. With the current availability of high-resolution data sets such as single nucleotide polymorphism (SNP) microarrays, it has become an important issue to develop a computational method to detect driving genes related to cancer development located in the focal regions of CNAs. Results: In this study, we introduce a novel method referred to as the wavelet-based identification of focal genomic aberrations (WIFA). The use of the wavelet analysis, because it is a multi-resolution approach, makes it possible to effectively identify focal genomic aberrations in broadly aberrant regions. The proposed method integrates multiple cancer samples so that it enables the detection of the consistent aberrations across multiple samples. We then apply this method to glioblastoma multiforme and lung cancer data sets from the SNP microarray platform. Through this process, we confirm the ability to detect previously known cancer related genes from both cancer types with high accuracy. Also, the application of this approach to a lung cancer data set identifies focal amplification regions that contain known oncogenes, though these regions are not reported using a recent CNAs detecting algorithm GISTIC: SMAD7 (chr18q21.1) and FGF10 (chr5p12). Conclusions: Our results suggest that WIFA can be used to reveal cancer related genes in various cancer data sets.

关键词： Wavelet Coefficient Cancer Related Gene Single Nucleotide Polymorphism Array Copy Number Aberration circular binary segmentation

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Detection of copy number variations in rice using array-based comparative genomic hybridization

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BMC GENOMICS 2011年第1期12卷 372-372页

作者： Yu, Ping Wang, Caihong Xu, Qun Feng, Yue Yuan, Xiaoping Yu, Hanyong Wang, Yiping Tang, Shengxiang Wei, Xinghua China Natl Rice Res Inst State Key Lab Rice Biol Hangzhou Zhejiang Peoples R China

Background: Copy number variations (CNVs) can create new genes, change gene dosage, reshape gene structures, and modify elements regulating gene expression. As with all types of genetic variation, CNVs may influence phenotypic variation and gene expression. CNVs are thus considered major sources of genetic variation. Little is known, however, about their contribution to genetic variation in rice. Results: To detect CNVs, we used a set of NimbleGen whole-genome comparative genomic hybridization arrays containing 718,256 oligonucleotide probes with a median probe spacing of 500 bp. We compiled a high-resolution map of CNVs in the rice genome, showing 641 CNVs between the genomes of the rice cultivars 'Nipponbare' (from O. sativa ssp. japonica) and 'Guang-lu-ai 4' (from O. sativa ssp. indica). The CNVs identified vary in size from 1.1 kb to 180.7 kb, and encompass approximately 7.6 Mb of the rice genome. The largest regions showing copy gain and loss are of 37.4 kb on chromosome 4, and 180.7 kb on chromosome 8. In addition, 85 DNA segments were identified, including some genic sequences. Contracted genes greatly outnumbered duplicated ones. Many of the contracted genes corresponded to either the same genes or genes involved in the same biological processes;this was also the case for genes involved in disease and defense. Conclusion: We detected CNVs in rice by array-based comparative genomic hybridization. These CNVs contain known genes. Further discussion of CNVs is important, as they are linked to variation among rice varieties, and are likely to contribute to subspecific characteristics.

关键词： Rice Genome circular binary segmentation aCGH Data Bacterial Blight Resistance Gene China National Rice Research Institute

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CNstream: A method for the identification and genotyping of copy number polymorphisms using Illumina microarrays

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BMC BIOINFORMATICS 2010年第1期11卷 1-18页

作者： Alonso, Arnald Julia, Antonio Tortosa, Rauel Canaleta, Cristina Canete, Juan D. Ballina, Javier Balsa, Alejandro Tornero, Jesus Marsal, Sara Hosp Univ Vall Hebron UAB Grp Recerca Reumatol Inst Recerca Barcelona Spain Hosp Clin Barcelona Barcelona Spain Hosp Univ Cent Asturias Oviedo Asturias Spain Hosp Univ La Paz Madrid Spain Hosp Univ Guadalajara Castilla La Mancha Spain

