Dissertations / Theses on the topic 'Genotype and Phenotype Relationship'
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Kemble, Henry. "The genotype-phenotype relationship across different scales." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC178/document.
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Avec la révolution moléculaire en biologie, une compréhension des mécanismes de la relation génotype-phénotype est devenue possible. Récemment, les progrès réalisés dans la synthèse et le séquençage de l’ADN ont permis le développement d’expériences de deep-mutational scanning capable de quantifier divers phénotypes pour un ensemble de génotypes sur toute la longueur d’un gène. Ces ensembles de données sont non seulement intéressants en eux-mêmes, mais permettent également de tester de manière rigoureuse des modèles phénotypiques quantitatifs. Nous avons utilisé cette technologie pour caractériser les cartes séquence-fitness de 3 systèmes bactériens modèles: un régulateur global, la CRP, une enzyme de résistance aux antibiotiques, la β-lactamase, et une petite voie métabolique constituée des enzymes AraA et AraB. Ces systèmes ont été choisis pour éclairer les rôles de différentes caractéristiques dans la formation de la relation génotype-fitness (réseaux de régulations, stabilité des protéines et flux métabolique). Nous constatons que la tendance globale des effets sur le fitness semble prévaloir sur les tendances spécifiques. Ceci nous conduit à penser qu’une grande partie de la relation entre le génotype et le fitness pourrait être expliquée à partir de la forme des fonctions de phénotype-fitness. Par ailleurs, nous voyons que la caractérisation de la relation génotype-fitness dans différents systèmes peut être un moyen puissant d’obtenir des informations sur les phénotypes pertinentsWith the molecular revolution in Biology, a mechanistic understanding of the genotype-phenotype relationship became possible. Recently, advances in DNA synthesis and sequencing have enabled the development of deep-mutational scanning experiments, capable of scoring comprehensive libraries of genotypes for a variety of phenotypes over the length of entire genes. Such datasets are not only interesting in themselves, but also allow rigorous testing of quantitative phenotypic models. We used this technology to characterise sequence-fitness maps for 3 model bacterial systems: a global regulator, CRP, an antibiotic-resistance enzyme, β-lactamase, and a small metabolic pathway, consisting of the enzymes AraA and AraB. These different systems were chosen to illuminate the roles of different mechanistic features in shaping the genotype-fitness relationship (regulatory wiring, protein stability and metabolic flux). We find that smooth patterns of fitness effects tend to prevail over idiosyncrasy, indicating that much of the genotype-fitness relationship could be understood from the global shape of smooth underlying phenotype-fitness functions. On the flip side, we see that characterising the genotype-fitness relationship in different systems can be a powerful way to glean phenotypic insights
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Jacques, Adam Matthew. "Hypertrophic and dilated cardiomyopathies, the relationship of genotype to phenotype." Thesis, Imperial College London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550457.
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Most familial dilated and hypertrophic cardiomyopathies are caused by mutations in sarcomeric proteins. What remains to be answered is how mutations cause the cardiac phenotype and why mutations in the same protein can cause cardiomyopathies at different ends of the phenotypic spectrum. We collected human myocardium from HCM patients undergoing surgical myectomy, and familial and acquired DCM patients, undergoing cardiac transplantation. Patients were phenotyped before operation and blood taken for genotyping. We used the ProQ Diamond, Western Blot and in vitro motility assays to assess levels of phosphorylation, expression and function respectively of sarcomeric proteins. In HCM patients with myosin binding protein C mutations expression of MyBPC was reduced by 24% in myofilaments arguing strongly for happloinsufficiency as the disease causing mechanism. HCM myosin and MyBPC mutations, also affect cardiac contractility by dominant negative effects. Myosin mutation, Va1606Met, has direct and indirect effects on cardiac contraction. Filament sliding speed was greater and relaxation at pCa9 less complete than with other HCM myosins tested without mutations. The DCM troponin C mutation, Gly159Asp, acts as a poison polypeptide, changing thin filament regulation. Ca2+ -sensitivity of G159D troponin C was independent of the level of troponin phosphorylation. The uncoupling of the relationship between troponin phosphorylation and Ca2+-sensitivity, provides a novel mechanism for initiation of familial DCM. Post-translational modifications in sarcomeric proteins occur independently of genotype. Troponin I is dephosphorylated in DCM and HCM, leading to changes in Ca2+-sensitivity and cross-bridge turnover rate. Also both troponin and myosin from HCM tissue is functionally abnormal and MyBPC phosphorylation is reduced. In acquired heart failure dephosphorylation of Serines 23/24 on troponin I could account for the contractile defect in seen and MyBPC phosphorylation is also decreased. In summary we observed a hypocontractile molecular phenotype in HCM human heart tissue, similar to that seen in heart failure. These findings conflict with the observed clinical phenotype seen in HCM, which is often regarded as a hyperdynamic or hypercontractile state.
