Dissertations / Theses: '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.

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Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009.
This 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.

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Kiritsy, Michael C. "Functional Genomics of Mammalian Innate Immunity." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1102.

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The breadth of genetic diversity in the mammalian immune response stands out amongst the ubiquity of variation seen in the genome, evidence that microbial infections have been a major driver of evolution. As technology has facilitated an understanding of the etiology of immunological diversity, so too has it enabled the assessment of its varied functions. Functional genomics, with its ability to assess both cause and effect, has revolutionized our understanding of fundamental biological phenomena and recalibrated our hypotheses. We build upon the model of host immunity established by rare genetic variants that are causative of immunodeficiencies, but that incompletely consider the complexities of the genome. To expand our understanding, we performed a series of forward genetic screens to identify regulators of distinct functions of the innate immune system. Our studies discovered genes with novel functions in antigen presentation and immunoregulation, including several involved in central metabolism. Studies in macrophages and dendritic cells identified mitochondrial respiration as a positive regulator of the interferon-gamma response, and cells incapable of respiration failed to activate T cells. Notably, human mutations in several of these genes are responsible for immune dysfunction. In summary, this work uses new methods in genetic engineering to systematically assess the regulation of innate immunity. Our results suggest that variation in these regulatory pathways is likely to alter immunity in states of health and disease. Thus, our work validates a new approach to identify candidate genes relevant to immune dysfunction.

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Villanueva, Cañas José Luis 1984. "Insights into mammalian adaptive evolution through genomics data." Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/397756.

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Although the genome sequencing revolution is still in its infancy, we must acknowledge it as the major driver of biology since the beginning of the 21st century. The availability of a large collection of complete mammalian genomes due to high-throughput sequencing technologies allows us to begin the exploration of how the evolutionary diversification of gene content reflects the ecological adaptations of different taxa. Novelty arises in evolution through the transformation or combination of existing systems and, as shown recently, also from scratch. This thesis is centered around these different mechanisms of evolutionary innovation. It includes a common methodological part in which we propose a simple method to optimize multiple alignments and examine its effect in positive selection analyses, the exploration of the origin and evolution of mammalian-specific genes, and the study of gene regulation in mammalian adaptations (e.g. hibernation) using high-throughput technologies.
Tot 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.

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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.

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Jordan, 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.

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Siepel, 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.

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Ratcliffe, 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.

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Hsiao, 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.

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Thesis (Ph.D.)--University of California, San Diego, 2005.
Title from p. 1 of PDF file (viewed October 21, 2005) Vita. Includes bibliographical references (p. 170-175 ). Available online via UMI ProQuest Digital Dissertations.

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Saini, Harleen. "Intron and Small RNA Localization in Mammalian Neurons." eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1044.

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RNA molecules are diverse in form and function. They include messenger RNAs (mRNAs) that are templates for proteins, splice products such as introns that can generate functional noncoding RNAs, and a slew of smaller RNAs such as transfer RNAs (tRNAs) that help decode mRNAs into proteins. RNAs can show distinct patterns of subcellular localization that play an important role in protein localization. However, RNA distribution in cells is incompletely understood, with prior studies focusing primarily on RNAs that are long (>200 nucleotides), fully processed, and polyadenylated. We examined the distribution of RNAs in neurons. Neuronal compartments can be separated by long distances and play distinct roles, raising the possibility that RNA localization is especially overt and functionally meaningful in these cells. In our exploration, we physically dissected projections from cell bodies of neurons from the rat brain and sequenced total RNA. We describe two main findings. First, we identified excised introns that are enriched in neuronal projections and confirmed their localization by single- molecule fluorescence in situ hybridization. These are a previously unknown set of circular RNAs in neuronal projections: tailless lariats that possess a non- canonical C branchpoint. Second, we observed a highly abundant population of small (20-150 nucleotide) RNAs in neuronal projections, most of which are tRNAs. For both circular introns and tRNAs, we did not observe known RNA localization signals. Thus, many types of RNA, if sufficiently stable, appear free to diffuse to distant locations, their localization perhaps aided by the movement of large organelles in the confines of neuronal projections. Our survey of RNA molecules across subcellular compartments provides a foundation for investigating the function of these molecules and the mechanisms that localize them.

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Endo, 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.

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Chaisson, 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.

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Thesis (Ph. D.)--University of California, San Diego, 2008.
Title from first page of PDF file (viewed February 6, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 151-161).

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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.