Background: Understanding the genetic basis of disease risk in depth requires an exhaustive knowledge of the types of genetic variation. Very recently, Copy Number Variants (CNVs) have received much attention because of their potential implication in common disease susceptibility. Copy Number Polymorphisms (CNPs) are of interest as they segregate at an appreciable frequency in the general population (i.e. > 1%) and are potentially implicated in the genetic basis of common diseases. Results: This paper concerns CNstream, a method for whole-genome CNV discovery and genotyping, using Illumina Beadchip arrays. Compared with other methods, a high level of accuracy was achieved by analyzing the measures of each intensity channel separately and combining information from multiple samples. The CNstream method uses heuristics and parametrical statistics to assign a confidence score to each sample at each probe;the sensitivity of the analysis is increased by jointly calling the copy number state over a set of nearby and consecutive probes. The present method has been tested on a real dataset of 575 samples genotyped using Illumina HumanHap 300 Beadchip, and demonstrates a high correlation with the Database of Genomic Variants (DGV). The same set of samples was analyzed with PennCNV, one of the most frequently used copy number inference methods for Illumina platforms. CNstream was able to identify CNP loci that are not detected by PennCNV and it increased the sensitivity over multiple other loci in the genome. Conclusions: CNstream is a useful method for the identification and characterization of CNPs using Illumina genotyping microarrays. Compared to the PennCNV method, it has greater sensitivity over multiple CNP loci and allows more powerful statistical analysis in these regions. Therefore, CNstream is a robust CNP analysis tool of use to researchers performing genome-wide association studies (GWAS) on Illumina platforms and aiming to identify CNVs associated with the varia

关键词： Gaussian Mixture Model Rheumatoid Arthritis Susceptibility Copy Number State circular binary segmentation Copy Number Polymorphism

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CNV Workshop: an integrated platform for high-throughput copy number variation discovery and clinical diagnostics

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BMC BIOINFORMATICS 2010年第1期11卷 74-74页

作者： Gai, Xiaowu Perin, Juan C. Murphy, Kevin O'Hara, Ryan D'arcy, Monica Wenocur, Adam Xie, Hongbo M. Rappaport, Eric F. Shaikh, Tamim H. White, Peter S. Childrens Hosp Philadelphia Ctr Biomed Informat Philadelphia PA 19104 USA Childrens Hosp Philadelphia Div Oncol Philadelphia PA 19104 USA Childrens Hosp Philadelphia Res Inst Philadelphia PA 19104 USA Univ Penn Dept Pediat Sch Med Philadelphia PA 19104 USA Childrens Hosp Philadelphia Div Genet Philadelphia PA 19104 USA

Background: Recent studies have shown that copy number variations (CNVs) are frequent in higher eukaryotes and associated with a substantial portion of inherited and acquired risk for various human diseases. The increasing availability of high-resolution genome surveillance platforms provides opportunity for rapidly assessing research and clinical samples for CNV content, as well as for determining the potential pathogenicity of identified variants. However, few informatics tools for accurate and efficient CNV detection and assessment currently exist. Results: We developed a suite of software tools and resources (CNV Workshop) for automated, genome-wide CNV detection from a variety of SNP array platforms. CNV Workshop includes three major components: detection, annotation, and presentation of structural variants from genome array data. CNV detection utilizes a robust and genotype-specific extension of the circular binary segmentation algorithm, and the use of additional detection algorithms is supported. Predicted CNVs are captured in a MySQL database that supports cohort-based projects and incorporates a secure user authentication layer and user/admin roles. To assist with determination of pathogenicity, detected CNVs are also annotated automatically for gene content, known disease loci, and gene-based literature references. Results are easily queried, sorted, filtered, and visualized via a web-based presentation layer that includes a GBrowse-based graphical representation of CNV content and relevant public data, integration with the UCSC Genome Browser, and tabular displays of genomic attributes for each CNV. Conclusions: To our knowledge, CNV Workshop represents the first cohesive and convenient platform for detection, annotation, and assessment of the biological and clinical significance of structural variants. CNV Workshop has been successfully utilized for assessment of genomic variation in healthy individuals and disease cohorts and is an ideal platform for c

