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1
Komp, Lindgren Patricia. "Mutations and Mutation Rate in the Development of Fluoroquinolone Resistance." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8275.
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Ibrahim, Daniel Murad. "ChIP-seq reveals mutation-specific pathomechanisms of HOXD13 missense mutations." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2015. http://dx.doi.org/10.18452/17102.
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Mutationen von Transkriptionsfaktoren (TF) betreffen nicht nur die Funktion des TFs, sondern auch die Expression seiner Zielgene und liegen häufig angeborenen Entwicklungsdefekten zugrunde. Über 20 Mutationen in HOXD13, einem TF der die Entwicklung der Extremitäten kontrolliert, sind bisher als Ursache verschiedenartiger Extremitätenfehlbildungen entdeckt worden. Eine molekularbiologische Grundlage für die Vielgestaltigkeit der HOXD13-Mutationen ist jedoch unbekannt. Die bisherigen Methoden zur funktionellen Charakterisierung von TF-Mutationen ermöglichten eine lediglich eingeschränkte Interpretation der molekularen Pathomechanismen. Die kürzlich entwickelte ChIP-seq Methode ermöglicht eine umfassende, funktionelle Charakterisierung eines TFs. In dieser Arbeit wurde eine Methode etabliert, um eine Vielzahl von Transkriptionsfaktoren und TF-Mutationen systematisch zu untersuchen. Zur Validierung wurden zwei neue Punktmutationen in HOXD13, p.Q317K und p.R298Q, charakterisiert. Beide Mutationen betreffen die DNA-bindende Domäne von HOXD13, rufen aber stark unterschiedliche Fehlbildungen hervor. Die Ergebnisse zeigen, dass die HOXD13Q317K Mutante eine veränderte Sequenzspezifität aufweist, welche nun jener eines anderen TFs, PITX1, ähnelt. Auch genomweit zeigt HOXD13Q317K ein Bindungsprofil, welches eher PITX1 als HOXD13wt entspricht. Durch weitere, unabhängige Analysen und Experimente wurde bestätigt, dass die p.Q317K Mutation HOXD13 in einen TF mit PITX1-ähnlichen Eigenschaften verändert. Die HOXD13R298Q-Mutante zeigt eine weitgehend unveränderte Bindungssequenz gegenüber HOXD13wt, jedoch eine veränderte Zusammensetzung der genomischen Bindestellen. Dies weist, in Kombination mit dem humanen Phänotyp auf einen dominant-negativen Pathomechanismus dieser Mutanten hin. Zusammengenommen zeigt diese Arbeit durch die Erhebung von experimentellen Daten, dass klar unterscheidbare molekularbiologische Mechanismen den HOXD13Q317K- und HOXD13R298Q-Mutationen zugrunde liegen.<br>Mutations in transcription factors (TF) do not only affect the function of the TF, but also the expression of its target genes and are frequently underlying congenital malformations. More than 20 distinct pathogenic mutations in HOXD13, a TF controlling limb development, have been associated with a broad range of limb malformations. However, a molecular basis underlying the variability of HOXD13-associated phenotypes remains elusive. To date, the experimental methods used to functionally characters TF mutations have allowed only limited insights into the underlying molecular pathomechanisms. The recently developed ChIP-seq technology has proven to be a powerful method to profile the binding characteristics of TFs; however a number of technical hurdles hinder its application for functional characterization of mutant TFs. This work describes the establishment of a ChIP-seq approach to investigate a wide spectrum of TFs and TF mutations. The approach was applied to characterize two previously unknown missense mutations in HOXD13, p.Q317K and p.R298Q, which both alter the DNA-binding domain of HOXD13 but cause very different disease phenotypes. The results show that the HOXD13Q317K mutant has an altered sequence specificity that resembles the recognition sequence of another TF, PITX1. Further, the genome-wide binding pattern of HOXD13Q317K shifts towards a more PITX1-like binding pattern. Even further analysis and viral overexpression in chicken limb buds confirm that the mutation partially converts HOXD13Q317K into a TF with PITX1-like properties. The HOXD13R298Q has a largely unchanged sequence specificity, but an altered composition of genomic binding sites. This, in combination with the human phenotype, indicates that the mutant might act in a dominant-negative manner. Collectively, this work shows through generation of direct experimental evidence, that clearly distinct molecular mechanisms underlie the pathogenicity of HOXD13Q317K and HOXD13R298Q mutations.
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Krasovec, Marc. "Estimation des taux de mutation : implications pour la diversification et l'évolution du phytoplancton eucaryote." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066371/document.
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Les mutations sont la principale source de diversité sur laquelle agit la sélection pour permettre aux espèces de s'adapter. Les études de l'effet des mutations sur la survie et du taux de mutation sont donc essentielles pour mieux comprendre l'évolution. Par une approche d'expérience d'accumulation de mutations, nous étudions ces deux questions chez cinq modèles d'algues vertes (Ostreococcus tauri, O. mediterraneus, Bathycoccus prasinos, Micromonas pusilla, et Picochlorum RCC4223). Il est mis en évidence une diminution de la fitness au cours du temps en raison des mutations délétères, et une importante interaction génotype-environnement sur l'effet des mutations. Le taux de mutation varie aux échelles intra-génomique et inter-spécifique, avec deux principaux résultats: une augmentation du taux de mutation dans les régions non codantes et une augmentation du taux de mutation avec la taille du génome chez les eucaryotes et en fonction de l'écart à l'équilibre en GC du génome. Aussi, l'assemblage et l'annotation d'une picoalgue du genre Picochlorum permettent d'étudier le rôle des transferts horizontaux de gènes chez les Chlorophytes<br>Mutations are the main source of diversity on which selection acts to allow species to adapt. Studies of the effect of mutations on survival and estimation of spontaneous mutation rates are essential to better understand evolution. Using mutation accumulation experimental approach, we investigated the issues of mutation effects and mutation rate in five models of green algae (Ostreococcus tauri, O. mediterraneus, Bathycoccus Prasinos, Micromonas pusilla, and Picochlorum RCC4223). It highlighted a decline in fitness over time because of deleterious mutations, and a significant genotype-environment interaction on the fitness effect of mutations. The mutation rate varies at inter-specific and intra-genomic scales, with two main results: a raise of the mutation rate in non-coding regions in accordance with trancriptional-coupled repair, and an increase of the mutation rate with an increase of the genome size in eukaryotes and the GC content deviation from the equilibrium. Also, a new Picochlorum genome is provided to investigate the role of horizontal gene transfer in the Chlorophyta group
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Krasovec, Marc. "Estimation des taux de mutation : implications pour la diversification et l'évolution du phytoplancton eucaryote." Electronic Thesis or Diss., Paris 6, 2016. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2016PA066371.pdf.
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Les mutations sont la principale source de diversité sur laquelle agit la sélection pour permettre aux espèces de s'adapter. Les études de l'effet des mutations sur la survie et du taux de mutation sont donc essentielles pour mieux comprendre l'évolution. Par une approche d'expérience d'accumulation de mutations, nous étudions ces deux questions chez cinq modèles d'algues vertes (Ostreococcus tauri, O. mediterraneus, Bathycoccus prasinos, Micromonas pusilla, et Picochlorum RCC4223). Il est mis en évidence une diminution de la fitness au cours du temps en raison des mutations délétères, et une importante interaction génotype-environnement sur l'effet des mutations. Le taux de mutation varie aux échelles intra-génomique et inter-spécifique, avec deux principaux résultats: une augmentation du taux de mutation dans les régions non codantes et une augmentation du taux de mutation avec la taille du génome chez les eucaryotes et en fonction de l'écart à l'équilibre en GC du génome. Aussi, l'assemblage et l'annotation d'une picoalgue du genre Picochlorum permettent d'étudier le rôle des transferts horizontaux de gènes chez les Chlorophytes<br>Mutations are the main source of diversity on which selection acts to allow species to adapt. Studies of the effect of mutations on survival and estimation of spontaneous mutation rates are essential to better understand evolution. Using mutation accumulation experimental approach, we investigated the issues of mutation effects and mutation rate in five models of green algae (Ostreococcus tauri, O. mediterraneus, Bathycoccus Prasinos, Micromonas pusilla, and Picochlorum RCC4223). It highlighted a decline in fitness over time because of deleterious mutations, and a significant genotype-environment interaction on the fitness effect of mutations. The mutation rate varies at inter-specific and intra-genomic scales, with two main results: a raise of the mutation rate in non-coding regions in accordance with trancriptional-coupled repair, and an increase of the mutation rate with an increase of the genome size in eukaryotes and the GC content deviation from the equilibrium. Also, a new Picochlorum genome is provided to investigate the role of horizontal gene transfer in the Chlorophyta group
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Maxwell, Megan Amanda, and n/a. "PEX1 Mutations in Australasian Patients with Disorders of Peroxisome Biogenesis." Griffith University. School of Biomolecular and Biomedical Science, 2004. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20040219.100649.
