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1
Jordan, Barbara M. (Barbara Marie) 1975. "Genome complexity reduction for genome-wide single nucleotide polymorphism analysis." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/8319.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2002.Vita.
Includes bibliographical references.
Millions of single nucleotide polymorphisms (SNPs) have been identified in the human genome, and more are cataloged every day. The challenge now is to use these SNPs to discover the genetic risk factors underlying common and complex diseases. Efficient, large-scale genotyping methods are one necessary component of this endeavor. Current SNP genotyping techniques all rely on an initial PCR amplification of each SNP locus. Individual or low-level multiplexed PCR reactions are sufficient for genotyping a few to a few hundred different SNPs, but genome-wide linkage and association studies in humans will require thousands to tens of thousands of different SNPs, each typed on a few thousand individuals. To efficiently reach this goal, PCR techniques capable of amplifying a few hundred loci per reaction are needed. To meet this need we investigated the use of PCR-based genome complexity reduction methods for SNP genotyping. We discovered that degenerate oligonucleotide primed PCR (DOP-PCR) is capable of amplifying a specific fraction of a genome in a highly reproducible manner. The genomic sequences amplified are determined by the oligonucleotide primer's nondegenerate, 8-12 nucleotide, 3' end sequence. The amplified complexity can be varied from one to over 10,000 loci by changing the DOP-PCR primer's length and specific sequence. We collected SNPs from a human DOP-PCR that amplifies roughly 600 loci, and demonstrated that about half of the SNPs tested could be genotyped directly from the DOP-PCR product mixture, using the allele specific oligonucleotide hybridization genotyping technique.
(cont.) We investigated using the human genome sequence to electronically predict, based on DOP-PCR primer 3' end sequence, the products of DOP-PCRs. We successfully demonstrated that approximately 80% of such predicted products were in fact amplified in DOP-PCRs done with human genomic DNA. Electronic prediction of DOP-PCR products, and the SNPs contained in them from SNP databases, could provide a method to compile a set of DOP-PCRs that amplify tens of thousands of SNP loci for genome-wide scans. We also tested SNP genotyping from a mouse DOP-PCR amplifying about 200 loci, and from several Arabidopsis thaliana DOP-PCRs that amplify about 100 loci each. Half of the SNPs collected in these DOP-PCRs were also amenable to genotyping, directly from the DOP-PCR product mixtures. We identified SNPs in these DOP-PCRs by resequencing, but as more species' genomes are sequenced and more SNPs are contributed to public databases, DOP-PCR will become easier to implement in these and other model organisms. Currently, we are developing a genome-wide set of SNPs amplified in 32 DOP-PCRs for the mouse.
by Barbara M. Jordan.
Ph.D.
2
Simonson, Matthew A. "Polygenic analysis of genome-wide SNP data." Thesis, University of Colorado at Boulder, 2013. http://pqdtopen.proquest.com/#viewpdf?dispub=3562047.
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One of the central motivators behind genetic research is to understand how genetic variation relates to human health and disease. Recently, there has been a large-scale effort to find common genetic variants associated with many forms of disease and disorder using single nucleotide polymorphisms (SNPs). Several genome-wide association (GWAS) studies have successfully identified SNPs associated with phenotypes. However, the effect sizes attributed to individual variants is generally small, explaining only a very small amount of the genetic risk and heritability expected based on the estimates of family and twin studies. Several explanations exist for the inability of GWAS to find the "missing heritability."
The results of recent research appear to confirm the prediction made by population genetics theory that most complex phenotypes are highly polygenic, occasionally influenced by a few alleles of relatively large effect, and usually by several of small effect. Studies have also confirmed that common variants are only part of what contributes to the total genetic variance for most traits, indicating rare-variants may play a significant role.
This research addresses some of the most glaring weaknesses of the traditional GWAS approach through the application of methods of polygenic analysis. We apply several methods, including those that investigate the net effects of large sets of SNPs, more sophisticated approaches informed by biology rather than the purely statistical approach of GWAS, as well as methods that infer the effects of recessive rare variants.
Our results indicate that traditional GWAS is well complemented and improved upon by methods of polygenic analysis. We demonstrate that polygenic approaches can be used to significantly predict individual risk for disease, provide an unbiased estimate of a substantial proportion of the heritability for multiple phenotypes, identify sets of genes grouped into biological pathways that are enriched for associations, and finally, detect the significant influence of recessive rare variants.
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Kung, Johnny Tsun-Yi. "Genome-wide Analysis of Ctcf-RNA Interactions." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11618.
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Ctcf is a "master regulator" of the genome that plays a role in a variety of gene regulatory functions as well as in genome architecture. Evidence from studying the epigenetic process of X-chromosome inactivation suggests that, in certain cases, Ctcf might carry out its functions through interacting with RNA. Using mouse embryonic stem (ES) cells and a modified protocol for UV-crosslinking and immunoprecipitation followed by high-throughput sequencing (CLIP-seq), Ctcf is found to interact with a multitude of transcripts genome-wide, both protein-coding mRNA (or noncoding transcripts therein) as well as many long-noncoding RNA (lncRNA). Examples of the latter include both well-characterized species from imprinted loci and previously unannotated transcripts from intergenic space. RNA binding targets of Ctcf are validated by a variety of biochemical methods, and Ctcf is found to interact with RNA through its C-terminal domain, distinct from its DNA-binding zinc-finger domain. Ctcf chromatin immunoprecipitation (ChIP)-seq done in parallel reveals distinct but correlated binding of Ctcf to DNA and RNA. In addition, allelic analysis of Ctcf ChIP pattern reveals significant differences between Ctcf binding to the presumptive inactive and active X chromosomes. Together, the current work reveals a further layer of complexity to Ctcf biology by implicating a role for Ctcf-RNA interactions in its recruitment to genomic binding sites.
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Chen, Stacy Yen-chun. "Genome-wide analysis of yeast meiotic recombination landscape." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3390037.
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Barrera, Leah Ortiz-Luis. "Genome-wide mapping and analysis of mammalian promoters." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3258393.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed June 1, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 151-169).
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Barrett, Jeffrey C. "Design and analysis of genome-wide association studies." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:45790b5c-e50c-406a-bb3c-a96868b11a28.
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Despite many years of effort, linkage and candidate gene association studies have yielded disappointingly few risk loci for common human diseases such as diabetes, auto-immune disorders and cancers. Large sample sizes, increased understanding of the patterns of correlation in genetic variation, and plunging genotyping costs have enabled genome-wide association studies, which have good power to detect common risk alleles of modest effect. I present an evaluation of SNP choice in study design and show that overall, despite substantial differences in genotyping technologies, marker selection strategies and number of markers assayed, the first generation platforms all offer good levels of genome coverage (∼ 70%). I next describe the largest such project undertaken to date, the Wellcome Trust Case Control Consortium, which consisted of 2000 cases from each of seven common diseases and 3000 shared controls. It identified nearly two dozen new associations. I demonstrate the importance of careful data quality control, including both standard and unorthodox analyses. I next focus on the association results therein for Crohn’s disease. I present a replication experiment in over 1000 additional Crohn’s patients which unambiguously confirmed six previously published loci and four new loci. Next I describe, in a general context, several issues impeding the combination of genome-wide scans, including data annotation, population structure and differences in genotyping platform. Each of these problems is shown to be tractable with available methods, provided that these methods are applied prudently. I present the results of a meta-analysis of three genome-wide scans for Crohn’s disease. The data showed a striking excess of significant associations, and a replication experiment involving over 4000 independent Crohn’s patients verified twenty new risk loci. Finally, I discuss the early success of genome-wide association and its consequences for further understanding the biology of human disease.
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Nilsson, Emil. "Genome wide methylation analysis and obesity related traits." Doctoral thesis, Uppsala universitet, Institutionen för neurovetenskap, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-248685.