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The first draft sequence of the human genome was published over a decade ago, yet interpreting the functional importance of nucleotides in genomes is still an ongoing challenge. I took a comparative genomic approach to identify functional sequence using signatures of natural selection in DNA sequences. Mutations that are purged or propagated by selection mark sequences of significance for biological fitness. I developed and refined methods for estimating the quantity of sequence constrained with respect to insertions and deletions (indels) between two genome sequences, a quantity I termed α_selIndel. This sequence is evolving more slowly than surrounding neutral sequence due to the purging of deleterious indel variants, and thus this sequence is likely to be functional. I estimated α_selIndel between diverse mammalian and avian species pairs, and found a strong negative correlation between α_selIndel and the divergence between the species’ genome sequences. This implies that functional sequence turns over rapidly as it is lost and gained over time. I quantified the variable levels of sequence constraint, and rates of sequence turnover, for different types of human biochemically annotated element. Furthermore, I found that similar rates of functional turnover have occurred across mammalian and avian evolution. Finally, I identified positively selected amino acid residues that may be important for Darwin’s finch beak development, and found evidence of adaptively evolving reproductive proteins in the ancestral songbird lineage. Collectively these results demonstrate the wide-spread nature of lineage-specific functional sequence with implications for understanding species traits and the use of model organisms to inform human biology.

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Broderick, Jennifer A. "Cooperativity in Mammalian RNA Silencing: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/548.

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Argonaute proteins are the core component of an RNA silencing complex. The human genome encodes four Argonaute paralogs –Ago1, Ago2, Ago3 and Ago4– proteins that are guided to target mRNAs by microRNAs. More than 500 miRNAs are conserved between mammals, and each microRNA can repress hundreds of genes, regulating almost every cellular process. We still do not fully understand the molecular mechanisms by which miRNAs regulate gene expression. Although we understand many aspects of microRNA biogenesis and formation of the RNA-induced silencing complex, much less is known about the subsequent steps leading to target mRNA regulation. Mammalian microRNAs rarely have complete complementarity to their target mRNAs so, instead of endonucleolytic cleavage by Ago2, microRNAs destabilize or repress translation of target mRNAs. Here I explored the functional limits of Argonaute proteins bound to their targets directly and indirectly through microRNAs in mammalian cells. I revealed the different abilities for Argonaute proteins bound at multiple sites in a target to generate cooperativity in silencing based on the extent of pairing between the microRNA and target mRNA. Further, I harnessed the endogenous microRNA silencing mechanism to repress an mRNA that is not a direct target of the microRNA by tethering the RNA-induced silencing complex to the 3´ UTR of an mRNA. This strategy allows tissue-specific gene silencing due to the limited endogenous expression profile of the recruited microRNA. Efforts made herein further our mechanistic knowledge of microRNA-induced gene silencing in mammalian cells and advance microRNA-based strategies toward treating human disease.

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Palace, 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.

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Yersinia pestis, the causative agent of plague, specializes in causing dense bacteremia following intradermal deposition of a small number of bacteria by the bite of an infected flea. This robust invasiveness requires the ability to evade containment by the innate immune system. Of the various mechanisms employed by Y. pestis to subvert the innate immune response and to proliferate rapidly in mammalian tissue, only a few are well-characterized. Here, I present two complementary genetic analyses of Y. pestis adaptations to the mammalian environment. In the first, genome-wide fitness profiling for Y. pestis by Tn-seq demonstrates that the bacterium has adapted to overcome limitation of diverse nutrients during mammalian infection. In the second, a series of combinatorial targeted mutations disentangles apparent functional redundancy among the effectors of the Y. pestis type III secretion system, and we report that YpkA, YopT, and YopJ contribute to virulence in mice. We have also begun to investigate a novel relationship between Y. pestis and mammalian platelets, a highly abundant cell type in plasma. I present evidence that Y. pestis has evolved specific mechanisms to interfere with platelet activation, likely in order to evade immune responses and promote maintenance of bacteremia by undermining platelet thrombotic and innate immune functions. The principles guiding this work – systematic genetic analysis of complex systems, coupled with rational modification of in vitro assays to more closely mimic the in vivo environment – are a generalizable approach for increasing the efficiency of discovering new virulence determinants in bacterial pathogens.

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Yau, 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.

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Laurie, Steven 1973. "Mutation, duplication, and selection in mammalian genomes." Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/120514.