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The peroxisome is a subcellular organelle that carries out a diverse range of metabolic functions, including the b-oxidation of very long chain fatty acids, the breakdown of peroxide and the a-oxidation of fatty acids. Disruption of peroxisome metabolic functions leads to severe disease in humans. These diseases can be broadly grouped into two categories: those in which a single enzyme is defective, and those known as the peroxisome biogenesis disorders (PBDs), which result from a generalised failure to import peroxisomal matrix proteins (and consequently result in disruption of multiple metabolic pathways). The PBDs result from mutations in PEX genes, which encode protein products called peroxins, required for the normal biogenesis of the peroxisome. PEX1 encodes an AAA ATPase that is essential for peroxisome biogenesis, and mutations in PEX1 are the most common cause of PBDs worldwide. This study focused on the identification of mutations in PEX1 in an Australasian cohort of PBD patients, and the impact of these mutations on PEX1 function. As a result of the studies presented in this thesis, twelve mutations in PEX1 were identified in the Australasian cohort of patients. The identified mutations can be broadly grouped into three categories: missense mutations, mutations directly introducing a premature termination codon (PTC) and mutations that interrupt the reading frame of PEX1. The missense mutations that were identified were R798G, G843D, I989T and R998Q; all of these mutations affect amino acid residues located in the AAA domains of the PEX1 protein. Two mutations that directly introduce PTCs into the PEX1 transcript (R790X and R998X), and four frameshift mutations (A302fs, I370fs, I700fs and S797fs) were identified. There was also one mutation found in an intronic region (IVS22-19A>G) that is presumed to affect splicing of the PEX1 mRNA. Three of these mutations, G843D, I700fs and G973fs, were found at high frequency in this patient cohort. At the commencement of these studies, it was hypothesised that missense mutations would result in attenuation of PEX1 function, but mutations that introduced PTCs, either directly or indirectly, would have a deleterious effect on PEX1 function. Mutations introducing PTCs are thought to cause mRNA to be degraded by the nonsense-mediated decay of mRNA (NMD) pathway, and thus result in a decrease in PEX1 protein levels. The studies on the cellular impact of the identified PEX1 mutations were consistent with these hypotheses. Missense mutations were found to reduce peroxisomal protein import and PEX1 protein levels, but a residual level of function remained. PTC-generating mutations were found to have a major impact on PEX1 function, with PEX1 mRNA and protein levels being drastically reduced, and peroxisomal protein import capability abolished. Patients with two missense mutations showed the least impact on PEX1 function, patients with two PTC-generating mutations had a severe defect in PEX1 function, and patients carrying a combination of a missense mutation and a PTC-generating mutation showed levels of PEX1 function that were intermediate between these extremes. Thus, a correlation between PEX1 genotype and phenotype was defined for the Australasian cohort of patients investigated in these studies. For a number of patients, mutations in the coding sequence of one PEX1 allele could not be identified. Analysis of the 5' UTR of this gene was therefore pursued for potential novel mutations. The initial analyses demonstrated that the 5' end of PEX1 extended further than previously reported. Two co-segregating polymorphisms were also identified, termed 137 T>C and 53C>G. The -137T>C polymorphism resided in an upstream, in-frame ATG (termed ATG1), and the possibility that the additional sequence represented PEX1 coding sequence was examined. While both ATGs were found to be functional by virtue of in vitro and in vivo expression investigations, Western blot analysis of the PEX1 protein in patient and control cell extracts indicated that physiological translation of PEX1 was from the second ATG only. Using a luciferase reporter approach, the additional sequence was found to exhibit promoter activity. When examined alone the -137T>C polymorphism exerted a detrimental effect on PEX1 promoter activity, reducing activity to half that of wild-type levels, and the -53C>G polymorphism increased PEX1 promoter activity by 25%. When co-expressed (mimicking the physiological condition) these polymorphisms compensated for each other to bring PEX1 promoter activity to near wild-type levels. The PEX1 mutations identified in this study have been utilised by collaborators at the National Referral Laboratory for Lysosomal, Peroxisomal and Related Genetic Disorders (based at the Women's and Children's Hospital, Adelaide), in prenatal diagnosis of the PBDs. In addition, the identification of three common mutations in Australasian PBD patients has led to the implementation of screening for these mutations in newly referred patients, often enabling a precise diagnosis of a PBD to be made. Finally, the strong correlation between genotype and phenotype for the patient cohort investigated as part of these studies has generated a basis for the assessment of newly identified mutations in PEX1.
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Maxwell, Megan Amanda. "PEX1 Mutations in Australasian Patients with Disorders of Peroxisome Biogenesis." Thesis, Griffith University, 2004. http://hdl.handle.net/10072/366184.
Full textAbstract:
The peroxisome is a subcellular organelle that carries out a diverse range of metabolic functions, including the b-oxidation of very long chain fatty acids, the breakdown of peroxide and the a-oxidation of fatty acids. Disruption of peroxisome metabolic functions leads to severe disease in humans. These diseases can be broadly grouped into two categories: those in which a single enzyme is defective, and those known as the peroxisome biogenesis disorders (PBDs), which result from a generalised failure to import peroxisomal matrix proteins (and consequently result in disruption of multiple metabolic pathways). The PBDs result from mutations in PEX genes, which encode protein products called peroxins, required for the normal biogenesis of the peroxisome. PEX1 encodes an AAA ATPase that is essential for peroxisome biogenesis, and mutations in PEX1 are the most common cause of PBDs worldwide. This study focused on the identification of mutations in PEX1 in an Australasian cohort of PBD patients, and the impact of these mutations on PEX1 function. As a result of the studies presented in this thesis, twelve mutations in PEX1 were identified in the Australasian cohort of patients. The identified mutations can be broadly grouped into three categories: missense mutations, mutations directly introducing a premature termination codon (PTC) and mutations that interrupt the reading frame of PEX1. The missense mutations that were identified were R798G, G843D, I989T and R998Q; all of these mutations affect amino acid residues located in the AAA domains of the PEX1 protein. Two mutations that directly introduce PTCs into the PEX1 transcript (R790X and R998X), and four frameshift mutations (A302fs, I370fs, I700fs and S797fs) were identified. There was also one mutation found in an intronic region (IVS22-19A>G) that is presumed to affect splicing of the PEX1 mRNA. Three of these mutations, G843D, I700fs and G973fs, were found at high frequency in this patient cohort. At the commencement of these studies, it was hypothesised that missense mutations would result in attenuation of PEX1 function, but mutations that introduced PTCs, either directly or indirectly, would have a deleterious effect on PEX1 function. Mutations introducing PTCs are thought to cause mRNA to be degraded by the nonsense-mediated decay of mRNA (NMD) pathway, and thus result in a decrease in PEX1 protein levels. The studies on the cellular impact of the identified PEX1 mutations were consistent with these hypotheses. Missense mutations were found to reduce peroxisomal protein import and PEX1 protein levels, but a residual level of function remained. PTC-generating mutations were found to have a major impact on PEX1 function, with PEX1 mRNA and protein levels being drastically reduced, and peroxisomal protein import capability abolished. Patients with two missense mutations showed the least impact on PEX1 function, patients with two PTC-generating mutations had a severe defect in PEX1 function, and patients carrying a combination of a missense mutation and a PTC-generating mutation showed levels of PEX1 function that were intermediate between these extremes. Thus, a correlation between PEX1 genotype and phenotype was defined for the Australasian cohort of patients investigated in these studies. For a number of patients, mutations in the coding sequence of one PEX1 allele could not be identified. Analysis of the 5' UTR of this gene was therefore pursued for potential novel mutations. The initial analyses demonstrated that the 5' end of PEX1 extended further than previously reported. Two co-segregating polymorphisms were also identified, termed –137 T>C and –53C>G. The -137T>C polymorphism resided in an upstream, in-frame ATG (termed ATG1), and the possibility that the additional sequence represented PEX1 coding sequence was examined. While both ATGs were found to be functional by virtue of in vitro and in vivo expression investigations, Western blot analysis of the PEX1 protein in patient and control cell extracts indicated that physiological translation of PEX1 was from the second ATG only. Using a luciferase reporter approach, the additional sequence was found to exhibit promoter activity. When examined alone the -137T>C polymorphism exerted a detrimental effect on PEX1 promoter activity, reducing activity to half that of wild-type levels, and the -53C>G polymorphism increased PEX1 promoter activity by 25%. When co-expressed (mimicking the physiological condition) these polymorphisms compensated for each other to bring PEX1 promoter activity to near wild-type levels. The PEX1 mutations identified in this study have been utilised by collaborators at the National Referral Laboratory for Lysosomal, Peroxisomal and Related Genetic Disorders (based at the Women's and Children's Hospital, Adelaide), in prenatal diagnosis of the PBDs. In addition, the identification of three common mutations in Australasian PBD patients has led to the implementation of screening for these mutations in newly referred patients, often enabling a precise diagnosis of a PBD to be made. Finally, the strong correlation between genotype and phenotype for the patient cohort investigated as part of these studies has generated a basis for the assessment of newly identified mutations in PEX1.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Biomolecular and Biomedical Sciences<br>Full Text
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COCCIADIFERRO, DARIO. "Mutational analysis of Kabuki Syndrome patients and functional dissection of KMT2D mutations." Doctoral thesis, Università di Foggia, 2018. http://hdl.handle.net/11369/369451.
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The discovery of histone methyltransferase KMT2D and demethylase KDM6A genetic alterations in Kabuki Syndrome (KS) expanded and highlighted the role of histone modifiers in causing congenital anomalies and intellectual disability syndromes. KS is a rare autosomal dominant condition characterized by facial features, various organ malformations, postnatal growth deficiency, and intellectual disability. Since 2011 we performed a mutational screening of our KS cohort, that includes now 505 KS patients, by Sanger sequencing and MLPA of KMT2D, followed by KDM6A analysis in those patients resulted as KMT2Dnegative. Of these 505 patients, we identified 196/505 (39%) patients with KMT2D variants and 208 different KMT2D variations; of them 37/208 (18%) never described before. The majority of KS patients carry nonsense and splicesite variants, suggesting the loss of function, and therefore haploinsufficiency, as the likely mechanism for the KS phenotype. RT-PCR and direct sequencing on cDNA from Kabuki patients carrying KMT2D splice site variants demonstrated that these cause aberrant splicing of the corresponding transcript, resulting in a truncating and not functional translated protein. Molecular assays also showed that KMT2D mRNAs bearing premature stop codon are degraded by the nonsense mediated mRNA decay, contributing to KMT2D protein haploinsufficiency. We hypothesized that KS patients may benefit from a readthrough therapy that mediates translational suppression of nonsense variants, restoring the physiologically levels of endogenous KMT2D protein. Fourteen KMT2D nonsense variants were tested for their response to readthrough treatment through an in vitro dual reporter luciferase vector system, identifying 11/14 variants that displayed high levels of readthrough in response to gentamicin treatment. Among our cohort we identified three new cases with a mosaic variants in KMT2D gene, consisting in single nucleotide change resulting in two already reported nonsense variants, the c.13450C=/>T (p.R4484X) and the c.15061C=/>T (p.R5021X) and in a new frameshift variant, the c.3596_3597=/del (p.L1199HfsX7) KMT2D, respectively. Moreover, relevant for diagnostic and counselling purposes, we implemented a number of bioinformatics tools to assess the pathogenicity of 69 KMT2D missense variants, found overall in our cohort of 505 KS patients, and for 14 of them we adopted a combination of biochemical and cellular approaches to investigate their role and characterize their functional impact in the pathogenesis of the disease. We found 9/14 missense variants showing altered H3K4 methylation activity. We additionally assessed the impact on complex formation with WRAD protein complex, and we found that the reduced methyltransferase activity could be a consequence of lack of interaction.
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Davis, Brad. "Compensatory and deleterious mutations." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/7722.
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My Ph.D. research has focused on some general properties of compensatory mutations, as well as the impact of compensatory mutations on fitness recovery and deleterious mutations on populations extinction risks. I have addressed these topics using a variety of techniques.
Chapter 2 addresses mutational meltdown using computer simulation models to explicitly incorporate both environmental stochasticity and mutation accumulation. The results show that a small amount of environmental stochasticity can significantly hasten extinction times and that the mutational meltdown process hastens time to extinction even when levels of environmental stochasticity are high enough to cause rapid extinctions on their own. Even large populations with 1000 individuals can be at risk of going extinct via the mutational meltdown with sufficient environmental stochasticity.
Chapter 3 looks at the potential for low fitness lines of Caenorhabditis elegans to recover lost fitness due to gene knockouts. Using gene knockout assures that any fitness recovery is due to compensatory mutations elsewhere in the genome and not back mutation. We show that rapid fitness recovery is possible, even in relatively small populations.
Chapter 4 examines the distribution of the number of compensatory mutations that exist per deleterious mutation, using published datasets. We determined that the distribution of number of compensatory mutations is best fit by a gamma distribution, with a mean of 11 compensatory mutations per deleterious mutation.
Chapter 5 utilizes the same dataset as was gathered for Chapter 4, but addresses a different set of questions. Are all amino acid positions equally capable of producing a compensatory mutation? Do compensatory mutations significantly cluster around the site of their associated deleterious mutations? Above and beyond the clustering found in the second question, do compensatory mutations cluster amongst themselves? All of these questions were answered in the affirmative.