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O'Brien, Kirtsy K. "Genotype - phenotype relationships in late onset dementia." Thesis, University of Newcastle Upon Tyne, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.402161.
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Vrcelj, Katarina. "Genotype and phenotype relationships in neurodevelopmental disorders." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:a7a9d22c-c92d-4078-9065-b9a9275c49a9.
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NeuroDevelopmental Disorders (NDDs) are a group of heterogeneous neuropsychiatric conditions, encompassing Developmental Delay (DD), Intellectual Disability (ID), Autism Spectrum Disorder (ASD) and Gilles de la Tourette Syndrome (GTS). NDDs often involve a life-long need of supportive services and represent a major economic and societal burden in Europe and the United States. Hitherto, no safe and effective treatment strategies are available, underpinning the urgency of deciphering their elusive aetiology. NDDs have a strong genetic component. Accordingly, the mechanistic understanding of disease involves (1) the description of mutational landscapes, (2) the molecular and cellular of characterisation of genetic variants and (3) their integration at circuit and system levels. In this thesis, we tackled these theoretical underpinnings to provide insights into the genetics of NDDs and the onset of associated clinical abnormalities. Firstly, aiming to shape the genetic architecture of GTS, a condition characterised by the presence of motor and vocal tics, we undertook a whole-genome CNV study of a cohort of Danish GTS cases and healthy controls. Using statistical and functional genomics approaches, we proposed novel potential candidate genes and implicated the disruption of early neurodevelopmental and late synaptic processes in the aetiology of GTS. Secondly, to elucidate the vast phenotypic heterogeneity of NDDs, we conducted a systematic investigation of genotype and phenotype relationships in DD, ID and ASD. Taking advantage of extensive phenotypic and genetic data available for DD/ID and ASD patients, we grouped individuals based on their functional rare CNV and gene disruptions but did not to identify distinguishing clinical archetypes. Instead, we showed converging molecular perturbations underlie the onset of globally more similar clinical presentations and investigated the role of common variants in modulating their expressivity. Lastly, we established the relevance of mouse models in the study of human disease. By applying comprehensive genomics approaches to over 1,000 mouse neuroanatomical knockouts, we implicated early neurodevelopmental and adult synaptic processes in the aetiology of ID and brain malformations. Furthermore, we showed that functionally converging genetic disturbances translate at the phenotypic level and proposed novel candidate ID genes.
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Squance, Michael Graham. "Computational modelling of the relationship between Miscanthus genotype, phenotype and environment." Thesis, Aberystwyth University, 2014. http://hdl.handle.net/2160/ca10d87a-2e3e-4e35-b156-7bdb80c3efb1.