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The most studied form of epigenetics is DNA methylation and several studies have investigated the link between the methylome and body weight. In paper I we analyzed the methylation profile of whole blood in 46 subjects measured with Illumina 27K chip. We provide evidence that obesity influences age driven epigenetic changes. These identified markers may prove to be valuable biomarkers for the understanding of the molecular basis of aging, obesity and associated diseases. In paper II we studied the effect of bariatric surgery, and subsequent weight loss, on methylation and relating this to normal weight controls. In paper II we found 115 promoters had altered methylation after surgery. Among these promoters, an enrichment for genes involved in metabolic processes was found (n=36, p<0.05). In addition, these 51 promoters was more similar after surgery to that of normal-weight controls, than it had been at baseline (p<0.0001). One of the major comorbidities of severe obesity is obstructive sleep apnea and lack of sleep is highly correlated with obesity. Paper III shows how acute sleep deprivation increases portion size and affects food choice in 16 young men. In paper VI, whole genome DNA methylation profiles of whole blood was assessed following both conditions by the Illumina 450K methylation in the same trial as in paper III. This paper shows how sleep deprivation affects DNA methylation profiles of whole blood in a manner both dependent and independent on monocyte subpopulations. Hypothesis free genome wide analysis revealed differential methylation in ING5, a gene previously known to be differentially expressed in sleep deprivation.
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Lin, Yu-fei. "Genome-wide analysis of Propionibacterium acnes gene regulation." Thesis, University of Leeds, 2013. http://etheses.whiterose.ac.uk/15231/.
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Sequencing of the genome of Propionibacterium acnes produced a catalogue of genes many of which enable this organism to colonise sites in human skin and survive a range of environmental challenges. However as yet, there is little understanding of the relationships and interactions between genes that give rise to an organism, which has major impact on human health and wellbeing as an opportunistic pathogen that causes infections beyond the skin. To provide a platform for better understanding gene regulation in P. acnes, this thesis shows using microarrays, reproducible genetic responses to external changes relevant to the skin environment in P. acnes can be studied using batch cultures. It then goes on to describe the generation of nucleotide-resolution maps of the primary and secondary transcriptome. The maps were produced by combining differential and global RNA sequencing approaches. Sites of transcriptional initiation, stable RNA processing and mRNA cleavage as well as riboswitches, small non-coding RNAs, vegetative promoters, and previously undetected genes were identified across the genome. In addition, evidence was obtained for the widespread use of leaderless mRNAs, which may be translated by specialised ribosomes. Preliminary evidence for the existence of the latter, in the form of particular ribosomal RNA processing, was obtained. The study also provided statistically robust evidence for pervasive transcription that is associated with both the sense and antisense strands of coding regions. Continuing annotation of the primary and secondary transcriptomes of pathogens will assist comparative and functional genomics approaches and may also aid the modelling of the disease process and therapeutic development.
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Yazdani, Akram. "Statistical Approaches in Genome-Wide Association Studies." Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3423743.
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Genome-wide association studies, GWAS, typically contain hundreds of thousands single nucleotide polymorphisms, SNPs, genotyped for few numbers of samples. The aim of these studies is to identify regions harboring SNPs or to predict the outcomes of interest. Since the number of predictors in the GWAS far exceeds the number of samples, it is impossible to analyze the data with classical statistical methods. In the current GWAS, the widely applied methods are based on single marker analysis that does assess association of each SNP with the complex traits independently. Because of the low power of this analysis for detecting true association, simultaneous analysis has recently received more attention. The new statistical methods for simultaneous analysis in high dimensional settings have a limitation of disparity between the number of predictors and the number of samples. Therefore, reducing the dimensionality of the set of SNPs is required.
This thesis reviews single marker analysis and simultaneous analysis with a focus on Bayesian methods. It addresses the weaknesses of these approaches with reference to recent literature and illustrating simulation studies. To bypass these problems, we first attempt to reduce dimension of the set of SNPs with random projection technique. Since this method does not improve the predictive performance of the model, we present a new two-stage approach that is a hybrid method of single and simultaneous analyses. This full Bayesian approach selects the most promising SNPs in the first stage by evaluating the impact of each marker independently. In the second stage, we develop a hierarchical Bayesian model to analyze the impact of selected markers simultaneously. The model that accounts for related samples places the local-global shrinkage prior on marker effects in order to shrink small effects to zero while keeping large effects relatively large. The prior specification on marker effects, which is hierarchical representation of generalized double Pareto, improves the predictive performance. Finally, we represent the result of real SNP-data analysis through single-maker study and the new two-stage approach.Lo Studio di Associazione Genome-Wide, GWAS, tipicamente comprende centinaia di migliaia di polimorfismi a singolo nucleotide, SNPs, genotipizzati per pochi campioni. L'obiettivo di tale studio consiste nell'individuare le regioni cruciali SNPs e prevedere gli esiti di una variabile risposta. Dal momento che il numero di predittori è di gran lunga superiore al numero di campioni, non è possibile condurre l'analisi dei dati con metodi statistici classici. GWAS attuali, i metodi negli maggiormente utilizzati si basano sull'analisi a marcatore unico, che valuta indipendentemente l'associazione di ogni SNP con i tratti complessi. A causa della bassa potenza dell'analisi a marcatore unico nel rilevamento delle associazioni reali, l'analisi simultanea ha recentemente ottenuto più attenzione. I recenti metodi per l'analisi simultanea nel multidimensionale hanno una limitazione sulla disparità tra il numero di predittori e il numero di campioni. Pertanto, è necessario ridurre la dimensionalità dell'insieme di SNPs. Questa tesi fornisce una panoramica dell'analisi a marcatore singolo e dell'analisi simultanea, focalizzandosi su metodi Bayesiani. Vengono discussi i limiti di tali approcci in relazione ai GWAS, con riferimento alla letteratura recente e utilizzando studi di simulazione. Per superare tali problemi, si è cercato di ridurre la dimensione dell'insieme di SNPs con una tecnica a proiezione casuale. Poiché questo approccio non comporta miglioramenti nella accuratezza predittiva del modello, viene quindi proposto un approccio in due fasi, che risulta essere un metodo ibrido di analisi singola e simultanea. Tale approccio, completamente Bayesiano, seleziona gli SNPs più promettenti nella prima fase valutando l'impatto di ogni marcatore indipendentemente. Nella seconda fase, viene sviluppato un modello gerarchico Bayesiano per analizzare contemporaneamente l'impatto degli indicatori selezionati. Il modello che considera i campioni correlati pone una priori locale-globale ristretta sugli effetti dei marcatori. Tale prior riduce a zero gli effetti piccoli, mentre mantiene gli effetti più grandi relativamente grandi. Le priori specificate sugli effetti dei marcatori sono rappresentazioni gerarchiche della distribuzione Pareto doppia; queste a priori migliorano le prestazioni predittive del modello. Infine, nella tesi vengono riportati i risultati dell'analisi su dati reali di SNP basate sullo studio a marcatore singolo e sul nuovo approccio a due stadi.
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Schleiermacher, Chris. "Algorithmic support for PCR and genome wide repeat analysis." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=963799495.
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Burston, Helen Elizabeth. "Genome-wide analysis of endocytic recycling in S. cerevisiae." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/36387.
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The process of endocytic recycling, in which cell surface proteins are internalized and re-delivered to the plasma membrane, is essential in all eukaryotes for maintaining plasma membrane composition and regulating the surface levels of signaling receptors. The applicability of Saccharomyces cerevisiae as a model to study endocytic recycling is a subject of debate, as there appears to be critical differences between yeast and mammalian cells. For example, while clathrin and its adaptors are critical for uptake in mammals, they do not seem to be essential in yeast. Endocytic recycling has not been comprehensively studied on a genetic level in yeast, and only limited cargo have been considered, making it difficult to accurately assess the similarity between the two systems. Furthermore, the transport of SNARE proteins is poorly understood, but appears to involve specialized mechanisms. This study uses a genome-wide screening approach to systematically and quantitatively identify genes required for the endocytic recycling of the yeast SNARE protein Snc1, homologous to the mammalian VAMP2/synaptobrevin.