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This thesis comprises comparative genomics analyses primarily focussing on the evolution of mammalian proteins. We concentrate on three species of direct relevance as model organisms, for which high quality genome sequences are available, and human. Having previously investigated protein evolution in terms of substitution rates, here we explored less well studied insertions and deletions (indels). We show that indel and substitution frequencies are correlated at the level of protein sequence, and that indels, and in particular insertions, are elevated in regions of low-complexity and repetitive sequence. Furthermore we observe that selection acts more strongly against the incorporation of insertions than deletions in coding sequence. We also look examine in detail the process of evolution following gene duplication in rodents. We show that in general there is a marked increase in evolutionary rate following duplication, which is restricted to the new copy. We find evidence that this increase is sometimes driven by positive selection, and often accompanied by changes in tissue expression profile. These results lead support to the role of neofuntionalisation following gene duplication.
Aquesta 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.

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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.

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Due to the complex adaptive costs and benefits of large brains and large neocortical volume, mammalian species exhibit huge variation in brain size. However, the precise nature of the genomic changes accounting for these variations remains poorly understood. Using genome-wide comparative analysis of gene family size of more than 39 fully sequenced mammalian species, I studied whether changes in the number of copies of genes involved in distinct cellular and developmental functions has contributed to shaping the morphological, physiological and metabolic machinery supporting brain evolution in mammalians. My results reveal an overrepresentation of gene families displaying a positive association between GFS and level of encephalization. This bias occurs most prominently in families associated with specific biological functions, such as cell-cell signalling, chemotaxis and immune system. Moreover, I find that most gene family size variations associated with increased brain size are mostly explained by the link between neocortex ratio and gene family size variations. The results in this study suggest that variations in gene family size underlie morphological adaptations during brain evolution in mammalian lineages. Lastly, using comparative transcriptomics analysis across different human tissue types with cellular longevities ranging from 120 days to over 70 years, I set out to identify the molecular signature of long term post-mitotic cell maintenance. I found that genes down regulated in Alzheimer’s and Parkinson’s disease are significantly enriched in genes whose expression levels are associated with increased post-mitotic cellular longevity (PMCL). This holds true also for genes down regulated in Hutchinson-Gilford progeria-derived fibroblasts. The work here presented suggest that PMCL-associated genes are part of a generalized machinery of post-mitotic maintenance and functional stability in both neural and non-neural that becomes compromised in two specific neurodegenerative conditions and supports the notion of a common molecular repertoire for cell maintenance differentially engaged in different cell types with differing survival requirements.

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Prakash, Ashwin. "Evolution and Function of Compositional Patterns in Mammalian Genomes." THE UNIVERSITY OF TOLEDO, 2012. http://pqdtopen.proquest.com/#viewpdf?dispub=3490731.

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Ward, 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.

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Lin, 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.

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Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2006.
Includes 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.

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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.

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Aitken, 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.

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CCCTC-binding factor (CTCF) binds DNA, thereby helping to partition the mammalian genome into discrete structural and regulatory domains. In doing so, it insulates chromatin and fine-tunes gene activation, repression, and silencing. Complete removal of CTCF from mammalian cells causes catastrophic genomic dysregulation, most likely due to widespread collapse of 3D chromatin looping within the nucleus. In contrast, Ctcf hemizygous mice with lifelong reduction in CTCF expression are viable but have an increased incidence of spontaneous multi-lineage malignancies. In addition, CTCF is mutated in many human cancers and is thus implicated as a tumour suppressor gene. This study aimed to interrogate the genome-wide consequences of a reduced genomic concentration of Ctcf and its implications for carcinogenesis. In a genetically engineered mouse model, Ctcf hemizygous cells showed modest but robust changes in almost a thousand sites of genomic CTCF occupancy; these were enriched for lower affinity binding events with weaker evolutionary conservation across the mouse lineage. Furthermore, several hundred genes concentrated in cancer-related pathways were dysregulated due to changes in transcriptional regulation. Global chromatin structure was preserved but some loop interactions were destabilised, often around differentially expressed genes and their enhancers. Importantly, these transcriptional alterations were also seen in human cancers. These findings were then examined in a hepatocyte-specific mouse model of Ctcf hemizygosity with diethylnitrosamine-induced liver tumours. Ctcf hemizygous mice had a subtle liver-specific phenotype, although the overall tumour burden in Ctcf hemizygous and wild-type mice was the same. Using whole genome sequencing, the highly reproducible mutational signature caused by DEN exposure was characterised, revealing that Braf(V637E), orthologous to BRAF(V600E) in humans, was the predominant oncogenic driver in these liver tumours. Taken together, while Ctcf loss is partially physiologically compensated, chronic CTCF depletion dysregulates gene expression by subtly altering transcriptional regulation. This study also represents the first comprehensive genome-wide and histopathological characterisation of this commonly used liver cancer model.