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Several major global challenges being faced in the 21st century, ranging from climate change, energy security and food security to the sustainable living. Innovative solutions are needed to address those challenges. Miscanthus is a highly productive C4 grass which naturally occurs in Asia with the potential use for as a bioenergy crop. Recent advances in technologies such as genomics, phenomics, bioinformatics and modelling, provide a unique opportunity to accelerate the domestication process of Miscanthus. Modern breeding programmes aim to utilise genetic information to assist in breeding decisions. High-throughput technologies such as genotyping-by-sequencing (GBS) generate massive datasets. Conventional analysis methods cannot handle large multi-dimensional datasets, therefore new methodologies are needed. This research aims to use machine learning to model marker trait association and genotype by environmental interaction on Miscanthus. Three studies were performed in this research: 1) Develop a machine learning based QTL analysis tool to detect QTL on a Miscanthus flowering time mapping population. 2) Conduct marker-trait associations in a GBS analysis. 3) Establish a predictive model to understand drought and thermal effects on flowering time in Miscanthus. The machine learning algorithm, random forest, was used to develop a QTL analysis tool, referred to as RFQTL. RFQTL identified several flowering QTL, with reduced computation time, consistent with conventional QTL analysis. Within the GBS study machine learning detected markers which when aligned with the Sorghum genome several homolog QTLs were found for the traits investigated. Using the prediction model of flowering time we were able to show that drought delays flowering whereas increased temperature led to earlier flowering. This research has demonstrated the power of machine learning as an effective method for marker trait association and genotype by environment modelling. It has great potential to play a crucial role in crop improvement and provide further scientific insights for genetic research.
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Brunklaus, Andreas. "Genotype phenotype relationships in SCN1A related childhood epilepsies." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4518/.
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Most mutations in SCN1A-related epilepsies are novel and when an infant presents with febrile seizures (FS) it is uncertain if they will have simple FS, FS+ or develop a severe epilepsy such as Dravet Syndrome. The main aim of this work has been to translate specific genetic findings in SCN1A related epilepsies not only to the phenotype, but to examine the implications this has on treatment and quality of life in children and their families. Clinical and genetic data were collected from 273 individuals with SCN1A mutations identified in our laboratory between November 2005 and February 2010. I examined whether the mutation class, distribution or nature of amino acid substitution correlated with the epilepsy phenotype, using the Grantham Score (GS) as a measure of physicochemical difference between amino acids. From structured referral data I analysed a range of clinical characteristics including epilepsy phenotype, seizure precipitants, EEG data, imaging studies, mutation class and response to medication and determined predictors of developmental outcome. I developed novel ideas on how to characterise mutations in SCN1A related epilepsies, showing that phenotypes are not determined by chance, but are in part determined by defined physico-chemical changes affecting a specific location in the protein structure. I was able to demonstrate that these principles not only apply to the SCN1A gene but also to the wider voltage gated sodium channel family and related diseases. This study has been the largest to date to systematically examine the prognostic, clinical and demographic features of Dravet syndrome. The overall incidence of Dravet syndrome was found to be at least one in every 28,600 UK births. Clinical features predicting a worse developmental outcome included status epilepticus, interictal EEG abnormalities in the first year of life and a motor disorder. No significant effect was seen for seizure precipitants, MRI abnormalities or mutation class (truncating vs. missense). Sodium valproate, benzodiazepines and topiramate were reported the most helpful medications and aggravation of seizures was reported for carbamazepine and lamotrigine. Health related quality of life (HRQOL) has emerged as a widely accepted measure to evaluate how chronic disease impacts on an individual’s well-being and I examined in detail the comorbidities and predictors of health related quality of life in Dravet syndrome. HRQOL was evaluated with two epilepsy-specific instruments, the Impact of Pediatric Epilepsy Scale (IPES) and the Epilepsy & Learning Disabilities Quality of Life Questionnaire (ELDQOL), a generic HRQOL instrument the Pediatric Quality of Life Inventory (PedsQL) and a behavioural screening tool, the Strength and Difficulties Questionnaire (SDQ). 