Endocytic defects for mutants of many yeast homologs of mammalian endocytosis genes were identified, for the first time. Significantly, a cargo-selective and partially-redundant role for clathrin and its adaptors yAP1801 and yAP1802 was identified. The lipid phosphatase Inp52 was found to mediate AP180 release from endocytic vesicles. Additionally, the previously uncharacterized protein Ldb17, homologous to the mammalian endocytic protein SPIN90, was identified as a new component of the endocytic machinery, and regulates both coat and actin dynamics at endocytic sites.
Factors regulating Snc1 recycling were also identified, including the variant clathrin adaptor AP-1R. This is the first reported function for this complex. The previously uncharacterized protein Ima1 was found to be a putative enzyme that specifically binds to AP-1R, and may have activity related to AP-1R function.
Overall, this study demonstrates that endocytic recycling in yeast and mammals is more similar than previously appreciated, and identifies new factors in this process. Furthermore, it raises awareness of the degree of cargo-selectivity underlying this pathway, and demonstrates quantitative methods that can be further applied to future studies in both systems.
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Ridley, Andrew James. "Genome wide analysis of dna repair by expression profiling." Thesis, Cardiff University, 2006. http://orca.cf.ac.uk/56167/.
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Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are syndromes characterised by defects iqf nucleotide excision repair (NER), they can be distinguished by contrasting clinical manifestations. Although the genes responsible for XP and CShave been identified, the precise molecular roles of the normal proteins remains poorly understood. In the present study, primary dermal fibroblasts derived from patients assigned to XP complementation group C (XP-C XP8CA) and CS type A (CS-A CS3BE) were characterised. Patient XP8CA was homozygous for a 2 bp TG deletion in the XPC gene at codon 547 resulting in a premature termination at position 572, while patient CS3BE was a compound heterozygote for a 37G>T (E13X) and a novel 479C>T (A 160V) mutation in CKNl, the jene that encodes the CSA protein. Permanent XP-C and CS-A cell lines were established by transducing primary XP8CA and CS3BE fibroblasts with a retroviral vector, expressing the catalytic subunit of telomerase, hTERT. The reconstitition of telomerase activity resulted in: (1) the preservation of the primary NER capabilities (2) an extension of proliferative lifespan (3) maintenance of the p53/p21WAF/CIPI and pRb/pl6INK4A tumour suppressor pathways. Using microarrays, the UV-induced global transcriptional response of telomerised XP-C ajd CS-A fibroblasts was characterised. The data indicate that UV-irradiation resulted in the differential regulation of a diverse range of cellular responses such as transcription, cell cycle arrest, DNA repair and apoptosis. Additionally, cell type-specific signatures were observed in telomerised XP-C and CS-A fibroblasts. The utility of RNAi was also demonstrated by transiently ablating XPC of CSA function in telomerised repair competent (MRC-5) fibroblasts, and a stable, permanent mutant was constructed by retrovirally transducing the telomerised CS-A cell line with an PC-specific shRNA construct. Thus, permanent and stable telomerase-immortalised XP-C and CS-A cell lines have been established and partially characterised at both the genetic and molecular level, so providing in vitro models for investigating NER.
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Parisi, Rosa. "Multi-locus statistical analysis of genome-wide association studies." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.535123.
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Drechsel, D. "Genome-wide analysis of two transcriptional programmes of neurogenesis." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1343935/.
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Transcription factors (TFs) of the basic helix-loop-helix (bHLH) family, so called 'proneural proteins', are key regulators of neuron generation in mammals. During embryonic development, Ascl1/Mash1 and Neurogenin2, the two main proneural factors in the mammalian CNS, activate programmes of neuronal differentiation that control the generation of inhibitory and excitatory neuronal populations in the arising forebrain. The cellular functions of these TFs during neurogenesis are well understood. Yet, the identity and overlap of their targets, and how these are regulated, has not been addressed in depth. Here, we introduce an in vitro model that allows studying neurogenesis downstream of the proneural TF Mash1/Ascl1 and Neurogenin2 in a temporally specific manner. Ascl1/Mash1 and Neurogenin2, fused to the modified ligand-binding domain of the estrogen receptor (ERT2), were expressed in a neural stem cell line, NS5. In the presence of the ERT2-ligand, 4-hydroxytamoxifen (4-0HT), these inducible proneural-fusion constructs are able to bind their targets and induce gene expression. A retroviral transgene delivery system with a selection marker allowed us to generate large, homogenous cultures of NS cells that can be induced to undergo Ascl1/Mash1 and Ngn2- specific neuronal differentiation in a synchronous manner. A combination of time-course expression analysis after proneural Gain-of-Function (GoF) and localization analysis of genomic proneural binding sites using genome-wide approaches allowed, firstly, to describe and compare the gene expression programme induced by Ascl1/Mash1 and Neurogenin2 in NS5 cells in a time-specific manner, and secondly, to catalogue Ascl1/Mash1 and Ngn2 target genes along with their expression kinetics as well as their proneural-binding regulatory regions on the chromatin. An analysis of these data showed that both Ascl1/Mash1 and Neurogenin2 regulate targets with different expression kinetics i.e. early as well as late expressed genes, and up- as well as down- regulated genes. Further analyses regarding putative mechanisms of this different temporal expression patterns in Ascl1/Mash1 target genes specifically identified enriched DNA motifs and putative co-regulator binding sites around regulatory regions that relate to different expression kinetics of the corresponding genes. Additionally, binding of Mash1 close to the transcription start site, and clustering of Mash1-binding sites are related to an early onset of Mash1 target gene expression. NS5 is a neural stem cell line that expresses ventral markers. Within this biological context' this study found that Ascl1/Mash1 regulates more direct target genes than Ngn2. Nevertheless' this study identifies common molecular pathways of Ascl1/Mash1 and Neurogenin2, as well as their molecular mediators, and gives first insights into their mode of regulation. Thereby, it defines a 'core neurogenesis' programme' which includes pathways involved in neuronal migration (Lis1- and Reelin pathways), patterning (Wnt/TFG-beta pathways) or neural progenitor as well as astrogenic signaling pathways that are shut down or repressed during neurogenesis (EGF-pathway, SMAD-signalling). Further, this study identified specific programmes for Ascl1/Mash1 and Ngn2, such as a role of Ascl1/Mash1 in progenitor cell cycle regulation. Thus' this work provides a starting point to elucidate of the molecular underpinnings of the cellular common and distinct functions of Ascl1/Mash1 and Neurogenin2 during neurogenesis. It further represents a first step towards the identification of the molecular regulatory logic of the lineage determining factors proneural factors in the CNS.
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Song, Lei. "Computational Analysis of Genome-Wide DNA Copy Number Changes." Thesis, Virginia Tech, 2011. http://hdl.handle.net/10919/32462.
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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.Master of Science
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Nilsson, Johan. "Membrane protein topology : prediction, experimental mapping and genome-wide analysis /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-963-3/.
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Raistrick, Christopher A. "Genome-wide analysis of polymorphisms affecting splicing and human disease." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.551307.
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Genetic polymorphism is an integral part of hereditary disease research, and cases have been demonstrated where alleles correlate with alternative splicing in pre-mRNA. A category of polymorphisms, termed splice translational efficiency polymorphisms (STEPs, classified following a discovery of such a polymorphism in the insulin gene (INS)) affect the splicing of untranslated regions leading in cases. to differential protein expression, whilst maintaining protein quality. Through the disruption of conserved splice regulatory elements, these present an unexplored mechanism for complex disease susceptibility. Studies into the conservation of the branch point sequence have suggested a degenerate sequence and location flexibility, making the confirmation of polymorphisms that may alter a branch point difficult. Further, the correlation between polymorphisms and disease is thought to indicate functionality near the associated variant. However, determining regions that are most likely to contain the functional variant is hindered by a potential for confounding where genes are selected by physical proximity in the reference sequence, instead of genetic distance (recombination interval). This misleading inference may lead to follow-up studies exploring incorrect pathways thought to be associated with a disease or trait.
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Zhou, Hua, Jin Zhou, Eric Sobel, and Kenneth Lange. "Fast genome-wide pedigree quantitative trait loci analysis using MENDEL." BioMed Central, 2014. http://hdl.handle.net/10150/610091.
