Дисертації з теми "Mammalian genomics"
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Mikkelsen, Tarjei Sigurd 1978. "Mammalian comparative genomics and epigenomics." Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/52808.
Повний текст джерелаThis electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student submitted PDF version of thesis.
Includes bibliographical references.
The human genome sequence can be thought of as an instruction manual for our species, written and rewritten over more than a billion of years of evolution. Taking a complete inventory of our genome, dissecting its genes and their functional components, and elucidating how these genes are selectively used to establish and maintain cell types with markedly different behaviors, are key challenges of modern biology. In this thesis we present contributions to our understanding of the structure, function and evolution of the human genome. We rely on two complementary approaches. First, we study signatures of evolutionary processes that have acted on the genome using comparative sequence analysis. We generate high quality draft genome sequences of the chimpanzee, the dog and the opossum. These species share a last common ancestor with humans approximately 6 million, 80 million and 140 million years ago, respectively, and therefore provide distinct perspectives on our evolutionary history. We apply computational methods to explore the functional organization of the genome and to identify genes that contribute to shared and species-specific traits. Second, we study how the genome is bound by proteins and packaged into chromatin in distinct cell types. We develop new methods to map protein-DNA interactions and DNA methylation using single-molecule based sequencing technology. We apply these methods to identify new functional sequence elements based on characteristic chromatin signatures, and to explore the relationship between DNA sequence, chromatin and cellular state.
by Tarjei Sigurd Mikkelsen.
Ph.D.
Kiritsy, Michael C. "Functional Genomics of Mammalian Innate Immunity." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1102.
Повний текст джерелаVillanueva, Cañas José Luis 1984. "Insights into mammalian adaptive evolution through genomics data." Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/397756.
Повний текст джерелаTot i que la denominada era de la genòmica es troba encara a la seva infància, ha estat un dels principals impulsors de la biologia des del començament del segle 21. L’accés a una creixent col•lecció de genomes complets de mamífers, gràcies a les tècniques de seqüenciació massiva, ens permet explorar com la diversificació evolutiva dels gens es tradueix en les diferents adaptacions ecològiques dels diferents tàxons. La innovació apareix a l’evolució a través de la transformació o la combinació de sistemes preexistents, fins i tot, nous gens poden aparèixer a partir de regions prèviament no codificants, com s’ha demostrat recentment. Aquesta tesi s’articula al voltant d’aquests mecanismes d’innovació evolutiva. Inclou una part metodològica comuna on es proposa un mètode simple per optimitzar alineaments múltiples i avaluar-ne l’efecte en anàlisis de selecció positiva, l’exploració de l’origen i evolució de gens específics de mamífers i l’estudi de la regulació gènica en una adaptació pròpia dels mamífers (hibernació) mitjançant tècniques de seqüenciació massiva.
Cheung, Hiu Tung (Tom). "Understanding mammalian transcriptional regulation using comparative and functional genomics." Diss., Connect to online resource, 2006. 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:3207751.
Повний текст джерелаJordan, Gregory. "Analysis of alignment error and sitewise constraint in mammalian comparative genomics." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610693.
Повний текст джерелаSiepel, Adam C. "Comparative mammalian genomics : models of evolution and detection of functional elements /." Diss., Digital Dissertations Database. Restricted to UC campuses, 2005. http://uclibs.org/PID/11984.
Повний текст джерелаRatcliffe, Sarah. "Identification of a silicon-responsive gene in the mammalian genome." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610011.
Повний текст джерелаHsiao, Albert. "Comparative functional genomics of energy metabolism and insulin resistance in mammalian systems." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2005. http://wwwlib.umi.com/cr/ucsd/fullcit?p3165076.
Повний текст джерелаTitle from p. 1 of PDF file (viewed October 21, 2005) Vita. Includes bibliographical references (p. 170-175 ). Available online via UMI ProQuest Digital Dissertations.
Saini, Harleen. "Intron and Small RNA Localization in Mammalian Neurons." eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1044.
Повний текст джерелаEndo, Yoshinori. "Comparative study of mammalian evolution by genomic analyses and pluripotent stem cell technology." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263514.
Повний текст джерелаChaisson, Mark. "Combinatorial methods in computational genomics mammalian phylogenetics using microinversions and fragment assembly with short reads /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3337222.