Chapter 6 is concerned with the evolution of cooperation through resource sharing. Here we showed that the evolution of cooperation through resource sharing is difficult to achieve and requires heterogeneity in resource state within the population and that an individual’s resource state must change frequently in order to create the conditions by which the evolution of cooperation is favoured.
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Bendall, Kate E. "Inheritance of mitochondrial mutations." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320141.
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Salamat, Majid. "Coalescent, recombinaisons et mutations." Thesis, Aix-Marseille 1, 2011. http://www.theses.fr/2011AIX10059.
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Cette thèse se concentre sur certains sujets en génétique des populations. Dans la première partie, nous donnons des formules y compris l'espérance et la variance de la hauteur et celles de la longueur du graphe de recombinaison ancestral (ARG) et l'espérance et la variance du nombre de recombinaison et nous montrons que l'espérance de la longueur de l'ARG est une combinaison linéaire de l'espérance de la longueur de la coalescence de Kingman et l'espérance de la hauteur de l'ARG. En outre, nous avons obtenu une relation entre l'espérance la longueur de l'ARG et l'espérance du nombre de recombinaisons. À la fin de cette partie, nous montrons que l'ARG descend de l'infini de telle sorte que X_0 =∞, alors que X_t < ∞ ; pour tout t et on trouve la vitesse à laquelle l'ARG descend de l'infini. Dans la deuxième partie on généralise la formule d'échantillonnage d'Ewens (GESF) en présence de la recombinaison pour les échantillons de taille n = 2 et n = 3. Dans la troisième partie de la thèse, nous étudions l'ARG le long du génome et nous avons trouvé la distribution du nombre de mutations dans le cas avec une seule recombinaison dans la généalogie de l'échantillon<br>This thesis is concentrated on some sub jects on population genetics. In the first part we give formulae including the expectation and variance of the height and the length of the ancestral recombination graph (ARG) and the expectation and variance of the number of recombination events and we show that the expectation of the length of the ARG is a linear combination of the expectation of the length of Kingman's coalescent and the expectation of the height of the ARG. Also we show give a relation between the expectation of the ARG and the expectation of the number of recombination events. At the end of this part we show that the ARG comes down from infinity in the sense that we can dfine it with X_0 = ∞, while X_t <∞ ; for all t and we find the speed that the ARG comes down from infinity. In the second part wfind a generalization of the the Ewens sampling formula (GESF) in the presence of recombination for sample of sizes n = 2 and n = 3. In the third part of the thesis we study the ARG along the genome and we we find the distribution of the number of mutations when we have one recombination event in the genealogy of the sample
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Ižák, Tomáš. "Detection of Correlated Mutations." Master's thesis, Vysoké učení technické v Brně. Fakulta informačních technologií, 2013. http://www.nusl.cz/ntk/nusl-236417.
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Tato práce zkoumá existující možnosti a metody detekce korelovaných mutací v proteinech. Práce začíná teoretickým úvodem do zkoumané problematiky. Využití informací o korelovaných mutacích je především při predikci terciální struktury proteinu či hledání oblastí s významnou funkcí. Dále následuje přehled v současnosti používaných metod detekce a jejich výhody a nevýhody. V této práci jsou zkoumány zejména metody založené na statistice (například Pearsonově korelačním koeficientu nebo Pearsonově chi^2 testu), informační teorii (Mutual information - MI) a pravděpodobnosti (ELSC nebo Spidermonkey). Dále jsou popsány nejdůležitější nástroje s informací o tom, které metody používají a jakým způsobem. Také je diskutována možnost návrhu optimálního algoritmu. Jako optimální z hlediska úspěšnosti detekce je doporučeno využít více zmíněných metod. Také je doporučeno při detekci využít fyzikálně-chemických vlastností aminokyselin. V praktické části byla vyvinuta metoda využívající fyzikálně-chemických vlastností aminokyselin a fylogenetických stromů. Výsledky detekce byly porovnány s nástroji CAPS, CRASP a CMAT.
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Champeimont, Raphael. "Combinatoire des mutations génétiques." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066636/document.
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Dans une première partie, je présente le travail que j’ai accompli sur la coévolution moléculaire. Je présente le contexte biologique et les différentes mesures qui permettent de détecter la conservation et la coévolution à l’échelle des acides aminés. Ensuite, je montre une application de ces mesures à la détection des résidus critiques dans la protéine P53 liée au cancer. Dans ce but, j’ai créé une évaluation des différentes méthodes de prédiction. J’utilise ensuite la même méthodologie sur une base de données de mutations liées à des maladies génétiques. Je montre également comment la coévolution au niveau des résidus permet de découvrir des interactions protéine-protéine sur le virus de l’hépatite C. Enfin, je présente l’algorithme PruneTree, qui permet de filtrer des ensembles de séquences utilisés comme entrée par les programmes de détection de coévolution.Dans une deuxième partie, je m’intéresse à l’étude de l’évolution à l’échelle du génome, en particulier aux mécanismes de recombinaison méiotique. Pour cela j’ai considéré le taux de recombinaison le long du génome et sa cause, les cassures double-brin de l’ADN. Je présente alors un modèle de la distribution de ces cassures et de la liaison des différentes protéines liées à la recombinaison. Je présente également une méthode de détection de périodicité le long du génome basée sur les transformées de Fourier.Enfin, dans la dernière partie, je présente un nouvel algorithme pour simuler l’évolution des génomes de façon à évaluer les outils de reconstruction, et le paquet R-CLAG permettant d’utiliser l’algorithme de classification CLAG depuis R<br>In a first part, I show the work I have done on molecular evolution. I present the general biological background and the measures that allow us to detect both conservation and coevolution at the amino-acid level. Then, I present an application of these measures to the detection of critical residues in the cancer protein P53. To this end, I have made a benchmark of different prediction methods. I then use the same methodology on a large scale database of pathogenic mutations linked to genetic diseases. After that, I show how residue-level coevolution can help us discover protein-protein interactions in the hepatitis C virus. Finally, I present the PruneTree algorithm, which allows filtering sequence sets used as input for molecular coevolution detection methods. In a second part, I have studied evolution at the genome level, in particular the recombination mechanisms that occur during meiosis. I have looked at the recombination rates along the genomes and its primary cause, the double-strand breaks, but also at the density of other proteins involved in recombination. I also present a method based on Fourier transforms to analyze these genomic signals, and a model for the distribution along the genome of double-strand breaks and recombination proteins. Finally, I present the other tools I have developed. I describe a novel algorithm that can simulate the evolution of genomes in order to benchmark the phylogenetic reconstruction algorithm PhyChro. Finally, I present the R-CLAG package that allows for easy use of the clustering algorithm CLAG
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Champeimont, Raphael. "Combinatoire des mutations génétiques." Electronic Thesis or Diss., Paris 6, 2014. http://www.theses.fr/2014PA066636.
Full textAbstract:
Dans une première partie, je présente le travail que j’ai accompli sur la coévolution moléculaire. Je présente le contexte biologique et les différentes mesures qui permettent de détecter la conservation et la coévolution à l’échelle des acides aminés. Ensuite, je montre une application de ces mesures à la détection des résidus critiques dans la protéine P53 liée au cancer. Dans ce but, j’ai créé une évaluation des différentes méthodes de prédiction. J’utilise ensuite la même méthodologie sur une base de données de mutations liées à des maladies génétiques. Je montre également comment la coévolution au niveau des résidus permet de découvrir des interactions protéine-protéine sur le virus de l’hépatite C. Enfin, je présente l’algorithme PruneTree, qui permet de filtrer des ensembles de séquences utilisés comme entrée par les programmes de détection de coévolution.Dans une deuxième partie, je m’intéresse à l’étude de l’évolution à l’échelle du génome, en particulier aux mécanismes de recombinaison méiotique. Pour cela j’ai considéré le taux de recombinaison le long du génome et sa cause, les cassures double-brin de l’ADN. Je présente alors un modèle de la distribution de ces cassures et de la liaison des différentes protéines liées à la recombinaison. Je présente également une méthode de détection de périodicité le long du génome basée sur les transformées de Fourier.Enfin, dans la dernière partie, je présente un nouvel algorithme pour simuler l’évolution des génomes de façon à évaluer les outils de reconstruction, et le paquet R-CLAG permettant d’utiliser l’algorithme de classification CLAG depuis R<br>In a first part, I show the work I have done on molecular evolution. I present the general biological background and the measures that allow us to detect both conservation and coevolution at the amino-acid level. Then, I present an application of these measures to the detection of critical residues in the cancer protein P53. To this end, I have made a benchmark of different prediction methods. I then use the same methodology on a large scale database of pathogenic mutations linked to genetic diseases. After that, I show how residue-level coevolution can help us discover protein-protein interactions in the hepatitis C virus. Finally, I present the PruneTree algorithm, which allows filtering sequence sets used as input for molecular coevolution detection methods. In a second part, I have studied evolution at the genome level, in particular the recombination mechanisms that occur during meiosis. I have looked at the recombination rates along the genomes and its primary cause, the double-strand breaks, but also at the density of other proteins involved in recombination. I also present a method based on Fourier transforms to analyze these genomic signals, and a model for the distribution along the genome of double-strand breaks and recombination proteins. Finally, I present the other tools I have developed. I describe a novel algorithm that can simulate the evolution of genomes in order to benchmark the phylogenetic reconstruction algorithm PhyChro. Finally, I present the R-CLAG package that allows for easy use of the clustering algorithm CLAG
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Magnússon, Kristinn P. "p53 inactivation by point mutations and splice mutations in human and mouse tumors /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980611magn.
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Yauk, Carole Lyn. "Germline minisatellite mutations in herring gulls, induced mutations at colonies situated near steel mills." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ51024.pdf.
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Yauk, Carole Lyn. "Germline minisatellite mutations in herring gulls : induced mutations at colonies situated near steel mills /." *McMaster only, 1998.
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Loukas, Andrew. "Sodium channel mutations causing epilepsy." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=80321.
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Ion channels mediate the electrical properties of neurons and other excitable cells. Mutations in ion channel genes have been linked to several neurological disorders. For example, a rare familial form of epilepsy, generalized epilepsy with febrile seizures plus (GEFS+), is associated with mutations in voltage gated sodium channels. We examined how two such mutations (C121W, D188V) alter the functional properties of the channel through voltage-clamp studies in Xenopus oocytes and HEK cells respectively. D188V is located in the alpha subunit and C121W in the auxiliary beta1 subunit of the sodium channel.<br>The C121W mutation causes a 100 fold reduction in efficacy of current modulation as well as a reduction of current amplitude. This may cause increased sodium currents via a negative shift of the steady-state inactivation curve. alpha-D188V channels recover faster from the inactivated state which causes a resistance to frequency-dependent cumulative inactivation of current amplitude. This may contribute to cellular hyperexcitability resulting in ictal events in the epileptic patient.
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McNeill, A. "Glucocerebrosidase mutations and Parkinson's disease." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1387497/.