163 individuals with Dravet syndrome and their families participated in the questionnaire study. HRQOL was significantly lower for children with Dravet syndrome compared to normative data. One third of children had conduct problems and two thirds had hyperactive or inattentive behaviour. Regression analysis revealed that behavioural problems were the strongest predictors of poorer HRQOL. Identification of specific comorbidities will help us to better recognise and understand the needs of children and families with Dravet syndrome and facilitate a distinct multi-disciplinary approach to management. Genetic testing in the epilepsies has become an increasingly accessible clinical tool and this is the first study to assess the impact of SCN1A testing on patient management from both carer and physician perspectives. The vast majority of parents whose children tested positive for a mutation reported genetic testing helpful, leading to treatment changes resulting in fewer seizures, and improved access to therapies and respite care. Nearly half of the physicians reported that a positive test facilitated diagnosis earlier than with clinical and EEG data alone. In two thirds it prevented additional investigations and altered the treatment approach; it influenced medication choice in three quarters of cases and through medication change improved seizure control in forty percent. In addition to confirming a clinical diagnosis, a positive SCN1A test enabled early diagnosis, influenced treatment choice and facilitated improvements in clinical management, especially in the very young. Finally I hope that this work will contribute to a better understanding of the causes of SCN1A related epilepsies. Furthermore I hope that it will provide evidence to aid earlier diagnosis and treatment of children with severe infantile epilepsies and that it will offer more information for genetic counselling. These improvements in epilepsy care and seizure control could help prevent or reduce the disability associated with SCN1A related epilepsies such as learning and behaviour problems and would improve the quality of life for children and families.
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Jeerooburkhan, Noorjahan Bibi. "Phenotype and genotype relationship in nitric oxide and pterin pathways in man." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269759.
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Harris, Tegan Maree. "B-lactamase-mediated resistance to antimicrobials : the relationship between genotype and phenotype." Thesis, Queensland University of Technology, 2014. https://eprints.qut.edu.au/77835/1/Tegan_Harris_Thesis.pdf.
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This thesis examined the ability to predict the emergence of bacteria resistant to antibiotics using genetic markers in the bacteria. Bacteria containing the genetic markers were able to become resistant to antibiotics, whereas bacteria that did not have the genetic markers remained susceptible. Existing techniques can identify the presence of resistance by looking at the characteristics of the bacteria during growth. However, having the ability to predict antibiotic resistance before it emerges could improve the preservation of currently available antibiotics and minimise treatment failure.
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Hart, Lesley Ruth. "Dissecting the genotype to phenotype relationships of genomic disorders." Thesis, University of Sussex, 2013. http://sro.sussex.ac.uk/id/eprint/47112/.
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Over the last decade, major advances in the development and application of microarray-based comparative genomic hybridisation (aCGH) technology have significantly contributed to our understanding of Genomic Disorders. My aims here were to provide insight into the genotype to phenotype relationships of three Genomic Disorders; CUL4B-deleted X-Linked Mental Retardation (XLMR), Wolf-Hirschhorn Syndrome (WHS) and 16p11.2 Copy Number Variant Disorder. CUL4B encodes a structural component of the Cullin-RING-ligase 4-containing class of E3 ubiquitin ligases. CUL4B-deleted XLMR represents a syndromal form of mental retardation whereby patients exhibit other clinical features aside from the MR, such as seizures, growth retardation and disrupted sexual development. I used CUL4B-deleted patient-derived cell lines to investigate the impacts of CUL4B loss on mitochondrial function. I have shown that loss of CUL4B is associated with a distinct set of mitochondrial phenotypes, identifying CUL4B-deleted XLMR as a disorder associated with mitochondrial dysfunction. Furthermore, I have uncovered a reciprocal relationship between CUL4B and Cereblon, providing evidence of a potential role for the CUL4-CRBN E3 ligase complex in maintaining mitochondrial function. Deletion or duplication of the 16p11.2 region is associated with macro-/microcephaly respectively. Here, I have evaluated the cellular consequences of 16p11.2 CNV, specifically with regards KCTD13 expression, DNA replication and checkpoint activation. WHS is typically caused by a small hemizygous telomeric deletion of the 4p16.1 region. Haploinsufficiency of 4p16.1 is associated with microcephaly, growth retardation and complex developmental abnormalities. I investigated the impacts of LETM1 copy number change in WHS patient-derived cells. Here, I have shown that copy number change of LETM1 specifically segregates with mitochondrial dysfunction, likely underlying the seizure phenotype exhibited by the large subgroup of WHS patients whose deletions incorporate LETM1 as well as the rarer instances of the reciprocal duplication. In this thesis I use patient-derived cell lines from three Genomic Disorders as a fundamental tool providing new pathomechanistic insight into the clinical presentation of these conditions.