Повний текст джерелаTitle from first page of PDF file (viewed February 6, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 151-161).
Rands, Chris M. D. "Analyses of functional sequence in mammalian and avian genomes." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:27e0ac20-eb27-423c-9493-a8a1c6cc57b8.
Повний текст джерелаBroderick, Jennifer A. "Cooperativity in Mammalian RNA Silencing: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/548.
Повний текст джерелаPalace, Samantha G. "Plague and the Defeat of Mammalian Innate Immunity: Systematic Genetic Analysis of Yersinia pestis Virulence Factors: A Dissertation." eScholarship@UMMS, 2016. http://escholarship.umassmed.edu/gsbs_diss/836.
Повний текст джерелаYau, Christopher. "Statistical methodologies for the identification of copy number variation in mammalian genomes from high-throughput genomic datasets." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504339.
Повний текст джерелаLaurie, Steven 1973. "Mutation, duplication, and selection in mammalian genomes." Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/120514.
Повний текст джерелаAquesta tesi consta d’anàlisis de genòmica comparada centrades principalment en l'evolució de les proteïnes de mamífers. Les anàlisis se centren en humans i en tres espècies de gran rellevància com a organismes model, per les quals les seqüències genòmiques són d’alta qualitat. Després d'haver investigat prèviament l'evolució de proteïnes considerant les taxes de substitució, en aquesta tesi hem explorat les insercions i delecions (indels), menys estudiades. Demostrem que existeix una correlació entre la freqüència d’indels i substitucions en la seqüència proteica, i que els indels, i en particular, les insercions, són habituals en les regions de baixa complexitat i seqüències repetitives. A més, observem que la selecció actua més fortament en contra de la incorporació d'insercions que de delecions en la seqüència codificant. D’altra banda, també pretenem analitzar detalladament el procés evolutiu després d’una duplicació gènica en rosegadors. Demostrem que, en general, hi ha un marcat augment en la taxa d'evolució després de la duplicació, que es limita a la nova còpia. I trobem evidències que aquest augment és, de vegades, impulsat per la selecció positiva, i, sovint acompanyada de canvis en el perfil d'expressió de teixits. Aquests resultats recolzen el procés de neofuncionalització després de la duplicació gènica.
Castillo, Morales Atahualpa. "Genomic signatures of neurodegeneration and the evolution of mammalian brain." Thesis, University of Bath, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.675727.
Повний текст джерелаPrakash, Ashwin. "Evolution and Function of Compositional Patterns in Mammalian Genomes." THE UNIVERSITY OF TOLEDO, 2012. http://pqdtopen.proquest.com/#viewpdf?dispub=3490731.
Повний текст джерелаWard, Michelle Claire. "The regulatory potential of repetitive elements in mammalian genomes." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648276.
Повний текст джерелаLin, Michael F. (Michael Fong-Jay). "Comparative gene identification in mammalian, fly, and fungal genomes." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/36807.
Повний текст джерелаIncludes bibliographical references (leaves 55-56).
An important step in genome interpretation is the accurate identification of protein-coding genes. One approach to gene identification is comparative analysis of the genomes of several related species, to find genes that have been conserved by natural selection over millions of years of evolution. I develop general computational methods that combine statistical analysis of genome sequence alignments with classification algorithms in order to detect the distinctive signatures of protein-coding DNA sequence evolution. I implement these methods as a software system, which I then use to identify previously unknown genes, and cast doubt on some existing gene annotations, in the genomes of the fungi Saccharomyces cerevisiae and Candida albicans, the fruit fly Drosophila melanogaster, and the human. These methods perform competitively with the best existing de novo gene identification systems, and are practically applicable to the goal of improving existing gene annotations through comparative genomics.
by Michael F. Lin.
M.Eng.
Prakash, Ashwin. "Evolution and Function of Compositional Patterns in Mammalian Genomes." University of Toledo Health Science Campus / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=mco1321301839.
Повний текст джерелаAitken, Sarah Jane. "The pathological and genomic impact of CTCF depletion in mammalian model systems." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/284403.
Повний текст джерелаClément, Yves [Verfasser]. "The evolution of base composition in mammalian genomes / Yves Clément." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1030488088/34.
Повний текст джерелаVamathevan, J. J. "Evolutionary analysis of mammalian genomes and associations to human disease." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/14733/.