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Clément, Yves [Verfasser]. "The evolution of base composition in mammalian genomes / Yves Clément." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1030488088/34.

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Vamathevan, 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/.

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Statistical models of DNA sequence evolution for analysing protein-coding genes can be used to estimate rates of molecular evolution and to detect signals of natural selection. Genes that have undergone positive selection during evolution are indicative of functional adaptations that drive species differences. Genes that underwent positive selection during the evolution of humans and four mammals used to model human diseases (mouse, rat, chimpanzee and dog) were identified, using maximum likelihood methods. I show that genes under positive selection during human evolution are implicated in diseases such as epithelial cancers, schizophrenia, autoimmune diseases and Alzheimer’s disease. Comparisons of humans with great apes have shown such diseases to display biomedical disease differences, such as varying degrees of pathology, differing symptomatology or rates of incidence. The chimpanzee lineage was found to have more adaptive genes than any of the other lineages. In addition, evidence was found to support the hypothesis that positively selected genes tend to interact with each other. This is the first such evidence to be detected among mammalian genes and may be important in identifying molecular pathways causative of species differences. The genome scan analysis spurred an in*depth evolutionary analysis of the nuclear receptors, a family of transcription factors. 12 of the 48 nuclear receptors were found to be under positive selection in mammalia. The androgen receptor was found to have undergone positive selection along the human lineage. Positively selected sites were found to be present in the major activation domain, which has implications for ligand recognition and binding. Studying the evolution of genes which are associated with biomedical disease differences between species is an important way to gain insight into the molecular causes of diseases and may provide a method to predict when animal models do not mirror human biology.

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Raj, 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.

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Hodges, 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/.

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Holtom, 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.

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The massive advancements in genomics over recent years has not only provided scope to examine what is shared between the genomes of multiple species but also a unique opportunity to investigate that which is responsible for the differences between species of interest. By comparing the proteomes of two species, certain genes can be' clustered and defined as 'inparalogs' - duplicated genes which are respectively unique to each of the species in question having arisen at a time-point subsequent to the speciation event that separated the two lineages in question. Here I report on several analyses that make use of inparalogous genes identified in the mouse genome with' reference to its close relative the rat. Firstly I describe the implementation of a novel .. ) investigative procedure that identifies regions of intragenomic conservation within the upstream sequences of inparalogous gene clusters and report upon the level of resolution that this approach offers with respect to identifying regulatory elements in genomic sequences. In addition to this study, I also describe an investigation into the density of interspersed repeat elements observed in the neighbourhood of inparalogous mouse genes which revealed a marked enrichment of long interspersed nuclear elements (LINEs), highlighting a possible role for these sequences in the evolution of gene duplicates in the mouse genome.

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Down, 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.

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Here, I investigate the question of identifying and annotating promoters, one of the most important regulatory signals in the genome, which mark the points where transcription is initiated, and regulate the transcription of genes. I present a new computational method, EponineTSS, which can predict transcription start sites in bulk genomic sequence data with excellent sensitivity and specificity. Unlike the existing methods, it gives an indication of the actual location of the transcription start site. Comparisons with available experimental data suggest that the positional accuracy of these predictions is very good. Results form this method are included as part of the Ensembl human genome annotation. Having located transcription start sites for genes, I also discuss the use of results from comparative genomics the estimate the extent of the fundamental promoter region upstream of the start site. I show that the extent of promoters is very variable, and that promoter size is correlated with the function of the gene for whose regulation it is responsible. Genes associated with developmental processes tend to have particularly large, and thus presumably complex, promoters, with the homeobox transcription factors among the most extreme examples. I also introduce sparse Bayesian learning, a recently developed approach to supervised machine learning which can be applied to the training of a wide range of model types, and embodies the principle of selecting the simplest possible model to explain the observed data. I demonstrate a new technique which makes sparse Bayesian learning much more scaleable, allowing it to be applied to very large and complex problems, and present a convenient, freely available Java library which provides a general-purpose implementation of this technique. This library was used here in the training of the transcription start site predictor, but has a wide range of applications in computational biology and beyond.

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Sanna, Chaitanya Ramesh. "Patterns of Two Types of Overlapping Genes in Five Mammalian Genomes." Thesis, Virginia Tech, 2006. http://hdl.handle.net/10919/43601.