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Hartman, Deirdre. "Investigation of Genotype-Phenotype relationships of sodium control mechanisms in hypertension." Thesis, St George's, University of London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498075.
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Flanagan, S. E. "Genotype/phenotype relationships in diabetes & hyperinsulinism resulting from KATP channel mutations." Thesis, Exeter and Plymouth Peninsula Medical School, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.700489.
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Underwood, M. I. "The relationship between ADAMTS13 genotype and phenotype in congenital thrombotic thrombocytopenic purpura and characterisation of ADAMTS13 mutants." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1462706/.
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Congenital thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy, usually involving ADAMTS13 gene defects. ADAMTS13 processes the multimeric plasma glycoprotein Von Willebrand factor making it less reactive to platelets. Patients differ in terms of disease severity and evidence suggests a relationship between ADAMTS13 genotype and disease phenotype. Over 140 mutations have been identified in patients but only ~30% of these has been expressed in vitro. The aim of this thesis was to study certain ADAMTS13 mutations identified in a homozygous form in congenital TTP patients to assess in vitro their effect on the secretion and activity of ADAMTS13 and to assess their contribution to disease phenotype. ADAMTS13 mutants (p.R102H, p.I143T and p.Y570C) and wild type (WT) were expressed in HEK293T cells. The p.R102H mutation partially affected the secretion of ADAMTS13 and reduced the catalytic efficiency of the mutant but not to the extent predicted based upon levels measured in patient plasma. Expressing this mutant with three ADAMTS13 polymorphisms (p.Q448E, p.P618A and p.A900V) which were also identified in the patient with this mutation further reduced the secretion and activity of ADAMTS13. When these three polymorphisms were expressed separately in WT ADAMTS13, the p.P618A polymorphism reduced the secretion and subsequently the activity of ADAMTS13 suggesting that this polymorphism in particular was responsible for the reduction observed. These results highlight the importance of ADAMTS13 polymorphisms. The p.I143T and p.Y570C mutations severely affected ADAMTS13 secretion. Immunofluorescence studies showed localisation of these mutants within the ER but less extensive localisation within the cis Golgi compared to WT ADAMTS13. The p.I143T mutant was characterised further and was shown to be degraded by the cell proteasome. Addition of a chemical chaperone (betaine) appeared to rescue the secretion defect caused by the p.I143T mutation. This may have future therapeutic implications for the treatment of some congenital TTP patients.
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Prinz, Stephanie Jeanette [Verfasser]. "Analysis of Genotype-Phenotype Relationships based on Drug Side Effects, Disease Symptoms and Mouse Phenotypic Traits / Stephanie Jeanette Prinz." München : Verlag Dr. Hut, 2016. http://d-nb.info/1106593456/34.
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Cooper-Knock, Johnathan. "Characterisation of genotype-phenotype relationships in ALS associated with hexanucleotide repeat expansion of C9orf72." Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/9613/.