Повний текст джерелаRaj, Towfique. "Molecular signatures of natural and artificial selection in mammalian genomes." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609021.
Повний текст джерелаHodges, Emily Carol. "High resolution genomic tools for the discovery of protein function in mammalian cells /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-775-8/.
Повний текст джерелаHoltom, Benjamin J. "A Paralogy Based Strategy for Identifying Regulatory Elements in Mammalian Genomes." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487255.
Повний текст джерелаDown, T. "Computational localization of promoters and transcription start sites in mammalian genomes." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598623.
Повний текст джерелаSanna, Chaitanya Ramesh. "Patterns of Two Types of Overlapping Genes in Five Mammalian Genomes." Thesis, Virginia Tech, 2006. http://hdl.handle.net/10919/43601.
Повний текст джерелаMaster of Science
Xu, Xiufeng. "Studies of mammalian mitochondrial genomes with special emphasis on the perissodactyla." Lund : Lund University, 1996. http://catalog.hathitrust.org/api/volumes/oclc/38161173.html.
Повний текст джерелаKrämer, Dorothee Charlotte Agathe. "Investigation of Mammalian Chromatin Folding at Different Genomic Length Scales using High Resolution Imaging." Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/19929.
Повний текст джерелаChromatin needs to organize gene regulation whilst fitting into the confined space of the nucleus. Chromatin organization is therefore intertwined with gene activation and silencing. In recent years many advances in the field of chromatin architecture have been made showing that chromatin is organized hierarchically. Folding occurs in subsequent units, where each level of organization contributes to the spatial compaction of DNA and gene regulation. In this dissertation different levels of 3D chromatin organization were analysed using single-cell, high-resolution imaging. On the smallest scale, the 3D organization of two neighbouring Topologically Associating Domains (TADs) at the Sox9 locus was investigated. Performing Fluorescence in situ Hybridization (FISH) in 3D and cryosectioned mouse embryonic stem cells, extensive contacts between the two neighbouring TADs across the TAD boundary were detected. Applying FISH in a cell line bearing a genomic duplication within the Sox9 locus, the occurrence of two different conformations that result from the duplication was shown. Recent evidence from GAM showed the formation of long-range, multimer contacts between distal regulatory elements. Investigating the occurrence of long-range contacts between super-enhancer TADs in single cells by FISH, showed that they establish frequent interactions at close spatial distances. Furthermore the formation of clusters containing distal super-enhancer TADs could be demonstrated, indicating the possibility of higher-order regulatory hubs between these enhancer-rich regions. Further investigation showed that super-enhancer regions form different clusters in different cell types. Finally, it was shown that super-enhancers are highly decondensed and preferentially located at splicing speckles.
Lee, Adam. "The in silico identification and analysis of ancient and recent endogenous retroviruses in mammalian genomes." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/39972.
Повний текст джерелаPelletier, Richard. "Functional genomic mapping of a centromeric mammalian origin of DNA replication and identification of its minimal functional sequence." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0021/NQ44551.pdf.
Повний текст джерелаPelletier, Richard. "Functional genomic mapping of a centromeric mammalian origin of DNA replication and identification of its minimal functional sequence." Thesis, McGill University, 1997. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35043.
Повний текст джерелаIn an attempt to define the sequence or structural elements that are important for mammalian origin function, a panel of deletion mutants of ors12 (812-bp) was generated. The deletion mutants were tested for their replication activity in vivo by the bromodeoxyuridine substitution assay, after transfection into HeLa cells, and in vitro by the DpnI resistance assay, using extracts from HeLa cells. A 215-bp internal fragment was identified as essential for the autonomous replication activity of ors12. When subcloned into the vector pML2 and similarly tested, this subfragment was capable of autonomous replication in vivo and in vitro. Several repeated sequence motifs are present in this 215-bp fragment, such as TGGG(A) and G(A)AG (repeated four times each); TTTC, AGG, and MA (repeated 3 times each); the motifs CACACA and CTCTCT, and two imperfect inverted repeats, 22-bp and 16-bp long, respectively.