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Increasing evidence suggests that overlapping genes is a common phenomenon in eukaryotic genomes too and are not restricted to prokaryotes alone. Here we determined overlapping genes in a set of orthologous genes in the genomes of human, chimp, mouse, rat, and dog and contrasted the patterns of overlapping between two principal types of overlapping genes, the same-strand-overlapping genes and different-strand-overlapping genes. The two types of overlapping genes are compared with respect to their frequencies, overlap lengths, region of overlap, and conservation of overlap in five species. Our results suggest the following: different-strand-overlaps are more common, both types show different patterns with respect to overlap lengths and regions of overlap, different-strand-overlapping genes are more evolutionarily conserved, and 3'-UTR evolution plays an important role in transitions between non-overlapping genes and overlapping genes. The thesis also presents a review of related work in terms of history, origin, types, biological significance of overlapping genes, human diseases associated with them, and their comparison in prokaryotes and eukaryotes.
Master of Science

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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.

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Krämer, 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.

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Chromatin ist ein Makromolekül, dessen Genregulation innerhalb des räumlich eingeschränkten Zellkerns organisiert werden muss. Die Genomorganisation ist eng mit Genaktivierung und Genrepression verknüpft. In den vergangenen Jahren wurde gezeigt, dass die DNA hierarchisch organisiert ist. Die Faltung läuft in aufeinander folgenden Schritten ab, wobei jede Organisationsebene sowohl zur räumlichen Komprimierung, als auch zur Genregulation beiträgt. In dieser Dissertation wurden mit Hilfe von hochauflösender Mikroskopie verschiedene Ebenen der 3D Chromatinorganisation auf Einzelzell-Basis untersucht. Auf der kleinsten Organisationsebene wurde die Struktur zweier, nebeneinander liegender topologischer Domänen (TADs) am Sox9-Lokus erforscht. Mit Hilfe von Fluoreszenz in situ Hybridisierung (FISH) in 3D Zellen, sowie Cryoschnitten in embryonalen Stammzellen von Mäusen konnten Interaktionen zwischen den benachbarten TADs festgestellt werden. FISH in Zellen mit genomischen Duplikationen, zeigte das Entstehen von zwei unterschiedlichen, durch die Duplikation entstandenen, Konformationen. Unter Verwendung von FISH wurden long-range Kontakte, die zuvor mit GAM entdeckt wurden, untersucht und es zeigte sich, dass sie häufig zwischen TADs die regulatorischen Domänen enthalten auftreten. Zudem zeigte sich die Bildung von Clustern zwischen mehreren, weit auseinander liegenden, regulatorischen Elementen. Dies lässt unter Umständen auf das Entstehen von regulatorischen Zentren zwischen diesen Enhancer-reichen Regionen schließen. Weitere Untersuchungen zeigten Veränderung der sogenannten Super-Enhancer Cluster in unterschiedlichen Zelltypen. Des Weiteren sind Super-Enhancer TADs sehr dekondensiert und wurden häufig an Splicing-Speckle Regionen vorgefunden.
Chromatin 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.

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32

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.

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Recent advances in DNA sequencing technologies have led to a vast plethora of vertebrate genomes being made available for bioinformatic analysis and investigation. This has presented retrovirologists with many new opportunities to study endogenous retroviruses (ERVs) - selfish genetic element (SGEs) endogenised within the genomic DNA of their hosts. Many of these ERVs exist as molecular fossils of past germline infections by their exogenous counterparts, representing approximately 8-10% of mammalian genomes. While the majority are thought to be inactive today, one particular retroviral group - HERV-K(HML-2) - has been implicated in recent activity. In this thesis, efficient, synergistic in silico techniques have been implemented, with which intensive, genome-wide retroviral screens were performed. This has culminated in the identification of 11 novel, insertionally polymorphic human ERVs (HERVs), belonging to the HERV-K(HML-2) lineage, in two high- coverage archaic hominid genomes. This thesis also identifies the oldest ERV described to date - orthologous across all placental mammals - estimated to have endogenised in the germline of an ancestral mammal, 128-140 million years ago. Three SGEs, found to be endogenised within this ancient ERV, have also been described and assigned a minimum age of 104 million years, making these the oldest, definitively dated SGEs. This thesis also presents a computer program for renaming all identified ERVs in vertebrate genomes, according to a newly designed nomenclature standard to be implemented globally, that aims to unambiguously catalogue all the ERVs identified, to date.

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Pelletier, 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.

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Pelletier, 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.