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The linkage era left a rich legacy of pedigree samples that can be used for modern genome-wide association sequencing (GWAS) or next-generation sequencing (NGS) studies. Family designs are naturally equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Unfortunately, pedigree likelihoods are notoriously hard to compute, and current software for association mapping in pedigrees is prohibitively slow in processing dense marker maps. In a recent release of the comprehensive genetic analysis software MENDEL, we implemented an ultra-fast score test for association mapping with pedigree-based GWAS or NGS study data. Our implementation (a) works for random sample data, pedigree data, or a mix of both(b) allows for covariate adjustment, including correction for population stratification
(c) accommodates both univariate and multivariate quantitative traits
and (d) allows missing values in multivariate traits. In this paper, we assess the capabilities of MENDEL on the Genetic Analysis Workshop 18 sequencing data. For instance, when jointly testing the 4 longitudinally measured diastolic blood pressure traits, it takes MENDEL less than 51 minutes on a standard laptop computer to read, quality check, and analyze a data set with 959 individuals and 8.3 million single-nucleotide polymorphisms (SNPs). Our analysis reveals association of one SNP in the q32.2 region of chromosome 1. MENDEL is freely available on http://www.genetics.ucla.edu/software webcite.
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Ridout, Kate E. "Genome-wide analysis of selection in mammals, insects and fungi." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:5a894760-9240-4e79-a50f-37547f108a00.
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Characterising and understanding factors that affect the rate of molecular evolution in proteins has played a major part in the development of evolutionary theory. The early analyses of amino acid substitutions stimulated the development of the neutral theory of molecular evolution, which later evolved into the nearly neutral theory. More recent work has lead to a better understanding of the role selection plays at the molecular level, but there is still limited understanding of how higher levels of protein organisation affect the way natural selection acts. The investigation of this question is the central aim of this thesis, which is addressed via the analysis of selective pressures in secondary protein structures in insects, mammals and fungi. The analyses for the first two groups were conducted using publically available datasets. To conduct the analyses in fungi, genome sequence data from the fungal genus Microbotryum (sequenced in our laboratory) was assembled and annotated, resulting in the development of a number of bioinformatics tools which are described here. The fungal, insect and mammalian datasets were interrogated with regard to a number of structural features, such as protein secondary structure, position of a site with regard to adaptively evolving sites, hydropathy and solvent-accessibility. These features were correlated with the signals of positive and purifying selection detected using phylogenetic maximum likelihood and Bayesian approaches. I conclude that all of the factors examined can have an effect on the rate of molecular evolution. In particular, disordered and hydrophilic regions of the protein are found to experience fewer physiochemical constraints and contain a higher proportion of adaptively evolving sites. It is also revealed that positively selected residues are ‘clustered’ together spatially, and these trends persist in the three taxa. Finally, I show that this variation in adaptive evolution is a result of both selective events and physiochemical constraint.
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Kokulapalan, Wimalanathan. "Genome-wide Computational Analysis of Chlamydomonas reinhardtii Promoters." Miami University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=miami1320638327.
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Zhao, Zhixin. "Genome-wide analysis of transcriptome dynamics in plants and algae." Miami University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=miami1385672751.
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Obama, Kazutaka. "Genome-wide analysis of gene expression in human intrahepatic cholangiocarcinoma." Kyoto University, 2006. http://hdl.handle.net/2433/143810.
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Melamed, Esther. "Genome-wide analysis of sex chromosome dosage compensation in birds." Diss., Restricted to subscribing institutions, 2007. http://proquest.umi.com/pqdweb?did=1472152621&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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De, Carli Francesco. "Towards genome-wide, single-molecule analysis of eukaryotic DNA replication." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066600/document.
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Chez les eucaryotes, la réplication de l'ADN démarre au niveau de multiples origines activées suivant un programme précis, qui peut être analysé à l'échelle du génome sur des populations cellulaires. Cependant, l'étude de la variabilité intercellulaire, la détection d'évènements rares et la mesure de la vitesse des fourches de réplication nécessitent des analyses en molécule unique. Avec les techniques actuelles, l'ADN néosynthétisé est marqué avec des analogues de la thymidine et révélé par des anticorps fluorescents. Les molécules d'intérêt sont identifiées par hybridation fluorescente in situ. Ces étapes sont complexes et le débit est faible. Cette thèse développe de nouvelles méthodes de détection et d'identification des molécules d'ADN réplicatives sans anticorps et à haut débit. L'ADN est répliqué en présence d'un dUTP fluorescent, purifié puis marqué en code-barre spécifique permettant l'alignement sur le génome de référence par coupure avec une endonucléase simple brin et incorporation d'un autre dUTP fluorescent. L'ADN est ensuite coloré avec un intercalant fluorescent, le YOYO-1. Les molécules d'ADN, leurs segments néorépliqués et leurs code-barres sont observés en trois couleurs différentes par épifluorescence directe. Les segments répliqués ont une fluorescence YOYO-1 plus intense, ce qui permet de détecter les bulles de réplication sans marquage métabolique. Ces outils ont été couplés à un dispositif nanofluidique dans lequel l'ADN est conduit dans des milliers de nanocanaux et imagé automatiquement, ce qui augmente massivement le débit. L'ensemble de ces résultats ouvre la voie à la cartographie pangénomique de la réplication de l'ADN en molécule uniqueIn eukaryotes, DNA replication starts at multiple origins that are activated following a specific program. Population methods allow genome-wide analysis of DNA replication. However, single-molecule methods are required to monitor cell-to-cell variability, detect rare events and measure individual replication fork speeds. With the existing techniques, newly-synthesized DNA is labelled with thymidine analogs and revealed with fluorescent antibodies. Fibres containing a locus of interest can be identified by fluorescent in situ hybridization. These steps are complex and the throughput is low. This work proposes novel, antibody-free tools to detect replication tracts and identify the locus of origin of all DNA molecules at much higher throughput. DNA replicated in the presence of a fluorescent dUTP was purified and specifically barcoded by using a nicking endonuclease, followed by limited nick-translation with another fluorescent dUTP. This allowed alignment to a reference genome map. DNA was then stained with the fluorescent DNA intercalator YOYO-1. Direct epifluorescence revealed the DNA molecules, their replication tracts and their barcodes in three distinct colours. Replicated segments showed a stronger YOYO-1 fluorescence, demonstrating that replication bubbles can be directly detected without metabolic labelling. Finally, these tools were coupled to a nanofluidic device: DNA was driven into 13,000 parallel nanochannels and automatically imaged, massively increasing the throughput. Altogether, these results provide a starting point for genome-wide, single-molecule mapping of DNA replication in eukaryotic organisms
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Lienhard, Matthias [Verfasser]. "Computational Analysis of Genome-wide Methylation Enrichment Experiments / Matthias Lienhard." Berlin : Freie Universität Berlin, 2017. http://d-nb.info/1143596005/34.
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TONELLI, CLAUDIA. "GENOME-WIDE ANALYSIS OF P53-DEPENDENT PROGRAMS IN TUMOR SUPPRESSION." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/257874.
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The transcriptional programs triggered by p53 during tumor suppression and in response to DNA damage remain to be clarified. Using whole genome mapping of p53 binding and gene expression profiling, we investigated the transcriptional circuitry induced by p53 in suppressing cancer development and in response to genotoxic injury. We studied the progression of Myc-induced lymphomas in Eμ-myc transgenic mice, as well as the regression of these lymphomas following restoration of p53 function, by either pharmacological or genetic means. In parallel, we determined the p53-dependent transcriptional program in splenic cells from mice exposed to ionizing radiation. We thus expanded our understanding of the p53 response to oncogenic and genotoxic stress and identified a set of novel components of the p53 transcriptional program. Currently, we are testing the impact of these new p53 target genes on tumorigenesis using an RNA interference (RNAi)-based functional genetic screen. Altogether our data represent an extensive characterization of the p53-regulated network in response to different stimuli and will hopefully highlight new tumor suppressive mechanisms, paving the way for their therapeutic application.