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Objectives - Gaucher disease (GD) is caused by bi-allelic mutations in the glucocerebrosidase gene (GBA). GD and heterozygous carriage of GBA mutations significantly increase the risk of developing Parkinson's disease (PD). Here we studied GD patients and carriers to identify a cohort of individuals with clinical signs of prodromal PD and generated fibroblast lines from them to study why GBA mutations cause PD. Methods - 83 patients with Type I GD and 41 of their heterozygous carrier relatives were recruited from lysosomal storage disorder clinics at the Royal Free Hospital and Addenbrooke's Hospital Cambridge, along with 30 mutation negative matched controls. They were clinically screened for hyposmia (University of Pennsylvania Smell Identification Test), cognitive impairment (Montreal Cognitive Assessment), autonomic dysfunction, REM sleep behaviour disorder and motor signs of PD. Two hundred and thirty cases of sporadic PD were screened for GBA gene mutations. Fibroblasts were generated from skin biopsies taken from a selection of patients. GBA metabolism (Western blotting for protein levels, enzyme activity, immunofluorescent localisation), mitochodrial metabolism, endoplasmic reticulum and oxidative stress markers were assayed in the cell lines. Results – GD patients and heterozygous carriers had significantly lower olfactory and cognitive function scores than controls. Several GD patients and carriers had motor signs of PD (e.g. rest tremor) while controls did not. Thirteen PD patients with heterozygous GBA mutations were identified. Their clinical phenotype was similar to mutation negative PD cases. GD fibroblast lines (n=5), and lines from heterozygous GBA mutation carriers with (n=4) and without PD (n=2) had reduced GBA enzyme activity due to endoplasmic reticulum retention of GBA protein. This was associated with upregulation of endoplasmic reticulum stress markers and oxidative stress (increased rate of dihydroethidium oxidation). Conclusions – a subset of GD patients and carriers express clinical markers of prodromal PD. Study of fibroblasts from these individuals indicates that endoplasmic reticulum and oxidative stress may contribute to increased PD risk in these individuals.
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Henriques, da Silva Darly. "Nouveaux matériaux et mutations industrielles." Paris 1, 1994. http://www.theses.fr/1994PA010077.
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Les nouveaux materiaux constituent un domaine tres complexe recouvrent des aspects sociaux, economiques et politiques de la societe. Dans notre etude, nous avons privilegie les aspects technico-economiques, sans pour autant negliger le cote social, en mettant en evidence le role des nouveaux materiaux sur les mutations en cours dans le systeme industriel, mouvement propre aux pays developpes. Ce mouvement de restructuration vise aussi bien la mise en valeur des nouvelles technologies, en particulier les applications des nouveaux materiaux, qu'une adaptation aux nouvelles regles d'organisation du travail, avec des consequences sur les pays en voie de developpement, producteurs de matieres premieres minerales<br>New materials technology represents a very complex field extending to social, economical and political aspects. In that study we have focused on technical-economical considerations, although social regards have been not neglected. We emphasize the importance taken by new materials technology on some current transformations arising on the industrial system of developed countries. They have been restructured to take further advantage from new techniques, especially regarding applications of new materials, and to be well adapted to a work organisation, with some consequences on developing countries, producers and transformers of mineral raw materials
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Lepez, Justine, and Justine Lepez. "Les mutations du droit moral." Master's thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/38198.
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Notre mémoire de maîtrise porte sur les mutations du droit moral en France. Traditionnellement, le droit moral est prédominant sur les droits patrimoniaux, en raison de la conception personnaliste qui irrigue le droit d’auteur français et en fait sa singularité. Cette prééminence engendre classiquement une stabilité et une position suffisamment forte pour résister au vent consumériste qui souffle sur le paysage juridique international occidental. Néanmoins, en raison de la dilution de la notion d’auteur, de la tendance à la collectivisation et donc l’émergence d’une multiplicité d’œuvres, de nouveaux modes de diffusion et de la mise en place systématique d’une balance des intérêts contra legem entre le droit moral et la liberté de création, ce droit extrapatrimonial témoigne d’un changement de paradigme manifeste en ce qu’il fait l’objet de mutations profondes, s’agissant des principes fondamentaux qui composent son socle commun, de la diversité des régimes spécifiques selon les objets protégés, et du renouvellement des méthodes du juge. La position hégémonique de la liberté d’expression artistique entraine inexorablement un affaissement considérable du droit moral de l’auteur. Une perspective inquiète en ce qu’elle menace la pérennité de la singulière institution romantique du droit d’auteur français.<br>Notre mémoire de maîtrise porte sur les mutations du droit moral en France. Traditionnellement, le droit moral est prédominant sur les droits patrimoniaux, en raison de la conception personnaliste qui irrigue le droit d’auteur français et en fait sa singularité. Cette prééminence engendre classiquement une stabilité et une position suffisamment forte pour résister au vent consumériste qui souffle sur le paysage juridique international occidental. Néanmoins, en raison de la dilution de la notion d’auteur, de la tendance à la collectivisation et donc l’émergence d’une multiplicité d’œuvres, de nouveaux modes de diffusion et de la mise en place systématique d’une balance des intérêts contra legem entre le droit moral et la liberté de création, ce droit extrapatrimonial témoigne d’un changement de paradigme manifeste en ce qu’il fait l’objet de mutations profondes, s’agissant des principes fondamentaux qui composent son socle commun, de la diversité des régimes spécifiques selon les objets protégés, et du renouvellement des méthodes du juge. La position hégémonique de la liberté d’expression artistique entraine inexorablement un affaissement considérable du droit moral de l’auteur. Une perspective inquiète en ce qu’elle menace la pérennité de la singulière institution romantique du droit d’auteur français.<br>Our master's dissertation focuses on the mutations of the author’s moral right in France. Traditionally, the moral right has been predominant over economic rights, due to the personalistic conception that underlies French copyright and makes its specificity. This pre-eminence typically generates a situation of stability and a strong enough position in order to resist the consumerist wind that blows on the Western international legal landscape. Nevertheless, because of the dilution of the notion of author, the tendency towards collectivization and thus the emergence of a multiplicity of works, new modes of distribution and the systematic establishment of a balance of interests between moral rights and freedom of creation, this extra-patrimonial right shows a clear paradigm shift in that it is subject to profound changes, with regard to the fundamental principles that constitute its common ground, the diversity of specific regimes depending on the protected objects, and the renewal of the judge’s methods. The hegemonic position of freedom of artistic expression inevitably leads to a considerable collapse of the author's moral right. A worrying prospect in that it threatens the sustainability of the outstanding romantic institution of French copyright.<br>Our master's dissertation focuses on the mutations of the author’s moral right in France. Traditionally, the moral right has been predominant over economic rights, due to the personalistic conception that underlies French copyright and makes its specificity. This pre-eminence typically generates a situation of stability and a strong enough position in order to resist the consumerist wind that blows on the Western international legal landscape. Nevertheless, because of the dilution of the notion of author, the tendency towards collectivization and thus the emergence of a multiplicity of works, new modes of distribution and the systematic establishment of a balance of interests between moral rights and freedom of creation, this extra-patrimonial right shows a clear paradigm shift in that it is subject to profound changes, with regard to the fundamental principles that constitute its common ground, the diversity of specific regimes depending on the protected objects, and the renewal of the judge’s methods. The hegemonic position of freedom of artistic expression inevitably leads to a considerable collapse of the author's moral right. A worrying prospect in that it threatens the sustainability of the outstanding romantic institution of French copyright.
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Leonardi, Emanuela. "Bioinformatic Analysis of Protein Mutations." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3426280.
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Many gene defects have been associated to genetic disorders, but the details of molecular mechanisms by which they contribute to the disease are often unclear. The study of mutation effects at the protein level can help elucidate the biological processes involved in the disease and the role of the protein in it. Bioinformatics can help to address this problem, being the connection between different disciplines including clinical, genetics, structural biology, and biochemistry. By using a computational approach I tackled the analysis of some examples of biomedical interesting proteins integrating various sources of data and addressing experimental and clinical investigations. Experimentally defined structures and molecular modelling were used as a basis to determine the protein structure-function relationship, which is essential to gain insights into disease genotype-phenotype correlation. Proteins have been further analyzed in their context, considering interactions that they take in specific cellular compartments. The results have been used to formulate functional hypotheses, which in some cases have been tested and confirmed by further investigations performed by cooperation groups. Mutations found in genes encoding these proteins have been evaluated for their impact on the protein structure and function by using several available prediction methods. These studies provided the idea for developing novel approaches, using residue interaction networks and an ensemble of methods. A novel strategy has been also designed to evaluate genomic data obtained by next generation sequencing technology. This consists in using available resources and software to prioritize rare functional variants and estimate their contribution to the disease. The novel approaches developed in this thesis have been applied and assessed at the Critical Assessment of Genome Interpretation (CAGI) experiment in 2011, providing in some cases very successful results<br>Alterazioni genetiche sono state identificate per molte malattie di natura genetica, ma in molti casi i meccanismi molecolari che contribuiscono all’insorgere della malattia non sono ancora chiari. Lo studio degli effetti delle mutazioni a livello della proteina permette di chiarire i processi biologici coinvolti nella malattia e il ruolo della proteina in essa. La bioinformatica può aiutare a affrontare questo problema rappresentando il punto di connessione tra diverse discipline quali la clinica, la genetica, la biologia strutturale e la biochimica.
In questa tesi ho impiegato un approccio computazionale per affrontare l’analisi di alcuni esempi di proteine di interesse biomedico, integrando diverse risorse di dati e indirizzando la ricerca sperimentale e clinica. Strutture proteiche determinate sperimentalmente o mediante il modelling molecolare sono state utilizzate come base per determinare la relazione tra struttura e funzione, essenziale per ottenere informazioni sulla correlazione genotipo-fenotipo. Le proteine prese in esame sono state inoltre analizzate nel loro contesto, considerando le interazioni che avvengono con altre proteine o ligandi nei diversi compartimenti cellulari. I risultati dell’analisi bioinformatica sono stati poi utilizzati per formulare ipotesi funzionali che in alcuni casi sono state verificate e confermate sperimentalmente da altri gruppi di ricerca. Le mutazioni identificate nei geni codificanti per le proteine in esame sono state valutate per il loro impatto sulla struttura e funzione della proteina utilizzando numerosi metodi di predizione disponibili online. Le diverse applicazioni descritte in questa tesi hanno fornito l’idea per lo sviluppo di nuovi approcci computazionali per lo caratterizzazione strutturale e funzionale di proteine e dei loro mutanti. Si è visto che la predizione migliora utilizzando un ensemble dei diversi metodi di predizione disponibili. Inoltre, per la predizione degli effetti di mutazioni è stato ideato un nuovo approccio computazionale che utilizza le reti di interazione tra residui per rappresentare la struttura proteica. Questi metodi sono stati utilizzati anche nell’analisi di dati genomici originati da nuove tecnologie di sequenziamento. Questo ambito necessita di nuove strategie di indagine per l’individuazione di poche varianti causative in un’enorme quantità di varianti identificate di dubbio significato. A questo scopo viene proposta una strategia di analisi che utilizza informazioni derivanti dalle reti di interazioni proteiche.