Tsurkan, Sarah [Verfasser], A. Francis [Gutachter] Stewart, and Yixin [Gutachter] Zhang. "Designer Nuclease-Assisted Targeting to Engineer Mammalian Genomes / Sarah Tsurkan ; Gutachter: A. Francis Stewart, Yixin Zhang." Dresden : Technische Universität Dresden, 2018. http://d-nb.info/1226895824/34.
Повний текст джерелаCaddy, Joanne. "The non-genomic effects of the PPAR-γ ligand rosiglitazone on intracellular calcium concentrations in mammalian monocytic and smooth muscle cells". Thesis, Cardiff Metropolitan University, 2010. http://hdl.handle.net/10369/921.
Повний текст джерелаMahmood, M. "The physiological actions and cellular signaling pathways mediating the acute non-genomic effects of DHT in isolated intact mammalian skeletal muscle fibre bundles." Thesis, University of East Anglia, 2011. https://ueaeprints.uea.ac.uk/34306/.
Повний текст джерелаSoh, Ying Qi Shirleen. "The genomic and genetic basis of mammalian sexual reproduction : sequence of the mouse Y chromosome, and a gene regulatory program for meiotic prophase." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98632.
Повний текст джерелаCataloged from PDF version of thesis.
Includes bibliographical references.
Mammalian sexual reproduction requires sexual determination, sexual differentiation, and the production of haploid gametes. In this thesis, I examined the genomic evolution of the mouse Y chromosome, which instructs sexual determination, and genetic regulation of a program of gene expression for meiosis, a specialized cell cycle which gives rise to haploid gametes. Chapter 2 describes the study of the mouse Y chromosome. Contrary to popular theory that Y chromosomes should be degenerate and gene poor, we find that the mouse male-specific region of the Y chromosome (MSY) is almost entirely euchromatic and contains about 700 protein-coding genes. Almost all of these genes belong to three acquired, massively amplified gene families that have no homologs on primate MSYs but do have acquired, amplified homologs on the mouse X chromosome. We propose that lineage-specific convergent acquisition and amplification of X-Y gene families is a result of sex-linked meiotic drive. Chapter 3 describes the gene regulatory program of meiotic prophase. Meiotic prophase comprises a complex chromosomal program results in the production of haploid gametes. This must be supported by a program of gene expression via which the required genes are induced. We interrogated gene expression in fetal ovaries over time and space, and in mutants of Dazl and Stra8 - key genes required for meiotic initiation. We determined that genes are regulated in three classes. Class 1 genes are expressed independently of Stra8, class 2 genes are expressed partially independently of Stra8, and Class 3 genes are dependent on Stra8 to be expressed. All genes require Dazl to be expressed. We propose that the Stra8-independent genes may represent genes required to be expressed prior to or early during meiotic initiation. Following initiation of meiosis, we found that Stra8 is required to induce down-regulation of its own expression. We propose that induction of down-regulation of the initiating signal by itself serves to ensure timely cessation of and one-time activation of the chromosomal program of meiotic prophase.
by Ying Qi Shirleen Soh.
Ph. D.
Krämer, Dorothee Charlotte Agathe [Verfasser], Ana [Gutachter] Pombo, Petra [Gutachter] Knaus, and Markus [Gutachter] Landthaler. "Investigation of Mammalian Chromatin Folding at Different Genomic Length Scales using High Resolution Imaging / Dorothee Charlotte Agathe Krämer ; Gutachter: Ana Pombo, Petra Knaus, Markus Landthaler." Berlin : Humboldt-Universität zu Berlin, 2019. http://d-nb.info/1189145944/34.
Повний текст джерелаKrämer, Dorothee [Verfasser], Ana [Gutachter] Pombo, Petra [Gutachter] Knaus, and Markus [Gutachter] Landthaler. "Investigation of Mammalian Chromatin Folding at Different Genomic Length Scales using High Resolution Imaging / Dorothee Charlotte Agathe Krämer ; Gutachter: Ana Pombo, Petra Knaus, Markus Landthaler." Berlin : Humboldt-Universität zu Berlin, 2019. http://d-nb.info/1189145944/34.
Повний текст джерелаRein, Katrin 1983. "The MRE11 complex and EX01 collaborate to support mammalian development and the cellular responses to DNA damage." Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/384236.