关键词： UCSC Genome Browser Copy Number Change Allelic Ratio circular binary segmentation aCGH Data

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R-Gada: a fast and flexible pipeline for copy number analysis in association studies

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BMC BIOINFORMATICS 2010年第1期11卷 1-12页

作者： Pique-Regi, Roger Caceres, Alejandro Gonzalez, Juan R. Univ So Calif Viterbi Sch Engn Inst Signal & Image Proc Los Angeles CA 90089 USA Childrens Hosp Los Angeles Dept Pediat Div Hematol Oncol Los Angeles CA 90027 USA Ctr Res Environm Epidemiol CREAL Barcelona 08003 Spain IMIM Barcelona 08003 Spain CIBERESP Barcelona 08003 Spain

Background: Genome-wide association studies (GWAS) using Copy Number Variation (CNV) are becoming a central focus of genetic research. CNVs have successfully provided target genome regions for some disease conditions where simple genetic variation (i.e., SNPs) has previously failed to provide a clear association. Results: Here we present a new R package, that integrates: (i) data import from most common formats of Affymetrix, Illumina and aCGH arrays;(ii) a fast and accurate segmentation algorithm to call CNVs based on Genome Alteration Detection Analysis (GADA);and (iii) functions for displaying and exporting the Copy Number calls, identification of recurrent CNVs, multivariate analysis of population structure, and tools for performing association studies. Using a large dataset containing 270 HapMap individuals (Affymetrix Human SNP Array 6.0 Sample Dataset) we demonstrate a flexible pipeline implemented with the package. It requires less than one minute per sample (3 million probe arrays) on a single core computer, and provides a flexible parallelization for very large datasets. Case-control data were generated from the HapMap dataset to demonstrate a GWAS analysis. Conclusions: The package provides the tools for creating a complete integrated pipeline from data normalization to statistical association. It can effciently handle a massive volume of data consisting of millions of genetic markers and hundreds or thousands of samples with very accurate results.

关键词： Copy Number Variation Copy Number Change Multiple Correspondence Analysis HapMap Sample circular binary segmentation

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Multiplex Amplicon Quantification (MAQ), a fast and efficient method for the simultaneous detection of copy number alterations in neuroblastoma

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BMC GENOMICS 2010年第1期11卷 298-298页

作者： Kumps, Candy Van Roy, Nadine Heyrman, Lien Goossens, Dirk Del-Favero, Jurgen Noguera, Rosa Vandesompele, Jo Speleman, Frank De Preter, Katleen Ghent Univ Hosp Ctr Med Genet B-9000 Ghent Belgium Univ Antwerp B-2020 Antwerp Belgium Univ Valencia Med Sch Valencia Dept Pathol Valencia Spain

Background: Cancer genomes display characteristic patterns of chromosomal imbalances, often with diagnostic and prognostic relevance. Therefore assays for genome-wide copy number screening and simultaneous detection of copy number alterations in specific chromosomal regions are of increasing importance in the diagnostic work-up of tumors. Results: We tested the performance of Multiplex Amplicon Quantification, a newly developed low-cost, closed-tube and high-throughput PCR-based technique for detection of copy number alterations in regions with prognostic relevance for neuroblastoma. Comparison with array CGH and the established Multiplex Ligation-dependent Probe Amplification method on 52 neuroblastoma tumors showed that Multiplex Amplicon Quantification can reliably detect the important genomic aberrations. Conclusion: Multiplex Amplicon Quantification is a low-cost and high-throughput PCR-based technique that can reliably detect copy number alterations in regions with prognostic relevance for neuroblastoma.