I nuovi approcci formulati in questa tesi sono stati applicati e valutati ad un nuovo esperimento internazionale, chiamato Critical Assessment of Genome Interpretation (CAGI), fornendo in alcuni casi ottimi risultati
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Tsui, Wai-yan. "Determination of PTEN mutations in prostate cancer in Chinese." Hong Kong : University of Hong Kong, 2001. http://sunzi.lib.hku.hk/hkuto/record.jsp?B23736173.
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Tsao, Chihyi. "The Effects of Mitochondrial DNA Mutations on Cell Growth." Thesis, University of Canterbury. Biological Sciences, 2005. http://hdl.handle.net/10092/1523.
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Mitochondrial DNA encodes thirteen protein subunits in the oxidative phosphorylation system (OXPHOS) that is responsible for cellular energy production. Mitochondrial disorders have been identified to be associated with mtDNA mutations. However, the molecular mechanisms of specific mtDNA mutations are still being explored in order to establish causative links. This study tries to elucidate the mutational effects of mtDNA on OXPHOS complex activities and cell growths. Using mouse 3T3 fibroblasts as a cell model, single-cell clones with different growth rates were isolated. The entire mtDNA genome was sequenced for mutations. The enzymatic activities of OXPHOS complex I to V were analysed. Three growth patterns represented by five clones were identified. Three clones (clone #2, #3, and #6) had the shortest doubling times (11.5 - 14.9 hours). Clone #1 had a medium growth rate (19.2 hous); and clone #5 had a significantly slow growth rate (22 hours). MtDNA sequencing results revealed that clone #5 had several heteroplasmic mutations (one in 16S rRNA, two in tRNAser (UCN), three in tRNAasp, one in tRNAlys, one in COI, five in COII, and one in ATPase8) while the other four clones showed sequence homology. Enzymatic analyses showed that on average clone #5 had significantly low complex III, IV, and V activities (p < 0.05). Changes in biochemical properties and protein structure were analyzed to deduct possible mechanisms for reduced respiration. In conclusion, the slow growth rate is associated with reduced OXPHOS enzyme functions. It is most likely that the combination of COI and COII mutations resulted in the reduction of complex IV function. It is still unclear whether the ATPase8 mutation (T7869A) in the non-conserved region alone can have such a pronounced phenotypic effect. A reduction in complex III also cannot be explained since there were no mutations in the only mtDNA-encoded complex III gene, but it is possible that there are mutations in the nDNA-encoded complex III genes. Mutations in tRNA and rRNA genes may also be responsible for reduced protein syntheses and consequently reduced OXPHOS activities. It is unclear why complex I activity was not affected. Although the mutational effect of individual mtDNA mutation observed cannot be clearly identified, this study establishes a correlation between mtDNA mutation and cell energy production and growth.
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Raymond, Kyle A. "APOBEC3, cytidine deaminases at the crossroads of cellular stress, viral editing and tumorigenesis." Electronic Thesis or Diss., Sorbonne université, 2024. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2024SORUS287.pdf.
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La famille de protéines APOBEC3 englobe une variété de fonctions importantes pour la santé humaine. Ces protéines ont la capacité intrinsèque de se lier et de modifier l'ADN simple brin grâce à un processus appelé la désamination de la cytidine. Les enzymes APOBEC3 jouent un rôle important dans le déclenchement de la réponse immunitaire innée. Elles sont par exemple, capables d'hyperéditer les génomes viraux et de restreindre leur réplication. Leur activité crée une mutation de la cytidine en thymine. La perturbation du mécanisme de régulation cellulaire qui contrôle l'activité nucléaire des protéines APOBEC3 conduit à une hypermutation généralisée de l'ADN. Ce phénomène est étroitement lié à l'instabilité génomique et favorise l'émergence de cancers. La première partie de cette thèse commence par l'examen des mutations du génome viral identifiées lors d'une épidémie mondiale de MPOX en 2022, rappelant les signatures d'édition des APOBEC3. Nous avons démontré la capacité de l'APOBEC3F à hypermuter le génome viral de la variole du singe. Nous avons corrélé ces mutations obtenues in vitro avec les mutations observées dans les isolats viraux de patients infectés. La deuxième partie de cette thèse examine le rôle de la protéine nucléaire APOBEC3B en tant que facteur de restriction de l'adénovirus. Nous avons démontré que l'expression d'APOBEC3B conduit à une diminution de la charge virale et des particules virales infectieuses de l'adénovirus. Nous avons également confirmé l'activité dépendante de la désaminase sur l'adénovirus en récupérant des séquences virales hypermutées en présence d'APOBEC3B. La troisième partie de cette thèse étudie une voie de signalisation unique des interférons (IFN) impliquée dans la détection de l'ADN mitochondrial (mt) cytosolique. Nous avons démontré dans un modèle cellulaire humain in vivo, la libération de l'ADNmt dans le cytosol lors de l'infection par le virus de la rougeole (MeV). Cet ADNmt cytosolique est associé à une forte production d'IFN, et à son tour, à la surexpression d'APOBEC3A. Cette surexpression n'est pas sans conséquence, car l'activité d'APOBEC3A entraîne la formation de cassures double-brin de l'ADN nucléaire.Comprendre les mécanismes cellulaires régissant l'APOBEC3A est essentiel, car une expression non contrôlée entraîne une instabilité génomique. Enfin, dans cette thèse, nous identifions le rôle de la protéine nucléaire RBMX. En effet, RBMX est capable de promouvoir l'intégrité génomique en bloquant l'accès d'APOBEC3A à l'ADN simple brin. Nous avons démontré que la perte de RBMX entraîne une augmentation des cassures double-brin de l'ADN induites par APOBEC3A. Tandis que la surexpression réduit la présence de mutations induites par APOBEC3A. De plus, les génomes tumoraux des patients cancéreux présentant un défaut de RBMX présentent davantage de mutations CG>TA associées à APOBEC3<br>The APOBEC3 family of proteins encompass a variety of functions that are critical to human health and disease. These proteins have an intrinsic ability to bind and edit single-stranded DNA through a process known as cytidine deamination. APOBEC3 enzymes comprise a significant branch of the innate immune system, capable of hyperediting viral genomes and restricting replication. Their activity leaves a trail of cytidine to thymine mutations in a context specific manner. Consequentially, loss of cellular control of nuclear localized APOBEC3 activity results in extensive DNA hypermutation which have been associated with genomic instability and the development of cancer. This thesis begins by investigating viral genome mutations identified during a global outbreak of MPOX in 2022 that presented in a context specific manner, reminiscent of APOBEC3 editing signatures. We demonstrated the capacity for APOBEC3F to hypermutate the monkeypox viral genome and correlated these mutations obtained in vitro to mutations observed in viral isolates from infected patients. The second part of this thesis investigates the role of the nuclear APOBEC3B protein to act as an adenovirus restriction factor. We demonstrated that expression of APOBEC3B leads to the decreased propagation, viral load and infectious viral particles of adenovirus. We further confirmed deaminase dependent activity on adenovirus by recovering hypermutated viral sequences in the presence of APOBEC3B. The third part of this thesis investigates a unique interferon signaling pathway involved in cytosolic mitochondrial (mt)DNA detection. We demonstrated the release of mtDNA within the cytosol upon Measles Virus (MeV) infection of both a human cellular model and an in vivo model. This cytosolic mtDNA is associated with a strong production of IFN, and in turn, the overexpression of APOBEC3A. This overexpression is not without consequence, as the activity of APOBEC3A resulted in the formation of nuclear double-strand DNA breaks. Understanding cellular mechanisms governing APOBEC3A is essential, as unchecked expression results in genomic instability. Finally, in this thesis, we identify a novel role of the nuclear localized protein, RBMX, to promote genomic integrity by blocking the access of APOBEC3A to single stranded DNA. We demonstrated that the loss of RBMX results in the increase of APOBEC3A induced genomic double-strand breaks, while overexpression reduces the presence of APOBEC3A induced mutations. Furthermore, tumor genomes from cancer patients with defective RBMX present higher CG>TA APOBEC3 associated mutations
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Hirashima, Takako. "Choroidal Vasculature in Bietti Crystalline Dystrophy With CYP4V2 Mutations and in Retinitis Pigmentosa With EYS Mutations." Kyoto University, 2020. http://hdl.handle.net/2433/253205.
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Azad, Priti. "The Role of New Mutations in Evolution and Cloning: Genetic Analysis to Identify the Role of New Beneficial Mutations in Increasing Viability and Salt Tolerance in Drosophila Melanogaster and the Influence of Deleterious Mutations on Cloning Efficiency." Connect to this title online, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=bgsu1159903219.
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Nagao, Kentaro. "Mutations and noncommutative Donaldson-Thomas theory." 名古屋大学多元数理科学研究科, 2009. http://hdl.handle.net/2237/12261.
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Kamanu, Frederick Kinyua. "Computational Verification of Published Human Mutations." Thesis, University of the Western Cape, 2008. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_2906_1269551415.
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<p>The completion of the Human Genome Project, a remarkable feat by any measure, has provided over three billion bases of reference nucleotides for comparative studies. The next, and perhaps more challenging step is to analyse sequence variation and relate this information to important phenotypes. Most human sequence variations are characterized by structural complexity and, are hence, associated with abnormal functional dynamics. This thesis covers the assembly of a computational platform for verifying these variations, based on accurate, published, experimental data.</p>
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Swalwell, Helen. "Mitochondrial DNA Mutations in Human Disease." Thesis, University of Newcastle upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485565.
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Pathogenic mutations in mitochondrial DNA (mtDNA) are recognised as an important cause of disease, and in many cases lead to well-characterised clinical syndromes. However in many cases the clinical phenotypes associated with mutations in mtDNA are highly variable and the genotype-phenotype correlation is not straightforward. The pathogenesis of mtDNA mutations in many cases remains poorly understood and as such, studies aimed at understanding the expression of mtDNA disease Will benefit genetic counselling, lead to more accurate estimations of mtDNA disease prevalence in popul~tions and hopefully lead to the development ofrational treatments. ,./' In collaboration with Dr. David Thorburn (Murdoch Children's Research Institute, Melbourne), the molecular basis of 15 paediatric patients with a diagnosis of complex I .deficiency has been investigated. These results demonstrate that following rigorous criteria to diagnose complex I deficiency, <25% of cases of paediatric complex I deficiency can be attributed to pathogenic mutations in mtDNA. Due to the highly polymorphic nature of mtDNA, the pathogenicity of any identified mutation must be established using well-defined published criteria. The pathogenicity of four rare/novel mutations in mt-tRNA genes is confirmed and the clinical and ' biochemical consequences of these mutations are investigated in these families. There is increasing evidence that additional homoplasmic variants can playa role in the expression of well-characterised pathogenic mutations. The role of a specific homoplasmic variant, m.7472A>C over the expression of the well-characterised pathogenic mtDNA mutation, m.7472Cins is investigated using both patient studies and transmitochondrial cybrid clones as a model for determining the functional consequences of these changes in an in vitro system. These results provide evidence that additional mutations in mtDNA can influence the expression of pathogenic mutations. Some mt-tRNA mutations are clearly inherited throughout several generations, whereas others arise sporadically and show little or no evidence of transmission. The features of a numb~r of published pathogenic mt-tRNA mutations have been evaluated in order to look for any characteristics that may determine transmission. Whilst the majority of features of these mutations show no correlation with the likelihood of transmission, one factor shows clear correlation. If the mutation is present in the patient's muscle but absent in blood, then the mutation is likely to have arisen sporadically in that patient, and is unlikely to be transmitted.