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The nature of origins of DNA replication in mammalians has yet to be elucidated. The localization of the initiation sites and the identification of the corresponding sequences and/or structures is important to understand the process of initiation at the molecular level. The objective of the research in this thesis is to localize the initiation site of DNA synthesis at a specific locus on the chromosomes of mammalian cells, and to characterize the minimal sequence requirements for the function of this origin of DNA replication in vivo. A genomic clone was isolated using ors12, a mammalian autonomously replicating sequence (812 bp) that was previously isolated by extrusion of African Green monkey (CV-1 cells) nascent DNA from active replication bubbles. Ors12 associates with the nuclear matrix in a cell cycle dependent manner, and is present at the centromeric region of six CV-1 cell chromosomes and that of a marker chromosome. This genomic clone was used to generate PCR primers in a region encompassing ors12, in order to amplify nascent DNA strands isolated from asynchronously growing CV-1 and African Green monkey primary kidney cells. A competitive PCR-based mapping methodology was used, and revealed that DNA replication initiates preferentially in vivo in a region colocalizing with ors12, providing evidence of its function as a bona fide chromosomal origin of DNA replication.
In 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.

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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.

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Caddy, 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.

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Thiazolidinediones such as rosiglitazone are used in the treatment of Type-2 Diabetes, and are ligands for peroxisome proliferator-activated receptor-gamma (PPARγ), a ligand-activated transcription factor that regulates expression of genes involved in glucose and lipid metabolism. However, rosiglitazone is known to exert PPARγ-independent effects alongside its classical receptor-dependent effects. This study investigated the PPARγ-independent effects of rosiglitazone on intracellular calcium (Ca2+i) signalling in cultured monocytic and vascular smooth muscle cells Rosiglitazone rapidly (5-30min) inhibited the Ca2+ sequestration activity of the ER-resident Ca2+ pump enzyme SERCA2b in a dose-dependent manner (IC50~2μM). 10μM Rosiglitazone triggered rapid increases in [Ca2+]i; however, restoration to basal levels occurred within 72h. Consequently, cell viability was not adversely affected by rosiglitazone treatment. Initiation of the unfolded protein response (UPR) was identified as the mechanism underpinning rosiglitazone's Ca2+ homeostatic restorative properties. Rosiglitazone induced alternate splicing of the UPR transcription factor XBP-1, which led to increased mRNA and protein expression of SERCA2b (shown via bioinformatics analysis to be a UPR target gene), and increased ER Ca2+-ATPase activity in rosiglitazone-treated cells. In tissue (rabbit aortic ring) samples, 10μM rosiglitazone induced transient (within 1h) non-significant losses in vasorelaxatory sensitivity to sodium nitroprusside, but extended treatment (4-24h) increased sensitivity beyond that of vehicle-treated samples. Thus, at cell and tissue levels, this data suggests that rosiglitazone initially causes increased [Ca2+]i due to inhibition of SERCA2b, but extended incubation induces - via upregulation of UPR target genes - the restoration of Ca2+ homeostasis, and possibly even improvements in function in some contexts. Clearly, the data presented in this in vitro study must be treated tentatively, and more research is needed before these potentially beneficial effects can be firmly identified as being clinically significant. Nevertheless, the data obtained here may constitute preliminary evidence that, alongside its PPARy-dependent effects, rosiglitazone may exert functional improvements on the vasculature.

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Mahmood, 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/.

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Soh, 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.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2015.
Cataloged 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.

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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.

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Krämer, 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.

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41

Rein, 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.

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The maintenance of genome stability is crucial for homeostasis, development and suppression of diverse pathologies that include developmental disorders, premature aging and cancer. The DNA damage response coordinates the appropriate cellular responses following the detection of lesions to prevent genomic instability. The MRE11 complex is a sensor of DNA double strand breaks and plays key roles in multiple aspects of the DNA damage signaling, including the initiation of DNA end resection that is critical for the accurate break repair and the replication fork maintenance. Many studies have implicated the exonuclease EXO1 in DNA resection and shown that the MRE11 complex functions upstream, but the exact influence of EXO1 on double strand break responses remain unclear. In this thesis we examine the genetic relationship between the MRE11 complex and EXO1 during mammalian development and the cellular responses to DNA damage. Our work shows that the deletion of Exo1 in mice expressing a hypomorphic allele of Nbs1, a member of the MRE11 complex, leads to severe developmental defects, embryonic death and chromosomal instability. While EXO1 deficiency does not strongly affect DNA replication, DNA repair or checkpoint signaling in normal cells, our results reveal a crucial role for EXO1 in these functions when the MRE11 complex is compromised.
El 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.