Повний текст джерелаEl mantenimiento de la estabilidad del genoma es esencial para la homeostasis y para la supresión de diversas patologías que incluyen trastornos del desarrollo, el envejecimiento prematuro y el cáncer. La adecuada respuesta al daño del ADN coordina las funciones celulares originadas por la detección de lesiones, para prevenir la acumulación de inestabilidad en el genoma. El complejo MRE11 es un sensor de roturas en el ADN de doble cadena y juega un papel clave en múltiples aspectos de la señalización del daño en el ADN; incluido el inicio de la resección del ADN terminal, que es a su vez fundamental para la reparación precisa de escisiones y el mantenimiento de la horquilla de replicación. La función del complejo MRE11 precede a las funciones de la exonucleasa EXO1, la cual está implicada en la resección del ADN y en las respuestas a los daños del ADN. En esta tesis examinamos la relación genética entre el complejo MRE11 y la proteína EXO1 durante el desarrollo de células de mamífero y las respuestas celulares al daño en el ADN. Nuestro trabajo muestra que la eliminación del gen Exo1 en ratones que expresan un alelo hipomórfico de Nbs1, un miembro del complejo MRE11, conduce a un defecto severo del desarrollo embrionario, la muerte del embrión y la inestabilidad cromosómica. Aún cuando la eliminación de EXO1 no afecta significativamente la replicación o reparación del ADN ni el control de la señalización, en conjunto, nuestros resultados revelan un papel crucial de EXO1 en estas funciones cuando el complejo MRE11 está comprometido.
Xu, Meng. "Specialised transcription factories." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:a41d3243-c233-491a-916b-4e329cace434.
Повний текст джерелаBuckley, Reuben Mackenzie. "Evolution of mammalian genome architecture through retrotransposition." Thesis, 2017. http://hdl.handle.net/2440/119371.
Повний текст джерелаThesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2017
Munger, Steven Carmen. "A systems-level view of mammalian sex determination." Diss., 2010. http://hdl.handle.net/10161/3006.
Повний текст джерелаPathologies of sexual development are common in humans and reflect the precarious processes of sex determination and sexual differentiation. The gonad forms as a bipotential organ, and recent results from the Capel lab revealed that it is initially balanced between testis and ovarian fates by opposing and antagonistic signaling networks. In XY embryos, this balance is disrupted by the transient expression of the Y-linked gene, Sry, which activates genes that promote the testis pathway and oppose the ovarian pathway. While the roles of a few genes have been defined by mutation, current evidence suggests that the interactions of many genes and signaling pathways are involved in the establishment of sexual fate. For example, most cases of disorders of sexual development (DSDs) are unexplained by mutations in known sex determination genes. In addition, recent microarray studies in the mouse revealed that nearly half the transcriptome is expressed in the gonad at the time of sex determination (Embryonic day 11.5, or E11.5), and as many as 1,500 genes are expressed in a sexually dimorphic pattern at this early stage. Thus the sexual fate decision in the developing gonad likely depends on a complex network of interacting factors that converge on a critical threshold.
To begin to elucidate the transcription network topology underlying sex determination, we exploited two inbred mouse strains with well-characterized differences in sex reversal. The common inbred strain C57BL/6J (B6) is uniquely sensitive to XY male-to-female sex reversal in response to a number of genetic perturbations, while other strains, including 129S1/SvImJ (129S1) and DBA/2J (D2) are resistant to sex reversal. We hypothesized that these strain differences in gonad phenotype likely result from underlying expression differences in the gonad at the critical timepoint of E11.5. Using microarrays, we identified significant, reproducible differences in the transcriptome of the E11.5 XY gonad between B6 and 129S1 indicating that the reported sensitivity of B6 to sex reversal is consistent with a higher expression of a female-like transcriptome in B6 XY gonads. Surprisingly, a well-characterized master regulator of the testis pathway, Sox9, was found to be upregulated in the sensitive B6 background, which may serve as a compensatory mechanism to counteract the female-leaning transcriptome and activate the testis pathway in wild type B6 XY gonads.
We extended our expression analysis to a large set of F2 XY gonads from B6 and 129S1 intercrosses. From each pair of gonads, we analyzed the expression of 56 sex-associated genes by nanoliter-scale quantitative RT-PCR (qRT-PCR). The expression levels of most genes were highly variable across the F2 population, yet strong correlations among genes emerged. We employed a First-Order Conditional Independence (FOCI) algorithm to estimate the F2 coexpression network. From this unbiased analysis of XY expression data, we uncovered two subnetworks consisting of primarily male and female genes. Furthermore, we predicted roles for genes of unknown function based on their connectivity and position within the network.