关键词： Multiplex Ligation Probe Amplification Copy Number Change Copy Number Alteration MYCN Amplification circular binary segmentation

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Whole-genome sequencing of a laboratory-evolved yeast strain

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BMC GENOMICS 2010年第1期11卷 88-88页

作者： Araya, Carlos L. Payen, Celia Dunham, Maitreya J. Fields, Stanley Univ Washington Dept Genome Sci Seattle WA 98195 USA Univ Washington Dept Med Seattle WA 98195 USA Univ Washington Howard Hughes Med Inst Seattle WA 98195 USA

Background: Experimental evolution of microbial populations provides a unique opportunity to study evolutionary adaptation in response to controlled selective pressures. However, until recently it has been difficult to identify the precise genetic changes underlying adaptation at a genome-wide scale. New DNA sequencing technologies now allow the genome of parental and evolved strains of microorganisms to be rapidly determined. Results: We sequenced >93.5% of the genome of a laboratory-evolved strain of the yeast Saccharomyces cerevisiae and its ancestor at >28x depth. Both single nucleotide polymorphisms and copy number amplifications were found, with specific gains over array-based methodologies previously used to analyze these genomes. Applying a segmentation algorithm to quantify structural changes, we determined the approximate genomic boundaries of a 5x gene amplification. These boundaries guided the recovery of breakpoint sequences, which provide insights into the nature of a complex genomic rearrangement. Conclusions: This study suggests that whole-genome sequencing can provide a rapid approach to uncover the genetic basis of evolutionary adaptations, with further applications in the study of laboratory selections and mutagenesis screens. In addition, we show how single-end, short read sequencing data can provide detailed information about structural rearrangements, and generate predictions about the genomic features and processes that underlie genome plasticity.

关键词： Read Depth Parental Genome Ancestor Genome circular binary segmentation Copy Number Amplification

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High resolution discovery and confirmation of copy number variants in 90 Yoruba Nigerians

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GENOME BIOLOGY 2009年第11期10卷 R125-R125页

作者： Matsuzaki, Hajime Wang, Pei-Hua Hu, Jing Rava, Rich Fu, Glenn K. Affymetrix Inc Santa Clara CA 95051 USA

Background: Copy number variants (CNVs) account for a large proportion of genetic variation in the genome. The initial discoveries of long (> 100 kb) CNVs in normal healthy individuals were made on BAC arrays and low resolution oligonucleotide arrays. Subsequent studies that used higher resolution microarrays and SNP genotyping arrays detected the presence of large numbers of CNVs that are < 100 kb, with median lengths of approximately 10 kb. More recently, whole genome sequencing of individuals has revealed an abundance of shorter CNVs with lengths < 1 kb. Results: We used custom high density oligonucleotide arrays in whole-genome scans at approximately 200-bp resolution, and followed up with a localized CNV typing array at resolutions as close as 10 bp, to confirm regions from the initial genome scans, and to detect the occurrence of sample-level events at shorter CNV regions identified in recent whole-genome sequencing studies. We surveyed 90 Yoruba Nigerians from the HapMap Project, and uncovered approximately 2,700 potentially novel CNVs not previously reported in the literature having a median length of approximately 3 kb. We generated sample-level event calls in the 90 Yoruba at nearly 9,000 regions, including approximately 2,500 regions having a median length of just approximately 200 bp that represent the union of CNVs independently discovered through whole-genome sequencing of two individuals of Western European descent. Event frequencies were noticeably higher at shorter regions < 1 kb compared to longer CNVs (> 1 kb). Conclusions: As new shorter CNVs are discovered through whole-genome sequencing, high resolution microarrays offer a cost-effective means to detect the occurrence of events at these regions in large numbers of individuals in order to gain biological insights beyond the initial discovery.

关键词： Additional Data File Gain Event segmentation Analysis circular binary segmentation Event Segment

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