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Jiang, Ruiwei. "Genome-wide analysis of DNA methylation variance in healthy human subjects." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/52977.
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DNA methylation is a type of epigenetic modification that modulates gene expression by acting as an intermediate between genes and environment; this in turn could trigger phenotypic changes with widespread implications in both disease and population models. Unlike DNA sequence, which is relatively stable and finite, DNA methylation presents itself differently in different tissues, and it is described as the sum of interactions affecting attachment of methyl groups to DNA mostly as a result of development and aging, with minor influences from stochastic variability, and environmental factors. Most studies involving DNA methylation focus on finding epigenetic changes related to pathogenicity or disease, as a result, there are certain foundational questions that remain unanswered. In order to translate the current knowledge into reliable insights, it is important to answer these questions, then standardize research methods and establish reference epigenomes. Here we begin to address this challenge through two avenues: epigenomic characterization and environmental interaction. To characterize the epigenome, we monitored the peripheral blood mononuclear cell DNA methylation levels from healthy subjects over a circadian day, a month, and under prolonged sample storage. We also investigated tissue specific variability in DNA methylation by comparing matched peripheral blood mononuclear and buccal epithelial cell samples from healthy subjects. Lastly, we analyzed the impact of diesel exhaust on the DNA methylation. We discovered that while overall DNA methylation was stable within a circadian day, certain loci demonstrated significant changes over the course of a month. Prolonged sample storage, on the other hand, had an even larger effect on DNA methylation. When we compared differences across tissues, we found that although both tissues showed extensive probe-wise variability, the specific regions and magnitude of that variability differed strongly between tissues. Lastly, in light of environmental influences, we observed that DNA methylation was sensitive to even short-term exposure to diesel exhaust, and we identified associated CpG sites across the functional genome, as well as in Alu and LINE1 repetitive elements, with most of these exposure sensitive sites demonstrating loss of DNA methylation.Science, Faculty of
Graduate
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Wu, Jiejun. "Genome-wide analysis of epigenetics and alternative promoters in cancer cells." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1187019769.
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Zhang, Shaojie. "Computational methods for genome-wide non-coding RNA discovery and analysis." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3271244.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed August 13, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 98-108).
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Ng, Felicia. "Genome-wide analysis of transcriptional control of haematopoietic cell type identity." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709017.
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Wyrick, John J. (John Jason) 1974. "Genome-wide analysis of transcription factors and chromatin in S. cerevisiae." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/8308.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2002.Includes bibliographical references.
The regulation of transcription initiation is a complex phenomenon, involving DNA-binding activator and repressor proteins, histones and chromatin factors, histone-modifying enzymes, and the general transcription apparatus. Though many of the genes encoding these factors have been identified in yeast, the role they play in regulating the expression of the yeast genome was not known. Genome-wide expression analysis of mutations in the Rpbl subunit of RNA polymerase II, the Srb4 subunit of Srb/Mediator complex, and the Kin28 subunit of TFIIH demonstrated that these factors are required for the transcription of essentially all protein-coding genes in yeast. However, other components of the Srb/Mediator complex (Srb5, Med6, SrblO, Swi2), the general transcription factor TFIID (Taf145, Taf17), and the SAGA histone-modifying complex (Gcn5, Taf17) were found not to be required for the transcription of all yeast genes but for distinct subsets of genes, revealing a surprising level of gene-specific regulation by the general transcription apparatus. The packaging of histones and DNA into nucleosomes was thought to generally repress gene expression, particularly at yeast telomeres, where the Sir protein complex silences genes located in the telomeric heterochromatin. To test this model, DNA microarrays were used to monitor the effects of depleting nucleosomal histones and silencing factors in yeast. Reducing nucleosome content caused increased expression of 15% of genes, reduced expression of 10% of genes, but had surprisingly little effect on expression of the majority (75%) of yeast genes.
(cont.) Telomere-proximal genes were derepressed over regions extending 20 kb from telomere ends, well beyond the extent of Sir protein binding and the effects resulting from loss of Sir function. These results indicate that histones make Sir-independent contributions to telomeric silencing, and that the role of histones located elsewhere in chromosomes is gene specific To map the in vivo binding sites of transcription factors, a new technique-genome-wide location analysis-was developed. Genome-wide location and expression analysis was used to identify the target genes of the yeast activator proteins Gal4 and Ste 12. All of the known targets for these two activators were confirmed, and new target genes in multiple functional pathways were identified.
by John J. Wyrick.
Ph.D.
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Iotchkova, Valentina Valentinova. "Bayesian methods for multivariate phenotype analysis in genome-wide association studies." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:66fd61e1-a6e3-4e91-959b-31a3ec88967c.
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Most genome-wide association studies search for genetic variants associated to a single trait of interest, despite the main interest usually being the understanding of a complex genotype-phenotype network. Furthermore, many studies collect data on multiple phenotypes, each measuring a different aspect of the biological system under consideration, therefore it can often make sense to jointly analyze the phenotypes. However this is rarely the case and there is a lack of well developed methods for multiple phenotype analysis. Here we propose novel approaches for genome-wide association analysis, which scan the genome one SNP at a time for association with multivariate traits. The first half of this thesis focuses on an analytic model averaging approach which bi-partitions traits into associated and unassociated, fits all such models and measures evidence of association using a Bayes factor. The discrete nature of the model allows very fine control of prior beliefs about which sets of traits are more likely to be jointly associated. Using simulated data we show that this method can have much greater power than simpler approaches that do not explicitly model residual correlation between traits. On real data of six hematological parameters in 3 population cohorts (KORA, UKNBS and TwinsUK) from the HaemGen consortium, this model allows us to uncover an association at the RCL locus that was not identified in the original analysis but has been validated in a much larger study. In the second half of the thesis we propose and explore the properties of models that use priors encouraging sparse solutions, in the sense that genetic effects of phenotypes are shrunk towards zero when there is little evidence of association. To do this we explore and use spike and slab (SAS) priors. All methods combine both hypothesis testing, via calculation of a Bayes factor, and model selection, which occurs implicitly via the sparsity priors. We have successfully implemented a Variational Bayesian approach to fit this model, which provides a tractable approximation to the posterior distribution, and allows us to approximate the very high-dimensional integral required for the Bayes factor calculation. This approach has a number of desirable properties. It can handle missing phenotype data, which is a real feature of most studies. It allows for both correlation due to relatedness between subjects or population structure and residual phenotype correlation. It can be viewed as a sparse Bayesian multivariate generalization of the mixed model approaches that have become popular recently in the GWAS literature. In addition, the method is computationally fast and can be applied to millions of SNPs for a large number of phenotypes. Furthermore we apply our method to 15 glycans from 3 isolated population cohorts (ORCADES, KORCULA and VIS), where we uncover association at a known locus, not identified in the original study but discovered later in a larger one. We conclude by discussing future directions.
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Mheni, Nafeti Titus. "Association Analysis and Genome-wide Selection for Early Maturity in Wheat." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417703279.
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Eleftherochorinou, Charikleia. "Pathway and gene-based analysis of genome wide association studies (GWAS)." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9175.
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My PhD thesis comprises the development and application of novel strategies to analyse genome-wide association studies (GWAS) in the context of functional pathways. I propose pathway and gene-centric methodologies as complementary tools to the conventional singlemarker analyses to mine further the GWAS hidden information. I developed the cumulative trend (CT) test statistic that assesses the cumulative genetic variation of single nucleotide polymorphisms (SNPs) of genes that interact in the same biological pathway and tests the association between a disease and the pathway as an entity. I applied this methodology to the genotypic data of the Wellcome Trust Case Control Consortium (WTCCC) study on Crohn’s disease (CD), type I diabetes (T1D), rheumatoid arthritis (RA), bipolar disorder, hypertension, type II diabetes, coronary artery disease; I identified highly significant associations between the autoimmune diseases (CD, T1D, RA) and inflammatory pathways; almost no association was identified between the same pathways and the non-inflammatory conditions. I extended my approach to a pathway-based gene stability selection methodology, which selects associated genes in the context of associated pathways. This methodology can be used to prioritise genes for follow up studies. I applied it on two GWAS of RA with different ethnic background and typed on different platforms and I demonstrated replication at the pathway, gene and in-silico functional levels. I finally extended my approach on family trios designed GWAS. I applied it on two casecontrol and family trio datasets of Kawasaki disease (KD). I explored the association between the TGF-β pathway and KD susceptibility. The involvement of this pathway in KD was further validated at the gene expression and protein levels. My proposed methodologies were tested on real datasets and provided reproducible results, which indicates rigor and robustness. I would therefore suggest their application to single or multiple GWAS as a complement to conventional single-SNP analysis.