To identify the genes responsible for these strain expression differences, we genotyped each F2 embryo at 128 single nucleotide polymorphisms (SNPs) located evenly throughout the 19 autosomes and X chromosome. We then employed linkage analysis to detect autosomal regions that control the expression of one or more of the 56 genes in the F2 population. These regions are termed expression quantitative trait loci, or eQTLs. We identified eQTLs for many sex-related genes, including Sry and Sox9, the key regulators of male sex determination. In addition, we identified multiple prominent trans-band eQTLs that controlled the expression of many genes. My work represents the first eQTL analysis of a developing vertebrate organ, the mouse gonad. This systems-level approach revealed the complex transcription architecture underlying sex determination, and provides a mechanistic explanation for sensitivity to sex reversal seen in some individuals.
Dissertation
"Life History Affects Cancer Gene Copy Numbers in Mammalian Genomes." Master's thesis, 2019. http://hdl.handle.net/2286/R.I.55516.
Повний текст джерелаDissertation/Thesis
Pipeline results for cancer genes
Phylogenetic regressions with correction tests
Pipeline results for housekeeping genes
Masters Thesis Biology 2019
Natarajan, Anirudh. "Uncovering the Transcription Factor Network Underlying Mammalian Sex Determination." Diss., 2014. http://hdl.handle.net/10161/8746.
Повний текст джерелаUnderstanding transcriptional regulation in development and disease is one of the central questions in modern biology. The current working model is that Transcription Factors (TFs) combinatorially bind to specific regions of the genome and drive the expression of groups of genes in a cell-type specific fashion. In organisms with large genomes, particularly mammals, TFs bind to enhancer regions that are often several kilobases away from the genes they regulate, which makes identifying the regulators of gene expression difficult. In order to overcome these obstacles and uncover transcriptional regulatory networks, we used an approach combining expression profiling and genome-wide identification of enhancers followed by motif analysis. Further, we applied these approaches to uncover the TFs important in mammalian sex determination.
Using expression data from a panel of 19 human cell lines we identified genes showing patterns of cell-type specific up-regulation, down-regulation and constitutive expression. We then utilized matched DNase-seq data to assign DNase Hypersensitivity Sites (DHSs) to each gene based on proximity. These DHSs were scanned for matches to motifs and compiled to generate scores reflecting the presence of TF binding sites (TFBSs) in each gene's putative regulatory regions. We used a sparse logistic regression classifier to classify differentially regulated groups of genes. Comparing our approach to proximal promoter regions, we discovered that using sequence features in regions of open chromatin provided significant performance improvement. Crucially, we discovered both known and novel regulators of gene expression in different cell types. For some of these TFs, we found cell-type specific footprints indicating direct binding to their cognate motifs.
The mammalian gonad is an excellent system to study cell fate determination processes and the dynamic regulation orchestrated by TFs in development. At embryonic day (E) 10.5, the bipotential gonad initiates either testis development in XY embryos, or ovarian development in XX embryos. Genetic studies over the last 3 decades have revealed about 30 genes important in this process, but there are still significant gaps in our understanding. Specifically, we do not know the network of TFs and their specific combinations that cause the rapid changes in gene expression observed during gonadal fate commitment. Further, more than half the cases of human sex reversal are as yet unexplained.
To apply the methods we developed to identify regulators of gene expression to the gonad, we took two approaches. First, we carried out a careful dissection of the transcriptional dynamics during gonad differentiation in the critical window between E11.0 and E12.0. We profiled the transcriptome at 6 equally spaced time points and developed a Hidden Markov Model to reveal the cascades of transcription that drive the differentiation of the gonad. Further, we discovered that while the ovary maintains its transcriptional state at this early stage, concurrent up- and down-regulation of hundreds of genes are orchestrated by the testis pathway. Further, we compared two different strains of mice with differential susceptibility to XY male-to-female sex reversal. This analysis revealed that in the C57BL/6J strain, the male pathway is delayed by ~5 hours, likely explaining the increased susceptibility to sex reversal in this strain. Finally, we validated the function of Lmo4, a transcriptional co-factor up-regulated in XY gonads at E11.6 in both strains. RNAi mediated knockdown of Lmo4 in primary gonadal cells led to the down-regulation of male pathway genes including key regulators such as Sox9 and Fgf9.