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Xu, Meng. "Specialised transcription factories." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:a41d3243-c233-491a-916b-4e329cace434.

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The intimate relationship between the higher-order chromatin organisation and the regulation of gene expression is increasingly attracting attention in the scientific community. Thanks to high-resolution microscopy, genome-wide molecular biology tools (3C, ChIP-on-chip), and bioinformatics, detailed structures of chromatin loops, territories, and nuclear domains are gradually emerging. However, to fully reveal a comprehensive map of nuclear organisation, some fundamental questions remain to be answered in order to fit all the pieces of the jigsaw together. The underlying mechanisms, precisely organising the interaction of the different parts of chromatin need to be understood. Previous work in our lab hypothesised and verified the “transcription factory” model for the organisation of mammalian genomes. It is widely assumed that active polymerases track along their templates as they make RNA. However, after allowing engaged polymerases to extend their transcripts in tagged precursors (e.g., Br-U or Br-UTP), and immunolabelling the now-tagged nascent RNA, active transcription units are found to be clustered in nuclei, in small and numerous sites we call “transcription factories”. Previous work suggested the transcription machinery acts both as an enzyme as well as a molecular tie that maintains chromatin loops, and the different classes of polymerases are concentrated in their own dedicated factories. This thesis aims to further characterise transcription factories. Different genes are transcribed by different classes of RNA polymerase (i.e., I, II, or III), and the resulting transcripts are processed differently (e.g., some are capped, others spliced). Do factories specialise in transcribing particular subsets of genes? This thesis developed a method using replicating minichromosomes as probes to examine whether transcription occurs in factories, and whether factories specialise in transcribing particular sets of genes. Plasmids encoding the SV40 origin of replication are transfected into COS-7 cells, where they are assembled into minichromosomes. Using RNA fluorescence in situ hybridisation (FISH), sites where minichromosomes are transcribed are visualised as discrete foci, which specialise in transcribing different groups of genes. Polymerases I, II, and III units have their own dedicated factories, and different polymerase II promoters and the presence of an intron determine the nuclear location of transcription. Using chromosome conformation capture (3C), minichromosomes with similar promoters are found in close proximity. They are also found close to similar endogenous promoters and so are likely to share factories with them. In the second part of this thesis, I used RNA FISH to confirm results obtained by tiling microarrays. Addition of tumour necrosis factor alpha (TNF alpha) to human umbilical vein endothelial cells induces an inflammatory response and the transcription of a selected sub-set of genes. My collaborators used tiling arrays to demonstrate a wave of transcription that swept along selected long genes on stimulation. RNA FISH confirmed these results, and that long introns are co-transcriptionally spliced. Results are consistent with one polymerase being engaged on an allele at any time, and with a major checkpoint that regulates polymerase escape from the first few thousand nucleotides into the long gene.

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Buckley, Reuben Mackenzie. "Evolution of mammalian genome architecture through retrotransposition." Thesis, 2017. http://hdl.handle.net/2440/119371.

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Retrotransposons, mobile DNA elements that replicate via a copy and paste mechanism, are a major component of mammalian genome architecture. They account for at least one-third of the human genome and are major drivers of lineage-specific gain and loss of DNA. While there are many examples of how specific retrotransposons have impacted evolution, their interaction with large-scale genome architecture remains poorly characterised. Throughout my thesis I investigated two fundamental questions regarding genome evolution and retrotransposons. Firstly, how does genome architecture shape retrotransposon accumulation? Secondly, how does retrotransposon accumulation in turn impact on genome architecture? The current model of retrotransposon accumulation largely relies on local sequence composition. However, this model fails to account for genome-wide chromatin structure, an important factor that regulates DNA accessibility to insertion machinery. By analysing retrotransposon accumulation at open chromatin sites I showed that genome structure strongly associates with retrotransposon accumulation patterns. In addition, by mapping retrotransposon accumulation patterns of non-human mammals back to human, I was able to observe large-scale positional conservation of lineage-specific retrotransposons. These findings suggest that through conservation of synteny, gene regulation and nuclear organisation, retrotransposon accumulation in mammalian genomes follows similar evolutionary trajectories. Beneath the conserved structural framework of mammalian genomes there exists a high degree of lineage-specific turnover of DNA. Outside of whole genome duplication, retrotransposons are the largest contributing factor to genome growth. In contrast to this, accumulation of retrotransposons can also increase the probability of unequal crossing over causing DNA loss through large deletion events. Using multiple pairwise alignments I calculated regional levels of lineage-specific DNA gain and loss in the human and mouse genomes. I found that while lineage-specific DNA loss overlapped with open chromatin regions in both genomes, different sources for lineage-specific DNA gain drove divergence in genome architecture. These findings reveal the turbulent nature of lineage-specific evolution of large-scale genome architecture, ultimately questioning the evolutionary stability of structural chromosomal domains. In addition to analysing large-scale genome architecture I performed two separate analyses on retrotransposons in the bovine genome. Due to the presence of BovB retrotransposons, the bovine retrotransposon landscape is clearly distinct from other placental mammals. For the first analysis, I identified bovine-specific retrotransposon associated gene coexpression networks. Following the genomic distribution of bovine retrotransposons, my results show that gene expression strongly associates with genome architecture. For the second analysis, I characterised retrotransposons surrounding tandem duplicate copies of the bovine NK-lysin gene. My results were consistent with retrotransposon accumulation causing genomic rearrangements via non-allelic homologous recombination. Altogether, my thesis reveals hidden interactions between retrotransposon accumulation, and mammalian genome structure and function. By re-purposing publicly available datasets I have characterised various aspects of the complex co-evolutionary relationships between retrotransposons and the genomes in which they reside in.
Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2017