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Heimiller, Joseph Karl. "Genome-wide analysis of splicing requirements and function through mRNA profiling." Thesis, University of Colorado at Boulder, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3607314.
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The RNA-binding proteins U2AF and PTB play important roles in gene expression in many eukaryotic species. Although U2AF and PTB have been well-studied, their functional requirements have not been investigated on a genome-wide scale. In this thesis, I analyze RNA expression data to determine the requirement of the general splicing factor U2AF in S. pombe and to identify genes misregulated in Drosophila PTB mutants. I find that many introns are insensitive to U2AF inactivation in a Schizosaccharomyces pombe U2AF59 mutant, prp2.1. Bioinformatics analysis indicates that U2AF-insensitive introns have stronger 5' splice sites and higher A/U composition. The importance of intronic nucleotide composition was further investigated using wild type RNA expression data sets. I show that nucleotide composition is a relatively important factor for regulated intron retention in a variety of species. I also analyzed the RNA-binding protein PTB using RNA Seq data to reveal genes misregulated in PTB mutants in D. melanogaster. I identify misregulation of alternative splicing in PTB mutants and putative PTB binding sites. In the PTB embryonic lethal mutant, which shows dorsoventral patterning defects, I show that dorsal fate genes are significantly up-regulated. I present a model to link PTB to dorsal closure defects. This thesis provides the first genome-wide analysis of U2AF in S. pombe and PTB in Drosophila melanogaster.
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Raborn, R. Taylor. "Genome-wide analysis of transcription initiation and promoter architecture in eukaryotes." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/4728.
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The transcriptome represents the entirety of RNA molecules within a cell or tissue at a given time. Recent advances have facilitated the production of large-scale, global interrogations of transcriptomes, finding that genomes are extensively transcribed and contain diverse classes of RNAs (Dinger et al., 2009). Information generated by high-throughput analyses of mRNA transcription start sites (TSSs) such as CAGE (Cap Analysis of Gene Expression) indicate that eukaryotic genomes have complex landscapes of transcription initiation. The TSS is important for the annotation of cis-regulatory sequences, because it provides a link between the mRNA transcript and the promoter. The patterns of TSS distributions observed within mRNA 5' end profiling studies prevent straightforward annotation of putative promoters.
To address this challenge, we developed a method to identify- on a genome-wide basis- the putative promoter, which we define by TSS distributions and designate the transcription start region (TSR). We applied a clustering method to identify and annotate TSRs within the budding yeast Saccharomyces cerevisiae using a full-length cDNA dataset (Miura et al., 2006). To validate these TSR annotations, we performed an integrative genomic analysis using multiple datasets. Our method identified TSRs at positions consistent with bona fide promoters in S. cerevisiae. In addition, using 5'RACE, we find overall agreement between computationally-defined TSRs and TSSs identified experimentally. From this analysis, we find that a significant proportion of genes exhibiting alternative promoter usage within sporulation are associated with respiration, suggesting that this is regulated on a condition-specific basis in budding yeast.
We further developed our TSS clustering method into a bioinformatics tool called TSRchitect, which identifies and annotates TSRs from large-scale TSS profiling information. TSRchitect is capable of handling both tag and sequence-based TSS information and efficiently computes TSRs from global TSS datasets on a desktop computer. We find support for TSRchitect's annotations in human from a CAGE experiment from the ENCODE (Encyclopedia of DNA Elements) project.
Finally, we use TSRchitect to identify TSRs from the transcriptomes of diverse eukaryotes. We investigated the conservation of TSRs among orthologous genes. We frequently identify multiple TSRs for a given gene, suggesting that alternative promoter usage is widespread. Overall, using TSS profiling data derived from separate tissues within mouse and human, we find that the positions of TSRs are relatively stable across tissues surveyed; however, a small fraction of genes exhibit tissue-specific differences in TSR use.
As transcriptome profiling information continues to be generated at an rapid pace, computational approaches are increasingly important. It is anticipated that the method and approach we describe within this dissertation will contribute to an improved of gene regulation and promoter architecture in eukaryotes.
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Yurkiewich, Alexander John. "An Analysis of Genome-Wide Association Studies to Produce Evidence Useful in Guiding Their Reporting and Synthesis." Thesis, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/20686.
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Introduction The present study evaluated reported methodological characteristics of GWAS, investigating relationships between reported methodological characteristics and outcomes observed.
Methods GWAS were identified from NHGRI’s catalogue of GWAS (2005 to 2009). Multivariate meta-regression models (random effects) were produced to identify the impact of reported study characteristics and the strength of relationships between the variables and outcomes.
Results The summary odds ratios for replication components of GWAS in cancer was 1.34 (95% CI 1.25, 1.43) and neuropsychiatric disorders was 1.43 (95% CI 1.30, 1.57). Heterogeneity was accounted for by nature of the control group, relationship between case/control groups, whether cases/controls were drawn from the same population, if data was a primary collection or a build on pre-existing data, if quality assurance was reported, and if the study reported power/sample size.
Conclusion Evidence supports the existence of variability in reporting, with index components demonstrating less variability than replication components in the GWAS.
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Burkert-Kautzsch, Cornelia. "Genome-wide analysis of TREX recruitment and analysis of Rpb1 ubiquitylation upon transcriptional impairment." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-181627.
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Wallin, Erik. "Theoretical studies of Membrane Proteins : Properties, Prediction Methods and Genome-wide analysis." Doctoral thesis, Stockholm : Univ, 1999. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-30.
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Carignano, Alberto. "Genome wide analysis of differentially expressed systems : an application to circadian networks." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708703.
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Mattison, Jenny. "Analysis of genome-wide, cancer-associated mutation datasets in mouse and human." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611118.
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Menghi, F. "Genome-wide analysis of gene expression and alternative splicing in human medulloblastoma." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/642570/.
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Medulloblastoma is a malignant embryonal tumour of the cerebellum which most commonly affects children. A subset of tumours is thought to arise from cerebellar granule cell precursors (GCPs) that fail to undergo normal neuronal development, following the hyper-activation of the Sonic hedgehog (Shh) signalling pathway. To identify candidate genes that might be important for medulloblastoma pathogenesis, I investigated patterns of gene expression and alternative splicing in 14 paediatric medulloblastoma and five normal cerebellar samples using Affymetrix Human Exon arrays. Statistical analysis of the gene expression data identified a group of medulloblastomas with a molecular signature of Shh pathway activation. These tumours showed higher expression levels of genes involved in spindle formation, cytokines, and cell cycle regulation. Further studies using an in vitro mouse GCP cell culture model, in which Shh is necessary for the maintenance of the progenitor state, showed that a selection of candidate genes was also over-expressed when GCPs were cultured in the presence of Shh, as compared to control cells, as well as in human medulloblastoma cell lines. Ongoing and future in vitro experiments will investigate the potential role of candidate genes in sustaining the growth of precursor and tumour cells. Exon-level analysis of gene expression showed that abnormal expression of different transcript variants is likely to occur in medulloblastoma. I selected several examples of differential exon usage and validated these using an independent set of normal and tumour specimens. Tumour-associated splicing alterations were highly consistent, enabling clear separation of normal and cancer samples and in some cases of different medulloblastoma molecular subgroups. Interestingly, Shh-treated GCPs recapitulated the splicing patterns observed in the tumour samples for six out of the eight genes analysed, suggesting that the preferential expression of specific transcript forms is regulated during normal cerebellar development. The possible relationship between inappropriate splicing and medulloblastoma pathogenesis will be the subject of future investigation.