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Jivraj, Shehnaaz. "Genetic thrombophilic mutations and recurrent miscarriage." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486914.
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Recurrent miscarriage (RM) affects 1% of the population. Some cases have a thrombotic aetiology. While it is known that the allele frequency of factor V Leiden (FVL), a thrombophilic gene mutation, is similar between women with and without RM, the miscarriage rate of a subsequent untreated pregnancy is significantly higher in RM women carrying FVL. The studies in the thesis explore the hypothesis that (a) women with FVL and RM, who went on to miscarry again may have an additional thrombophilia that increased their risk of miscarriage (b) thrombophilia genotype inherited by the fetus may determine pregnancy outcome. The first study in the thesis demonstrates that the allele frequencies of FVL, Prothrombin G20210A (pTG) and MTHFR C677T (MTHFR) gene mutations and the prevalence of multiple thrombophilia are similar in couples with RM (n=357), late pregnancy loss (n=69) and a race matched control population (n=68). The second study describes a prospective study which shows that in couples with RM, the miscarriage rate in a subsequent untreated pregnancy was significantly higher if the male or the female partner carried multiple thrombophilic defects than if neither carried a thrombophilic defect (83% vs 44%, RR 1.9; 95% CI, 1.3-2.8). This study suggested that the paternal thrombophilia genotype, and by inference the fetal thrombophilia genotype contributes to determining pregnancy outcome. The third study explores this hypothesis by analysing the allele frequencies of FVL, PTG and MTHFR in miscarried products of conception from first trimester miscarriages (n=31) and umbilical cord blood from live-births (n=89). The allele frequency of PTG was higher in products of conception from first trimester miscarriages than live births (4.8% vs 1.1%, OR 4.47; 95% CI 0.49-54.36). The prevalence of multiple thrombophilic defects was also higher in products of conception from first trimester miscarriages than live births (6.4% vs 2.2% OR 3.00; 95% CI 0.2-42.6) This research suggests that the paternal thrombophilia genotype influences pregnancy outcome. This is a new concept in our understanding of the aetiology of RM and highlights the importance of investigating the male partner with RM. If further studies and larger datasets confirm our findings, the concept of paternal thrombophilia genotype and by inference fetal thrombophilia genotype could lead to a whole new paradigm in the way couples with RM are investigated.
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Kugelberg, Elisabeth. "Mechanisms of adaptive mutations in bacteria /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-446-5/.
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Vestling, Monika. "Alzheimer's disease mutations and cellular signalling /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4993-X.
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Bahubeshi, Mohamed-Amin. "Germline DICER1 mutations in human disease." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104870.
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The DICER1 gene, which codes for a protein of the same name, is vital to the production of microRNA. As small ~20nt fragments of RNA, microRNAs alter gene expression post-transcriptionally by directly binding to mRNA and affecting translation. Current estimates suggest that expression of 30-70% of all protein-coding genes is modified by microRNA activity.Germline DICER1 mutations have recently been associated with cases of pleuropulmonary blastoma, a childhood lung tumor. We have discovered germline DICER1 mutations to be associated with other diseases by identifying mutations in nearly 60 individuals within 15 different families and across 7 different disease phenotypes. These include cases of pleuropulmonary blastoma, cystic nephroma - a benign kidney tumor, and Wilms tumor - the malignant version of cystic nephroma. Furthermore, we have identified DICER1 mutations in several families with Sertoli-Leydig cell tumor (SLCT) - a rare, androgen producing cancer of the ovaries, and multinodular goiter (MNG) - a relatively common thyroid hyperplasia. We have demonstrated that DICER1 is the genetic link between SLCT and MNG first hypothesized in 1974 by Fraumeni and colleagues. Also, we have identified DICER1 to be the gene of the MNG1 locus at 14q32, which was first pinpointed to this region in 1997 and identified in several MNG families. We further expanded the disease phenotype associated with DICER1 mutation to include cervical embryonal rhabdomyosarcoma.While DICER1 is a postulated to be a human tumor suppressor gene, we found no evidence of loss of heterozygosity in tumor DNA, a finding supported by recent evidence that DICER1 is a tumor suppressor with unique characteristics. Profiling of miRNA in affected cells showed significant differences in expression of miRNAs compared to controls. We demonstrate that DICER1 mutations are associated with diseases other than pleuropulmonary blastoma, an unsurprising revelation when the far-reaching implications of microRNA production are considered. These developments may be utilized in future therapeutic endeavors and for screening of families which present with a similar array of disease.<br>Le gène DICER1, qui code pour la protéine du même nom, est essentiel pour la production de microARNs. Ceux-ci étant aussi courts que 20 nucléotides, modifient l'expression des gènes ciblés en phase de posttranscription en se liant directement aux mARNs et en conséquences affectant leur translation. Présentement, on estime que l'expression de 30 à 70% de tous les gènes qui codent pour une protéine sont modifiés par des microARNs. Récemment, 60 à 70% de tous les cas de blastomes pleuropulmonaires, tumeurs pulmonaires infantiles, ont été associés à des mutations germinales de DICER1. Nous avons découvert que des mutations germinales de DICER1 sont impliquées dans un tableau de maladies en identifiant des mutations dans 60 personnes provenant de 15 familles différentes, ayant 7 phénotypes de maladies différents. Ceux-ci incluent des cas de blastomes pleuropulmonaires, de néphromes kystiques – des tumeurs rénales bénignes, et des tumeurs de Wilms – une forme maligne de la néphrome kystique. Par ailleurs, nous avons identifié des mutations de DICER1 dans plusieurs familles affectées par des tumeurs de cellules Sertoli-Leydig (TCSL) – un cancer rare de l'ovaire produisant de l'androgen, et la goitre multinodulaire (GMN) - une hyperplasie relativement fréquente de la thyroïde. Nous avons demontré que DICER1 est le lien entre TCSL et GMN ce qui a été suggéré en 1974 par Fraumeni et ses collegues. Nous avons également identifié que le gène MNG1 au locus 14q32 est DICER1. Cette région était découverte en 1997 dans plusieurs familles avec GMN. Nous avons élargi le phénotype des maladies associées avec DICER1, et ajouté le rhabdomyosarcome embryonnaire cervical à la liste. Quoique DICER1 est un gène suppresseur de tumeur, nous n'avons pas trouvé une preuve de la perte d'hétérozygotie dans l'ADN des tumeurs testées. Ceci est validé par des preuves récentes que DICER1 est un gène suppresseur de tumeur à caractère unique. L'expression des microARNs dans les cellules cancéreuses était significativement différente de celui observée dans les cellules normales. Nous avons démontré que les mutations de DICER1 sont associées à des maladies variées, une découverte pas très surprenante considérant son rôle de grande envergure dans la production de microARNs. Ces développements peuvent être utilisés dans de futurs efforts thérapeutiques et pour le dépistage des familles avec des maladies semblables.
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Krook, Anna Christina. "Insulin receptor mutations in human disease." Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266558.
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McGettrick, Aileen Jane. "Molecular consequences of mutations in FBNI." Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249501.
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Sharma, Oliver. "Detecting worm mutations using machine learning." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/469/.
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Worms are malicious programs that spread over the Internet without human intervention. Since worms generally spread faster than humans can respond, the only viable defence is to automate their detection. Network intrusion detection systems typically detect worms by examining packet or flow logs for known signatures. Not only does this approach mean that new worms cannot be detected until the corresponding signatures are created, but that mutations of known worms will remain undetected because each mutation will usually have a different signature. The intuitive and seemingly most effective solution is to write more generic signatures, but this has been found to increase false alarm rates and is thus impractical. This dissertation investigates the feasibility of using machine learning to automatically detect mutations of known worms. First, it investigates whether Support Vector Machines can detect mutations of known worms. Support Vector Machines have been shown to be well suited to pattern recognition tasks such as text categorisation and hand-written digit recognition. Since detecting worms is effectively a pattern recognition problem, this work investigates how well Support Vector Machines perform at this task. The second part of this dissertation compares Support Vector Machines to other machine learning techniques in detecting worm mutations. Gaussian Processes, unlike Support Vector Machines, automatically return confidence values as part of their result. Since confidence values can be used to reduce false alarm rates, this dissertation determines how Gaussian Process compare to Support Vector Machines in terms of detection accuracy. For further comparison, this work also compares Support Vector Machines to K-nearest neighbours, known for its simplicity and solid results in other domains. The third part of this dissertation investigates the automatic generation of training data. Classifier accuracy depends on good quality training data -- the wider the training data spectrum, the higher the classifier's accuracy. This dissertation describes the design and implementation of a worm mutation generator whose output is fed to the machine learning techniques as training data. This dissertation then evaluates whether the training data can be used to train classifiers of sufficiently high quality to detect worm mutations. The findings of this work demonstrate that Support Vector Machines can be used to detect worm mutations, and that the optimal configuration for detection of worm mutations is to use a linear kernel with unnormalised bi-gram frequency counts. Moreover, the results show that Gaussian Processes and Support Vector Machines exhibit similar accuracy on average in detecting worm mutations, while K-nearest neighbours consistently produces lower quality predictions. The generated worm mutations are shown to be of sufficiently high quality to serve as training data. Combined, the results demonstrate that machine learning is capable of accurately detecting mutations of known worms.
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Emuss, Victoria Louise. "C-RAF Mutations in human cancer." Thesis, Institute of Cancer Research (University Of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511164.
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Ali, Muhammad Akhtar. "Understanding Cancer Mutations by Genome Editing." Doctoral thesis, Uppsala universitet, Genomik, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-235680.
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Mutational analyses of cancer genomes have identified novel candidate cancer genes with hitherto unknown function in cancer. To enable phenotyping of mutations in such genes, we have developed a scalable technology for gene knock-in and knock-out in human somatic cells based on recombination-mediated construct generation and a computational tool to design gene targeting constructs. Using this technology, we have generated somatic cell knock-outs of the putative cancer genes ZBED6 and DIP2C in human colorectal cancer cells. In ZBED6-/- cells complete loss of functional ZBED6 was validated and loss of ZBED6 induced the expression of IGF2. Whole transcriptome and ChIP-seq analyses revealed relative enrichment of ZBED6 binding sites at upregulated genes as compared to downregulated genes. The functional annotation of differentially expressed genes revealed enrichment of genes related to cell cycle and cell proliferation and the transcriptional modulator ZBED6 affected the cell growth and cell cycle of human colorectal cancer cells. In DIP2C-/-cells, transcriptome sequencing revealed 780 differentially expressed genes as compared to their parental cells including the tumour suppressor gene CDKN2A. The DIP2C regulated genes belonged to several cancer related processes such as angiogenesis, cell structure and motility. The DIP2C-/-cells were enlarged and grew slower than their parental cells. To be able to directly compare the phenotypes of mutant KRAS and BRAF in colorectal cancers, we have introduced a KRASG13D allele in RKO BRAFV600E/-/-/ cells. The expression of the mutant KRAS allele was confirmed and anchorage independent growth was restored in KRASG13D cells. The differentially expressed genes both in BRAF and KRAS mutant cells included ERBB, TGFB and histone modification pathways. Together, the isogenic model systems presented here can provide insights to known and novel cancer pathways and can be used for drug discovery.