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Munger, Steven Carmen. "A systems-level view of mammalian sex determination." Diss., 2010. http://hdl.handle.net/10161/3006.

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Pathologies 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

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"Life History Affects Cancer Gene Copy Numbers in Mammalian Genomes." Master's thesis, 2019. http://hdl.handle.net/2286/R.I.55516.

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abstract: Cancer is a disease which can affect all animals across the tree of life. Certain species have undergone natural selection to reduce or prevent cancer. Mechanisms to block cancer may include, among others, a species possessing additional paralogues of tumor suppressor genes, or decreasing the number of oncogenes within their genome. To understand cancer prevention patterns across species, I developed a bioinformatic pipeline to identify copies of 545 known tumor suppressor genes and oncogenes across 63 species of mammals. I used phylogenetic regressions to test for associations between cancer gene copy numbers and a species’ life history. I found a significant association between cancer gene copies and species’ longevity quotient. Additional paralogues of tumor suppressor genes and oncogenes is not solely dependent on body size, but rather the balance between body size and longevity. Additionally, there is a significance association between life history traits and genes that are both germline and somatic tumor suppressor genes. The bioinformatic pipeline identified large tumor suppressor gene and oncogene copy numbers in the naked mole rat (Heterocephalus glaber), armadillo (Dasypus novemcinctus), and the two-fingered sloth (Choloepus hoffmanni). These results suggest that increased paralogues of tumor suppressor genes and oncogenes are these species’ modes of cancer resistance.
Dissertation/Thesis
Pipeline results for cancer genes
Phylogenetic regressions with correction tests
Pipeline results for housekeeping genes
Masters Thesis Biology 2019

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Natarajan, Anirudh. "Uncovering the Transcription Factor Network Underlying Mammalian Sex Determination." Diss., 2014. http://hdl.handle.net/10161/8746.

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Understanding 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.

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47

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.

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Badve, Abhijit. "Discovery and evolutionary dynamics of RBPs and circular RNAs in mammalian transcriptomes." Thesis, 2015. http://hdl.handle.net/1805/7820.

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Indiana University-Purdue University Indianapolis (IUPUI)
RNA-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.

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49

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.

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Abstract:

>Magister Scientiae - MSc
Human 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.

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50

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.

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Recent work has demonstrated that microRNAs (miRNAs) are involved in critical biological processes by suppressing the translation of coding genes. This work develops an integrated database, miRNAMap, to store the known miRNA genes, the putative miRNA genes, the known miRNA targets and the putative miRNAtargets. The knownmiRNAgenes in fourmammalian genomes such as human, mouse, rat and dog are obtained from miRBase, and experimentally validated miRNA targets are identified in a survey of the literature. Putative miRNA precursors were identified by RNAz, which is a non-coding RNA prediction tool based oncomparative sequence analysis. The mature miRNA of the putative miRNA genes is accurately determined using a machine learning approach, mmiRNA. Then, miRanda was applied to predict the miRNAtargets within the conserved regions in 30-UTR of the genes in the four mammalian genomes. The miRNAMap also provides the expression profiles of the known miRNAs, cross-species comparisons, gene annotations and cross-links to other biological databases. Both textual and graphical web interface are provided to facilitate the retrieval of data from the miRNAMap.

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Dissertations / Theses on the topic 'Mammalian genomics'

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