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Teixeira, Pedro Filipe de Sá. "Genome wide analysis of antibiotic and metal resistance in Pseudomonas and Chromobacterium." Master's thesis, Universidade de Aveiro, 2016. http://hdl.handle.net/10773/21188.
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Mestrado BiotecnologiaAtualmente, a resistência a antibióticos constitui uma grande ameaça para a saúde pública, reconhecida globalmente. O uso excessivo e incorreto de antibióticos é considerado um problema sério que contribui para o aparecimento de bactérias resistentes responsáveis pelo aumento da taxa de mortalidade de pacientes infetados. Para além disso, a contaminação ambiental com estes compostos é também considerada um factor potenciador do aumento da prevalência de resistência a antibióticos. O objetivo deste estudo foi analisar o perfil de resistência e avaliar a co-seleção para características de resistência a antibióticos e metais em isolados ambientais de Pseudomonas e Chromobacterium utilizando uma estratégia de sequenciação dos genomas. Para isso, os genomas dos isolados foram sequenciados e a identificação destes foi confirmada através de uma análise filogenética baseada na sequencia de marcadores moleculares. As características fenotípicas obtidas foram consistentes com a afiliação P. aeruginosa e C. haemolyticum. A análise do genoma efectuada com base em várias ferramentas bioinformáticas permitiu a identificação de genes provavelmente envolvidos na resistência a antibióticos β-lactâmicos , aminoglicosídeos, cloranfenicol e polimixinas. Vários determinantes genéticos associados a sistemas de fluxo responsáveis pela expulsão de vários antibióticos foram também detectados. Determinantes génicos que contribuem para a motilidade destes genes foram também identificados, como por exemplo integrases, relaxases, transposases e recombinases . Os resultados obtidos mostram que ambos isolados P. aeruginosa E67 e C. haemolyticum IR17 possuem um vasto arsenal de determinantes de resistência codificados no seu genoma, e que no caso do isolado de Pseudomonas, provavelmente contribuem para a sua sobrevivência num ecossistema altamente poluído. Para além disso, alguns destes genes encontram-se associados a estruturas móveis, o que enfatiza o contributo destas plataformas no desenvolvimento de fenótipos de multirresistência. Desta forma, este trabalho possibilitou um avanço no conhecimento global do resistoma destas duas espécies, reforçando o interesse em estudar isolados ambientais que podem conter mecanismos de resistência com relevância clínica.
Nowadays, antibiotic resistance is a well-acknowledged global health problem. The overuse and misuse of antibiotics is considered to be a serious threat that contributes to the appearance of clinically relevant resistant bacteria responsible for the increase of infected patients mortality rates. Furthermore, the environmental contamination with these compounds is also considered an enhancer factor to the increase the antibiotic resistance prevalence. The aim of this study is to analyse the resistance profile and to assess coselection for antibiotic and metal resistance traits in Pseudomonas and Chromobacterium environmental isolates using a WGS approach. To do this, the isolates genomes were sequenced and the species identification thereof was confirmed by phylogenetic analysis based on the sequence of molecular markers. The phenotypic characteristics observed were consistent with the affiliation with P. aeruginosa and C. haemolyticum. Genome analysis using several bioinformatics tools allowed identifying genes probably involved in resistance to β-lactams, aminoglycosides, chloramphenicol and polymyxins. Many genetic determinants associated to efflux systems able to export a variety of compounds were also identified. Genetic determinants contributing to the motility of genes, such as integrases, relaxases, transposases and recombinases were identified, for instance. Results show that both P. aeruginosa E67 and C. haemolyticum IR17 have a vast arsenal of resistance determinants encoded in its genome, and in the case of the Pseudomonas isolate, it probably contributes to its survival in a highly polluted ecosystem. In addition, some of these genes are associated with mobile structures, which emphasizes the contribution of these platforms in the development of multidrug resistance phenotypes. Thus, this work enabled a breakthrough in the global knowledge of the resistome of these two species, reinforcing the interest in studying environmental isolates that may contain mechanisms of resistance of clinical relevance.
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Bloxam, Leanne. "Genome wide analysis of small heat shock proteins involved in yeast ageing." Thesis, University of Liverpool, 2013. http://livrepository.liverpool.ac.uk/15873/.
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Ageing is a phenomenon common to almost all living organisms and is characterised by the accumulation of changes with time that are associated with the ever-increasing susceptibility to disease and inevitably death. The rate of ageing is species-specific, indicating a strong genetic component. It is now widely accepted that genes involved in basic cellular processes such as stress resistance, metabolic regulation and genomic stability determine longevity in divergent organisms from yeast to mammals. This suggests that there may be conserved universal mechanisms involved in ageing. Furthermore, lifespan can be increased in all these model organisms by reducing the nutrients consumed - a phenomenon known as dietary restriction (DR). Saccharomyces cerevisiae is a useful model organism in which to study ageing and has been at the forefront of recent pioneering work on the molecular mechanisms underlying lifespan extension by DR. DR can be studied by reducing the glucose concentration from the standard 2% down to 0.5% or below, or by using genetic mimics. However, the exact mechanisms of lifespan extension by dietary restriction remain unclear and highly controversial. Research in our laboratory has identified two proteins in yeast that are induced in response to DR and thus correlate with longevity. Both proteins, Hsp12 and Hsp26, belong to the small heat shock protein (sHsp) family. Previous work by the Morgan laboratory has found that Hsp12 is essential for the longevity effect of DR and have solved the structure of the protein by NMR. Further studies have revealed a genetic interaction between HSP12 and HSP26, as hsp12/hsp26Δ double knockouts show a strongly reduced mean and maximum replicative lifespan. Despite this, the hsp12/hsp26∆ double knockout is not defective in various processes associated with yeast ageing, including stress resistance, rDNA silencing or protein aggregation. To shed light on the mechanisms by which Hsp12 and Hsp26 affect longevity, we employed unbiased approaches of synthetic genetic array (SGA) and quantitative fitness analysis (QFA) to identify genetic interactions of HSP12 and HSP26 on a genome-wide scale. This involved the generation of thousands of double mutant strains and analysis of their growth under various conditions, including DR. Results from the SGA analysis have revealed genetic interactions between HSP12 and HSP26 with the regulation of transcription from RNA polymerase II and processes associated with the mitochondria and vacuoles. QFA data is still to be analysed but ultimately we hope that QFA will re-confirm the genetic interactions identified by SGA analysis. We hope both SGA analysis and QFA data will provide insight into the cellular functions of Hsp12 and Hsp26 and how these proteins affect ageing, in particular lifespan extension by DR.
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Aragam, Nagesh Ramarao. "Genome-Wide Association Analysis of Major Depressive Disorder and Its Related Phenotypes." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etd/1368.
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Major Depressive Disorder (MDD) is a complex and chronic disease that ranks fourth as cause of disability worldwide. Thirteen to 14 million adults in the U.S. are believed to have MDD and an estimated 75% attempt suicide making MDD a major public health problem. Recently several genome-wide association (GWA) studies of MDD have been reported; however, few GWA studies focus on the analysis for MDD related phenotypes such as neuroticism and age at onset of MDD. The purpose of this study is to determine risk factors for MDD, identify genome-wide genetic variants affecting neuroticism and age at onset as quantitative traits, and detect gender differences influencing neuroticism.
Bivariate and multiple logistic regression analyses were performed on 1,738 MDD cases and 1,618 non-MDD controls to determine phenotypic risk factors for MDD. Multiple linear regression analyses in PLINK software were used for GWA analyses for neuroticism and age at onset of MDD with 437,547 Single Nucleotide Polymorphisms (SNPs).
Gender (OR: 1.43; 95% CI: 1.24 - 1.64) and a family history (OR: 2.88; 95% CI: 2.48 - 3.35) were significantly associated with an increased risk of MDD, which supports the findings of prior studies. Through GWA analysis 34 SNPs were identified to be associated with neuroticism (p < 10-4). The best SNP was rs4806846 within the TMPRSS9 gene (p = 7.79 x10-6). Furthermore, 46 SNPs were found showing significant gene x gender interactions for neuroticism with p<10-4. The best SNP showing gene x gender interaction was rs2430132 (p = 5.37x10-6) in HMCN1 gene. In addition, GWA analysis showed that several SNPs within 4 genes (GPR143, ASS1P4, MXRA5 and MAGEC1/2) were significantly associated with age at onset of MDD (p < 5x10-7).