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Ng, Pei-Suin. "Mutations of pastness : time, cinema, ontology." Thesis, University College London (University of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526854.
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The thesis investigates how recent digital technologies of cinema-digital video, CGI, virtual cinematography and motion capture-reconfigure the nature (and, in turn, temporalities) of the moving image. Its objectives are to rework the ontology of the image, revisit the meaning of time in relation to the image and re-evaluate the significance of cinema for ourselves and our consciousness of time. The thesis revolves around the central premise of the photographic image's (Peircian) indexicality-the imprint of light on film/celluloidwhereby the referent "adheres" to the photograph through existential, causal and physical connection. It argues that this connection transmits not only reality but also time, specifically pastness. By virtue of this, we may analyse the photographic image as a trace not only of an object but also of time past. Extending this premise of ontology and pastness from still photography to cinema, the thesis investigates how this temporality of pastness mutates in cinema's digital transformations. Chapter One deals with pastness in the indexicality of the photographic image in relation to its presentness qua moving image, i. e. as cinema unreels before us in our viewing of it. Chapter Two explores how computer code inherent in the technologies of DV, CGI and virtual cinematography revises the nature of the image so as to generate its own form of timelessness. Chapter Three examines the novel manner in which motion capture technologies create cinematic imagery by recording non-visible movement rather than visible light, in turn transfiguring time in the image as space and temporal between-ness. Studying cinema as an object of time rather than as an object of reality, the thesis suggests how cinema might exist-in all its transformations, in all its different waysin distinctive temporalities.
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Luo, Da. "Transposon-induced mutations in Antirrhinum majus." Thesis, University of East Anglia, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280022.
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Elliott, Hannah. "Epidemiology of mitochondrial DNA point mutations." Thesis, University of Newcastle Upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442343.
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Lopes, Carlos. "Les Kaabunke : structures politiques et mutations." Paris 1, 1988. http://www.theses.fr/1988PA010657.
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Cette these essaye de presenter l'evolution politique et economique d'un etat malinke du soudan occidental, entre le xiiie et le xixe siecles: le kaabu et son systeme de mansaya. La creation du kaabu est liee a l'expansion de l'empire du mali de sunjata keita et il semble que c'est un de ses hommes de guerre - tiramakan traore - qui a ete le fondateur de l'etat du kaabu (kaabunke) dans les plaines de la haute cote de guinee. L'arrivee - particulierement des portugais, aux "rivieres du sud" (xve siecle) provoquera la naissance de nouvels axes commerciaux qui seront a la base d'un developpement du kaabu dans la region comprise en- tre les fleuves gambie et corubal. Des sa creation le kaabu a cree une rotation du pouvoir entre trois clans de malinkes nobles - un sane et deux mane - base de classe nyantio qui a gouverne le pays sans partage. Les nyantio qui suivaient de pres les regles de succession matrilineaires ont ete a l'origine d'une malinkisation des autres ethnies de la region. Ils ont developpe une economie dependante du commerce de longue distance des dyula en uti- lisant les esclaves comme principal produit d'echange. Le controle territorial exerce par le kaabu a commence a flechir avec la diminution du flux d'esclaves, et ensuite l'autonomisation des pouvoirs locaux. Les interets coloniaux aidant plusieurs ethnies mettront en cause la legitimite des nyantio et le dernier chef kaabunke janke wali sera oblige de capituler dans la bataille de turban kelo ou kansala en 1867. L'interet de l'etude du kaabu resulte du fait qu'elle permet de demontrer que nous sommes en presence d'un pouvoir qui a rayonne en fonction de ses espaces d'influence plutot que sur la centralisation de son pouvoir<br>This study presents the political and economic development of the malinke state of kaabu, in the western sudan, between the 13th and 19th centuries. The beginning of kaabu is linked to the expansion of sunjata keita's mali empire and one of this captains - tiramakan traore - is considered as the founder of the kaabu state (kaabunke) on the upper guinea coast. The arrival of the europeans on the guinea coast, especially the portuguese, in the 15th century, crea- ted new trade routes through the kaabu, contributing to the development of the region between gambia and corubal rivers. The kaabunke power was controled by three proeminent malinke clans - one sane and two mane's - from the aristocratic nyantio class who governed the country the nyantio which where of matrilinear discent tried to assimilate to their culture all the other ethnic groupes in the region. They where especially related, economically, with the dyula long distance slave traders (for the slave trade). The territorial control of the nyantio over the kaabu was very weak and declined even more after the end of the slave trade era and the beginning of independance of the different local powers. With the powerfun presence of the europeans, with their purposes of colonisation the nyantio legitimay was perturbed and the last kaabu chief, janke wali, was obliged to surender in the turban kello (ou kansala) battle in 1867. The kaabu history is interesting because of his original political structure based on different space influences rather than centralized power
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Faucompré, Éric. "Permanence et mutations du secret médical." Paris 8, 2012. http://octaviana.fr/document/18199061X#?c=0&m=0&s=0&cv=0.
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Sous des apparences de simplicité, le secret médical professionnel est malaisé à cerner, les textes se révélant parfois incertains, la jurisprudence souvent contradictoire et les commentateurs généralement divisés. La loi du 4 mars 2002 en annonçant une évolution majeure du secret médical, déplace le devoir au silence du médecin sanctionné par le Code pénal vers un droit du patient garanti par le Code de la santé publique. Ce droit, rendu au malade, peut être aussi celui du tiers ; si le secret est unique quant à son objet, l’état de santé du patient, il est dual quant à ses sujets, le patient et le médecin et multiple quant à sa circulation entre le patient, le médecin et tous ceux qui ont intérêt à le connaitre. L’irruption du tiers dans le partage du secret peut conduire à faire primer l’intérêt légitime du destinataire de l’information sur celui du patient et apparaît donc comme une question majeure à venir et la plus difficile à éclaircir. La tyrannie de la transparence et les impératifs d’une société moderne conduisent probablement à l’affaiblissement inéluctable de tous les secrets. Le consentement à l’acte thérapeutique suppose la confiance qui dépend du secret. Si le législateur choisit de ruiner le secret professionnel et peut être le secret médical, il prend alors le risque d’anéantir dans le médecin, la confiance publique comme celle du particulier, portant ainsi une atteinte irrémédiable à la santé publique et donc à l’intérêt fondamental des malades, celui d’être soignés<br>While being a seemingly straightforward notion, professional medical confidentiality is uneasy to define. Laws sometimes appear uncertain, legal precedents often contradictory and commentors generally divided. Heralding a major evolution of professional confidentiality, the 4 March 2002 Act introduced a shift from the onus of secrecy on the practitioner sanctioned by the penal code towards a patient's right guaranteed by the public health code. This right granted to the patient may also be a third party's. Confidentiality is unique regarding its object, i. E. The patient's condition, but it is dual as for its subjects, i. E. The patient and the practitioner, and it is diverse regarding the circulation of information between the patient, the practitioner and all those who have an interest in gaining access to this information. This sudden appearance of a third party may lead to a breach of confidentiality in which the patient's interests become subservient to the legitimate interests of those to whom that information is destined. We are here faced with a major issue that will need to be overcome. The tyranny of transparency and the necessities of a modern society are likely to bring about a gradual weakening of all forms of confidentiality. Agreeing to a therapeutic act inevitably involves trust and confidentiality. If a legislator chose to destroy professional and possibly medical confidentiality, they would run the risk of destroying public and individual trust in practitioners. They would thereby irrevocably damage public health and harm patients' fundamental interests, that of being cared for
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Roques, Michel. "Mutations récentes dans l'espace péricentral bordelais." Bordeaux 3, 1987. http://www.theses.fr/1987BOR30049.
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La premiere couronne de banlieues de bordeaux a l'ouest et au sud (begles, talence, st. Augustin, cauderan, le bouscat) se presente plus comme un espace urbain peri-central que comme un ensemble de communes et de quartiers tres differents de la ville centre elle meme. Comme l'espace pericentral "intra muros" de bordeaux ces vieilles banlieues subissent vieillissement et depopulation. Ces phenomenes peuvent particulierement etre mesures a l'echelle de l'ilot de maisons et se manifestent par la decroissance rapide de la population scolaire. Ce vieillissement est plus sensible que dans d'autres banlieues proches de grandes villes. Outre leur perte de population ces communes et quartiers perdent leur vitalite tant au niveau de la vie sociale que de leurs commerces de proximite ou de leurs industries en ce qui concerne les communes au sens juridique du terme, elles ont perdu tout (pour cauderan) ou partie (pour les autres) de leur autonomie, en particulier avec la creation de la communaute urbaine. Cette perte se manifeste aussi par la multiplication des migrations alternantes. Cette zone tend a voir se transformer son profil social par une sorte d'uniformisation autour des classes moyennes (y compris pour begles la commune qui reste cependant la plus populaire). La encore, les mutation sont plus rapides que dans d'autres agglomerations du pays. L'avenir des vieilles banlieues repose sur trois questions : l'evolution de la construction et du bati ancien, le dynamisme du commerce et les mutations commerciales des "barrieres", la possibilite d'animer une vie sociale. Au total, plus vieilles que les banlieues proches des autres grandes villes francaises, ces communes et quartiers de la premiere couronne apparaissent comme un espace typique de l'agglomeration bordelaise qui, dans d'autres villes, s'inscrirait plutot dans l'espace du pericentre avec des caracteritiques identiques<br>The first belt of suburbs surrounding bordeaux, west and south of the town (begles, talence, cauderan, le bouscat) is more an urban pericentral space than a gathering of townships and districts very different from the town centre itself. Like the pericentral space of intramural bordeaux, these suburbs are going through a process of ageing and depopulation. Those phenomena can be measured in a more accurate way on the basis of a block of houses and can be seen through a rapid decrease in school-age population. This ageing is more obvious than in any other suburb close to other french cities. Apart from their loss of population, these townships and districts lose their vitality, whether you consider their social life or their small trade and their industry. As far as the the townships are concerned, they have lost all (this is true of cauderan) or part of their autonomy, particularly because of the creation of the "communaute urbaine" (sort of greater bordeaux). This loss of autonomy can also be seen ni the increase in commuting. This area sees its social outlook change through a standardization around the middle classes, including in begles, the township which nevertheless remains the more working- class. There again, the changes are faster than in other french towns. The future of older suburbs rets with three matters : what will happen to new buildings and old stutures, the vitality of trade and the changes in trade within the "barrieres" (i. E. Within the boundaries of the old octrois), the possibility of promoting asocial life. As a whole, older than the suburbs closer to big french cities, these townships and suburbs of the firts belt look like a space typical of the greater bordeaux, which in other towns would be include in the pericentral space with identical features
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Gérardin, Frédéric. "Transférabilité des qualifications et mutations productives." Paris 1, 1997. http://www.theses.fr/1997PA010022.