To find the enhancers in the XY gonad, we conducted DNase-seq in E13.5 XY supporting cells. In addition, we conducted ChIP-seq for H3K27ac, a mark correlated with active enhancer activity. Further, we conducted motif analysis to reveal novel regulators of sex determination. Our work is an important step towards combining expression and chromatin profiling data to assemble transcriptional networks and is applicable to several systems.
Dissertation
El-Mogharbel, Nisrine Abdul Karim. "Evolution of mammalian XY sex chromosomes from a bird-like ZW system." Phd thesis, 2008. http://hdl.handle.net/1885/150481.
Повний текст джерелаBadve, Abhijit. "Discovery and evolutionary dynamics of RBPs and circular RNAs in mammalian transcriptomes." Thesis, 2015. http://hdl.handle.net/1805/7820.
Повний текст джерелаRNA-binding proteins (RBPs) are vital post-transcriptional regulatory molecules in transcriptome of mammalian species. It necessitates studying their expression dynamics to extract how post-transcriptional networks work in various mammalian tissues. RNA binding proteins (RBPs) play important roles in controlling the post-transcriptional fate of RNA molecules, yet their evolutionary dynamics remains largely unknown. As expression profiles of genes encoding for RBPs can yield insights about their evolutionary trajectories on the post-transcriptional regulatory networks across species, we performed a comparative analyses of RBP expression profiles across 8 tissues (brain, cerebellum, heart, lung, liver, lung, skeletal muscle, testis) in 11 mammals (human, chimpanzee, gorilla, orangutan, macaque, rat, mouse, platypus, opossum, cow) and chicken & frog (evolutionary outgroups). Noticeably, orthologous gene expression profiles suggest a significantly higher expression level for RBPs than their non-RBP gene counterparts, which include other protein-coding and non-coding genes, across all the mammalian tissues studied here. This trend is significant irrespective of the tissue and species being compared, though RBP gene expression distribution patterns were found to be generally diverse in nature. Our analysis also shows that RBPs are expressed at a significantly lower level in human and mouse tissues compared to their expression levels in equivalent tissues in other mammals: chimpanzee, orangutan, rat, etc., which are all likely exposed to diverse natural habitats and ecological settings compared to more stable ecological environment humans and mice might have been exposed, thus reducing the need for complex and extensive post-transcriptional control. Further analysis of the similarity of orthologous RBP expression profiles between all pairs of tissue-mammal combinations clearly showed the grouping of RBP expression profiles across tissues in a given mammal, in contrast to the clustering of expression profiles for non-RBPs, which frequently grouped equivalent tissues across diverse mammalian species together, suggesting a significant evolution of RBPs expression after speciation events. Calculation of species specificity indices (SSIs) for RBPs across various tissues, to identify those that exhibited restricted expression to few mammals, revealed that about 30% of the RBPs are species-specific in at least one tissue studied here, with lung, liver, kidney & testis exhibiting a significantly higher proportion of species specifically expressed RBPs. We conducted a differential expression analysis of RBPs in human, mouse and chicken tissues to study the evolution of expression levels in recently evolved species (i.e., humans and mice) than evolutionarily-distant species (i.e., chickens). We identified more than 50% of the orthologous RBPs to be differentially expressed in at least one tissue, compared between human and mouse, but not so between human and an outgroup chicken, in which RBP expression levels are relatively conserved. Among the studied tissues (brain, liver and kidney) showed a higher fraction of differentially expressed RBPs, which may suggest hyper- regulatory activities by RBPs in these tissues with species evolution. Overall, this study forms a foundation for understanding the evolution of expression levels of RBPs in mammals, facilitating a snapshot of the wiring patterns of post-transcriptional regulatory networks in mammalian genomes. In our second study, we focused on elucidating novel features of post-transcriptional regulatory molecules called as circRNA from LongPolyA RNA-sequence data. The debate over presence of nonlinear exon splicing such as exon-shuffling or formation of circularized forms has finally come to an end as numerous repertoires have shown of their occurrence and presence through transcriptomic analyses. It is evident from previous studies that along with consensus-site splicing non-consensus site splicing is robustly occurring in the cell. Also, in