This study confirmed previous findings that MDD is associated with an increased prevalence in women (about 43% more compared to men) and is highly heritable among first degree relatives. Several novel genetic loci were identified to be associated with neuroticism and age at onset. Gender differences were found in genetic influence of neuroticism. These findings offer the potential for new insights into the pathogenesis of MDD.
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PORCU, GIAMPIERO. "Genome wide analysis of effects of protein farnesylation inhibition on saccharomyces cerevisiae." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2008. http://hdl.handle.net/2108/559.
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Farmaci anticancro basati sull’inibizione della farnesil-transferasi (FTIs) sono in grado di inibire la prenilazione di Ras e la crescita tumorale in un gran numero di tumori, come evidenziato durante gli studi preclinici. Tuttavia, se testati in studi clinici, gli FTIs hanno dimostrato di avere effetti anti-tumorali solo se usati in combinazione con altri farmaci. Nonostante una decade di studi, il meccanismo d’azione tramite cui gli FTIs agiscono sulle cellule tumorali rimane sconosciuto, tanto più che è evidente che tali farmaci agiscono su molteplici vie e varie proteine prenilate oltre a Ras.
Nel presente studio è stata determinata la risposta primaria in lievito all’ FTase Inhibitor I (FTI-I) a livello genomico, usando tale composto a concentrazioni con cui la sopravvivenza cellulare e la farnesilazione di Ras sono scarsamente modificate. Il profilo di espressione genomico di cellule wild-type evidenzia un effetto dell’ FTI-I sulla trascrizione di geni coinvolti nella regolazione della polimerizzazione e depolimerizzazione dei microtubuli, nella segregazione cromosomica, e nella resistenza multipla ai farmaci (multi drug resistance, MDR). Il profilo chimico risultante dal trattamento con FTI-I dei ceppi di lievito della banca di delezione EUROSCARF ha confermato tali risultati. In aggiunta essa implica le chinasi attivate da p-21 (PAKs) nella resistenza all’ FTI-I. Complessivamente, il presente studio sottolinea l’importanza di esaminare la risposta MDR nell’uso clinico degli FTIs e indica le chinasi PAK come target secondari da usare nella terapia degli FTIs in combinazione con altri farmaci.Anticancer agents based on inhibition of farnesyl-transferase (FTIs) inhibit Ras prenylation and tumour growth in a wide range of malignancy in preclinical studies. However, when tested in clinical trials, FTIs showed their beneficial effects only when used in combinatorial therapies. Despite a decade of studies, how FTIs promote morphological reversion remains unclear as they clearly impact multiple pathways and/or other prenylated proteins than Ras. Here, we combined genomic approaches to assess the primary yeast response to FTase inhibitor I (FTI-I) by using this compound at doses at which yeast viability and Ras farnesylation is poorly affected. Genomic expression profiling of wild-type cells show an FTI-I action in changing transcription of genes involved in microtubule polymerization/depolymerization and chromosome stability and in multi drug resistance (MDR). Chemical profiling of the EUROSCARF yeast deletion collection confirmed these data. In addition, it implicates the p-21 activated kinases (PAKs) in FTI-I resistance. Overall this study highlight the importance of carefully address the multi drug resistance response when using FTIs in clinical therapy and indicates PAKs as second target to use in combinatorial therapies.
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Salih, Hanni. "An updated object oriented bovine QTL viewer and genome-wide bovine meta-analysis." [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-2969.
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Hassanin, Ola. "Genome-wide analysis of Marek's disease virus proteins and their role in modulating the innate immune response in chickens." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4793.
Full textAbstract:
Marek’s disease virus (MDV), the causative agent of Marek’s disease in chicken, is an important oncogenic avian pathogen which leads to world-wide economic losses in the poultry industry. It targets the chicken's immune system by initially causing a lytic infection in B-lymphocytes in lymphoid organs (spleen, bursa of Fabricius and thymus), followed by a latent infection of T-lymphocytes, which may lead to tumour formation. Despite the presence of well-established vaccination programs against MDV, it is still a major concern for the poultry industry due to the emergence of more virulent strains. As MDV is also considered an excellent model for herpesvirusinduced oncogenicity and immunosuppression, a better understanding of its pathogenesis, including the functional roles of individual MDV proteins, is of both biomedical as well as economical importance. All open reading frames (ORFs) of the CVI988 vaccine strain and the RB1B virulent strain were PCR-amplified from BAC DNA and cloned into the pDONR 207 entry vector by recombinatorial cloning (Gateway® system). Subsequently, all ORFs were subcloned into the yeast-two-hybrid (Y2H) vectors pGBKT7–DEST (bait) and pGADT7-DEST (prey), as well as other expression vectors. The Y2H bait and prey vector clone collections were transformed into the yeast strains AH109 and Y187, respectively. More than 140 ORFs, or ORF fragments, were analysed against each other in a comprehensive Y2H assay. Of > 20.000 interactions tested, 435 positive interactions between 115 ORFs were observed. Several of these interactions have previously been reported in other species of herpesvirus indicating that they may be conserved within the family. A subset of the positive interactions were confirmed using co-immunoprecipitation and LUMIER pull-down assays as a second independent assay. In the second part of the project all MDV proteins were tested for their ability to inhibit the chicken interferon-alpha (chIFN-α)-induced immune response. In functional luciferase reporter assay with a chicken Mx1 promoter containing an interferon stimulated responsive element (ISRE), four MDV-encoded chIFN-α inhibitors were identified, including UL12, UL26, UL50, and Meq, the main MDV oncoprotein. Both isoforms Meq and L-Meq derived from the oncogenic and the non-oncogenic vaccine strain, respectively, similarly inhibited the interferon response in a dose-dependent way, and Meq deletion mutants revealed that the Cterminal, proline-rich transactivating domain is not required for this inhibitory effect. In transient transfection experiments, Meq induced a dose-dependent proteasomal degradation of the chicken interferon regulatory factor 7 (chIRF7), which is required for chIFN-α- induced activation of ISRE. Over-expression of chIRF7 lead to a dosedependent degradation of Meq and its accumulation in the cytoplasm, suggesting that proteasomal degradation of both Meq and chIRF-7 is linked. Consistent with these findings, MDV deletion mutant lacking both copies of the Meq gene was more sensitive to chIFN-α treatment compared to wild-type virus.
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Scott, Nigel A. "An Application of Armitage Trend Test to Genome-wide Association Studies." Digital Archive @ GSU, 2009. http://digitalarchive.gsu.edu/math_theses/74.
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Genome-wide Association (GWA) studies have become a widely used method for analyzing genetic data. It is useful in detecting associations that may exist between particular alleles and diseases of interest. This thesis investigates the dataset provided from problem 1 of the Genetic Analysis Workshop 16 (GAW 16). The dataset consists of GWA data from the North American Rheumatoid Arthritis Consortium (NARAC). The thesis attempts to determine a set of single nucleotide polymorphisms (SNP) that are associated significantly with rheumatoid arthritis. Moreover, this thesis also attempts to address the question of whether the one-sided alternative hypothesis that the minor allele is positively associated with the disease or the two-sided alternative hypothesis that the genotypes at a locus are associated with the disease is appropriate, or put another way, the question of whether examining both alternative hypotheses yield more information.
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Narayanan, Kanchana. "MAVEN: a tool for Visualization and Functional Analysis of Genome-Wide Association Studies." Cleveland, Ohio : Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1269455528.
Full textAbstract:
Thesis (Master of Sciences)--Case Western Reserve University, 2010Department of EECS - Computer and Information Sciences Title from PDF (viewed on 2010-05-25) Includes abstract Includes bibliographical references and appendices Available online via the OhioLINK ETD Center