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Cette thèse d'économie et de sociologie du travail développe une problématique alternative de la transférabilité des qualifications des salariés qui propose d'y voir un processus social permanente de reproduction à l'élargi de modalités tout à la fois de formation professionnelle de la main-d'oeuvre, d'application productive individuelle et collective par les salariés de leurs savoirs professionnels et de reconnaissance de qualités professionnelles aux individus. Elle remet la question de la dynamique sociale de qualifications inaliénablement collectives et individuelles des salariés en mode de production capitaliste, sur l'établi de la recherche dans les deux disciplines susmentionnées et au-delà en sciences sociales. Elle reformule une problématique de la transférabilité en terme d'instrument d'appréhension, de compréhesion et d'explication de la dynamique des réalités des qualifications, notamment aux plus forts des mutations productives alors que, les polysémies et controverses récurrentes des acceptions de la qualification limitent la portée de ces mêmes notions en matière d'analyse du mouvement et de la complexité des réalités qu'elles sont censées restituer et que l'approche beckerienne, certes hégémonique mais aussi beaucoup trop individualiste de la transférabilité des qualifications, ne peut finalement rendre compte que d'un aspect très partiel du mouvement des qualifications des salariés en mode de production capitaliste. Le succès de la formulation d'une problématique de la transférabilité de plus grande portée heuritstique doit à un retour aux analyses des transformations des qualifications proposées dans les grands corpus de l'économie politique occidentale et dans les approches plus contemporaines du développement de la division capitaliste du travail. Il doit aussi à un examen approfondi des avancées récentes sur la transférabilité à proprement parler dans la recherche en sciences sociales. Il doit enfin à l'application de la problématique de la transférabilité reformulée au cas des transformations des qualifications de la main-d'oeuvre de chantier du secteur de la construction en France<br>The main objective of this research is to develop an alternative concept of transferability of skills which is available to analyse the realities of skills in their social complexity and dynamics. Defined as a permanent process of reproduction of social modalities of, vocational training, individual and collective productive use of the vocational knowledges and recognition of individual degrees of vocational quality, the transferability is here conceptualized in opposition to the G. S. Becker's theory of the investment in human capital. By this way, the social aspects of the skills are reintegrated in the economical analysis of the dynamic of the capitalist system, especially during the periods of crisis. Finally, the previous alternative concept of transferability is applied in an analysis of the transformations of skills in the French construction industry during the last half-century
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Merrad, Benyamina Badra. "Déplacements et mutations spatiales à Alger." Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCH017.
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Alger, ville et port doit son histoire exceptionnelle à son site remarquable sur un éperon rocheux. Mais, cette morphologie s’est révélée contraignante d’une ville pour la croissance urbaine d’une ville qui prétend aujourd’hui rejoindre le rang de métropole. Au cours de son histoire, les relations entre le port et la ville ont pris de formes multiples souvent compatibles parfois opposées voire contradictoires, inversant les relations de domination. Alger, capitale d’un pays de 40 millions d’habitants a toujours été un laboratoire des politiques urbaines de la période coloniale aux différentes constructions institutionnelles de l’Algérie indépendante, en dépit d’un appareil statistique déficient. Mais, l’espace algérois est aujourd’hui confronté à des défis de grande ampleur avec une croissance anarchique difficilement contrôlée de sa population, une fragmentation des espaces urbanisés et des contraintes de déplacements difficilement soutenables.Si des infrastructures routières et de transports collectifs sont programmés et progressivement réalisés par les Plans successifs, leur articulation avec les zones bâtis et les lotissements construits pour permettre l’éradication des bidonvilles n’apparait pas marquée par une très grande cohérence. De même la localisation des différents équipements collectifs, qui semble plus relever d’opportunités foncières, ajoute à la complexité du tissu urbain. Toutefois, sous cette apparente complexité, apparaissent des logiques urbaines profondes qu’il convient de mettre en évidence et de modéliser<br>Algiers port and city’s exceptional history is driven by its remarkable site nestled on a rocky spur. Revealed.Yet this morphology constrained the urban growth of a city that could pretend joigning the ranks of large metropolis. During its history port and city relationship took multiple forms, frequently compatible yet sometimes divergent and even opposed, leading to inversing domination status of both actors. Algiers capital of a 40 million inhabitants state, has always been a laboratory of urban politics since the colonial era to the institutional constructions of independent Algeria, regardless of deficient statistical tools. However, the space in Algiers is confronted to great challenges due to an anarchic growth of its population, fragmented urban spaces and unbearable motion constraints. If road and collective transportation infrastructures are growingly programed and achieved by successive plans, their articulation with built-up areas and housing developments with the aim of eradicating slums does not seem to be really coherent. Furthermore, the location of communal amenities which seem to be relating to real estate opportunities, adds to the complexity of the urban fabric.However, under this apparent complexity, arise deep urban logics that should be highlighted and modeled
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Young, Emma. "Recurrent Genetic Mutations in Lymphoid Malignancies." Doctoral thesis, Uppsala universitet, Experimentell och klinisk onkologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-314956.
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In recent years, the genetic landscape of B-cell derived lymphoid malignancies, including chronic lymphocytic leukemia (CLL), has been rapidly unraveled, identifying recurrent genetic mutations with potential clinical impact. Interestingly, ~30% of all CLL patients can be assigned to more homogeneous subsets based on the expression of a similar or “stereotyped” B-cell receptor (BcR). Considering that biased distribution of genetic mutations was recently indicated in specific stereotyped subsets, in paper I, we screened 565 subset cases, preferentially assigned to clinically aggressive subsets, and confirm the SF3B1 mutational bias in subset #2 (45%), but also report on similarly marked enrichment in subset #3 (46%). In contrast, NOTCH1 mutations were predominantly detected in subsets #1, #8, #59 and #99 (22-34%). This data further highlights a subset-biased acquisition of genetic mutations in the pathogenesis of at least certain subsets. Aberrant NF-κB signaling due to a deletion within the NFKBIE gene previously reported in CLL warranted extended investigation in other lymphoid malignancies. Therefore, in paper II, we screened 1460 patients with various lymphoid malignancies for NFKBIE deletions and reported enrichment in classical Hodgkin lymphoma (27%) and primary mediastinal B-cell lymphoma (PMBL) (23%). NFKBIE-deleted PMBL cases had higher rates of chemorefractoriness and inferior overall survival (OS). NFKBIE-deletion status remained an independent prognostic marker in multivariate analysis. EGR2 mutations were recently reported in advanced stage CLL patients; thus, in paper III we screened 2403 CLL patients for mutations in EGR2. An overall mutational frequency of 3.8% was reported and EGR2 mutations were associated with younger age, advanced stage and del(11q). EGR2 mutational status remained an independent marker of poor outcome in multivariate analysis, both in the screening and validation cohorts. Whole-genome sequencing (WGS) of 70 CLL cases, assigned to poor-prognostic subsets #1 and #2 and indolent subset #4, were investigated in Paper IV and revealed a similar skewing of SF3B1 mutations in subset #2 and NOTCH1 mutations in subset #1 to that reported in Paper I. Additionally, an increased frequency of the recently proposed CLL driver gene RPS15 was observed in subset #1. Finally, novel non-coding mutational biases were detected in both subset #1 and #2 that warrant further investigation.
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Simpson, Andreja. "Fibulin-4 mutations in cutis laxa." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/fibulin4-mutations-in-cutis-laxa(fcf5936a-e6a4-42a0-b58a-a16876b0f01f).html.
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Fibulin-4 is an extracellular matrix protein which plays an essential function in the assembly of elastic fibres, and may be involved in the modulation of TGFβ bioavailability and smooth muscle cell differentiation. Mutations in fibulin-4 can cause autosomal recessive cutis laxa, a frequently lethal connective tissue disorder. Although patient studies have provided some insights into the pathological mechanisms of this disease, a detailed analysis of the consequences of fibulin-4 mutations on a molecular and cellular level was required.The findings presented in this thesis demonstrate that cutis laxa-causing fibulin-4 mutations may lead to reduced extracellular levels of fibulin-4 due to its increased susceptibility to protease degradation and misfolding/aggregation. An accumulation of autophagic vesicles was observed, indicating a blockage of autophagy, possibly due to intracellular accumulation of aggregated/misfolded mutant protein. In the extracellular matrix, mutations affected the ability of fibulin-4 to interact with the major components of the elastic fibre assembly, heparin, LTBP-1 and fibronectin. In addition, fibulin-4 mutations generally reduced expression levels of elastic fibre assembly components. In summary, these findings contribute to the understanding of fibulin-4 associated cutis laxa, and provide a basis upon which future therapeutic interventions may be developed.
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Roques, Michel. "Mutations récentes dans l'espace péricentral bordelais." Lille 3 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb37609469m.
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Bokhari, Yahya. "DISCOVERING DRIVER MUTATIONS IN BIOLOGICAL DATA." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5637.
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Background
Somatic mutations accumulate in human cells throughout life. Some may have no adverse consequences, but some of them may lead to cancer. A cancer genome is typically unstable, and thus more mutations can accumulate in the DNA of cancer cells. An ongoing problem is to figure out which mutations are drivers - play a role in oncogenesis, and which are passengers - do not play a role. One way of addressing this question is through inspection of somatic mutations in DNA of cancer samples from a cohort of patients and detection of patterns that differentiate driver from passenger mutations. Results
We propose QuaDMutEx an QuadMutNetEx, a method that incorporates three novel elements: a new gene set penalty that includes non-linear penalization of multiple mutations in putative sets of driver genes, an ability to adjust the method to handle slow- and fast-evolving tumors, and a computationally efficient method for finding gene sets that minimize the penalty, through a combination of heuristic Monte Carlo optimization and exact binary quadratic programming.
QuaDMutNetEx is our proposed method that combines protein-protein interaction networks to the method elements of QuaDMutEx. In particular, QuaDMutEx incorporates three novel elements: a non-linear penalization of multiple mutations in putative sets of driver genes, an ability to adjust the method to handle slow- and fast-evolving tumors, and a computationally efficient method for finding gene sets that minimize the penalty. In the new method, we incorporated a new quadratic rewarding term that prefers gene solution set that is connected with respect to protein-protein interaction networks. Compared to existing methods, the proposed algorithm finds sets of putative driver genes that show higher coverage and lower excess coverage in eight sets of cancer samples coming from brain, ovarian, lung, and breast tumors. Conclusions
Superior ability to improve on both coverage and excess coverage on different types of cancer shows that QuaDMutEx and QuaDMutNetEx are tools that should be part of a state-of-the-art toolbox in the driver gene discovery pipeline. It can detect genes harboring rare driver mutations that may be missed by existing methods.