spite of applying different high-throughput approaches (both computational and experimental) to determine their abundance, the signal is consistent and strongly conforming the plausible circularization mechanisms. Earlier studies hypothesized and hence focused on the ribo-minus non-polyA RNA-sequence data to identify circular RNA structures in cell and compared their abundance levels with their linear counterparts. Thus far, the studies show their conserved nature across tissues and species also that they are not translated and preferentially are without poly (A) tail, with one to five exons long. Much of this initial work has been performed using non-polyA sequencing thus probably underestimates the abundance of circular RNAs originating from long poly (A) RNA isoforms. Our hypothesis is if the circular RNA events are not the artifact of random events, but has a structured and defined mechanism for their formation, then there would not be biases on preferential selection / leaving of polyA tails, while forming the circularized isoforms. We have applied an existing computational pipeline from earlier studies by Memczack et. al., on ENCODE cell-lines long poly (A) RNA-sequence data. With the same pipeline, we achieve a significant number of circular RNA isoforms in the data, some of which are overlapping with known circular RNA isoforms from the literature. We identified an approach and worked upon to identify the precise structure of circular RNA, which is not plausible from the existing computational approaches. We aim to study their expression profiles in normal and cancer cell-lines, and see if there exists any pattern and functional significance based on their abundance levels in the cell.
Mwangi, Sarah Wambui. "An evolutionary genomics approach towards analysis of genes implicated in transmission of trypanosomes between tsetse fly and mammalian host." Thesis, 2009. http://hdl.handle.net/11394/3407.
Повний текст джерелаHuman African trypanosomiasis is the world’s third most important parasitic disease affecting human health after malaria and schistosomiaisis. The world health organization estimates approximately 60 million people at risk in sub-Saharan Africa and up to 50,000 deaths per year caused by trypanosomiasis. Current management of human African trypanosomiasis relies on active surveillance and chemotherapy of infected patients. Efforts to develop a vaccine to immunize the human host have been hampered by antigenic variation of the parasites cell coat. The advent of the genome era has opened up opportunities for developing novel strategies for interrupting the transmission cycle of trypanosomes, specifically using any of the three players,the human host, the tsetse fly vector and/or the parasite. The human genome has been deciphered and the genomes of several trypanosome species have been sequenced. Sequencing of additional neglected trypanosome species is in progress. The tsetse fly genome is currently being sequenced as part of the genomic activities of the International Glossina genome initiative (IGGI). In an attempt to support the tsetse fly sequencing effort, expressed sequence tags (ESTs) from various tissues and developmental stages of Glossina morsitans have been generated.In this study, tsetse fly EST data was analyzed using bioinformatics approaches, focusing on transcripts encoding serpin genes implicated in the immune defenses of tsetse flies. Glossina morsitans homologues to Drosophila melanogaster serpin4, serpin5, and serpin27A and Anopheles gambiae serpin10 were identified in the tsetse fly EST contigs. Comparison of the reactive center loop of tsetse fly serpins with human α-1-antitrypsin suggests that these tsetse serpins are inhibitory. Preliminary EST clustering did not succeed in assembling 3564 Tsal encoded ESTs into one contig. In this study, these ESTs were assembled together with three published Tsal cDNAs. A total of 29 Tsal-encoded contigs were generated. An analysis of the sequence variation within the Tsal EST assembled contigs identified five single base mismatches namely A-T, T-A, G-T and T-G.Results from this study form a basis onto which genetic and biochemical experimental studies can be designed, a process that will be successfully carried out once we have a reference genome. Specifically, studies aimed at genetic modification of tsetse flies towards populations that are inhabitable to trypanosomes. Ultimately, this will supplement current vector control strategies towards elimination of human African trypanosomiasis.
Hsu, Paul W. C., Hsien-Da Huang, Sheng-Da Hsu, Li-Zen Lin, Ann-Ping Tsou, Ching-Ping Tseng, Peter F. Stadler, Stefan Washietl, and Ivo L. Hofacker. "miRNAMap: genomic maps of microRNA genes and their target genes in mammalian genomes." 2006. https://ul.qucosa.de/id/qucosa%3A32947.
Повний текст джерела