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The papers selected represent characterisation of amyotrophic lateral sclerosis (ALS) patients belonging to the C9orf72 genetic variant. The general introduction describes ALS more broadly, both clinically and pathologically, including a summary of proposed molecular mechanisms of pathogenesis. It goes on to discuss the discovery that GGGGCC-repeat expansions of C9orf72 represent the most common genetic variant of this disease. The first group of papers in section 3 relate to clinical and pathological characterisation of the C9orf72 genetic variant. This includes genetic screening of cohorts of patients suffering from ALS, frontotemporal dementia (FTD), multiple sclerosis and parkinsonism. The second group of papers in section 4 describes the use of transcriptome analysis, biochemical techniques and immunohistochemistry to study pathogenic mechanisms in C9orf72-ALS. Characterisation of the interactions and behaviour of RNA foci derived from the C9orf72 repeat expansion suggest that these foci sequester proteins important to mRNA splicing. Novel methodology was then used to describe an increase in the splicing error rate in lymphoblastoid cell lines derived from C9orf72-ALS patients, which correlates with disease severity. The final group of papers in section 5 describes the study of genetic modifiers of the C9orf72-disease phenotype. This includes the development and use of a Southern blotting protocol to size the expansion. This led to some interesting suggestions: that patients with intermediate length, but reputedly pathogenic, expansions do not exhibit haploinsufficiency or typical C9orf72-neuropathology. Finally contribution was made to a larger study of the interaction between TMEM106B genotype and C9orf72-disease.
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Farrell, Sam Hanno. "Adaptive evolution in the Pseudomonas fluorescens Wsp signalling pathway : exploring the relationship between genetic cause and phenotypic effect." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/adaptive-evolution-in-the-pseudomonas-fluorescens-wsp-signalling-pathway-exploring-the-relationship-between-genetic-cause-and-phenotypic-effect(d4fc7a28-6da0-477b-9315-34f4b4d71f76).html.
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When provided with spatial niches by growth in static nutrient medium, Pseudomonas fluorescens diversifies through adaptive radiation into several well-defined phenotype classes. One of these classes, named wrinkly spreader (WS) for its morphology on agar medium, forms a biofilm at the air-liquid interface through mutations in one of several loci including the genes wspF and awsX. These genes code for negative regulators of di-guanylate cyclases (DGCs). These DGCs catalyse synthesis of cyclic-di-GMP, a second messenger, overproduction of which effects physiological changes leading to overproduction of a cellulose polymer and the WS phenotype. Intriguingly, a diverse range of wspF mutations leads to diversity both in colony morphology and strain fitness.In this study, I investigate genetic and fitness diversity in wrinkly spreaders with the aim of identifying the causal factors that link genetic diversity and physiological factors with diversity in fitness. I approach the subject from several directions, examining the historical context of genetic diversity in wspF and awsX, distribution of control over output in the Wsp pathway and overall fitness effects of different causal factors. I investigate the genetic basis of wrinkly spreader evolution through generation of a large number of novel WS strains and exploration of the distribution of mutations in the wspF and awsX genes. In combination with this I calculate estimates of the past rates of mutation in these genes, derived from a phylogenetic investigation of a group of orthologues. I examine the response of the Wsp pathway to change in WspF function through a novel computational analysis that is capable of revealing valuable information on control in a biological system based purely on model structure. In addition I show how this analysis can be refined through specification of broad estimates of system parameters, thereby avoiding issues related to over-reliance on specific parameter values. Finally, I investigate the fitness implications of these factors, as well as a variety of others, through assays of fitness in a group of WS strains combined with machine learning analyses of predictive relationships between protein and mutation characteristics and experimentally measured strain fitness, and consider the implications of this analysis in the context of intermediate physiological effects.I find that mutations in the WspF protein that lead to the WS phenotype tend to be located in regions of historically strong conservation, the first time that any such pattern to WS mutations has been identified. Mutations in AwsX, on the other hand, do not fit such a pattern. Computational analysis of the Wsp pathway shows that, regardless of model parameters, pathway output is always more sensitive to changes in methylesterase activity by WspF than to changes in phosphorylation of WspF, which may explain the greater frequency of mutations fixed in vivo seen in the methylesterase domain. Despite these patterns, none of a wide range of mutation and sequence-based biochemical characteristics, including local rates of past evolution and size and position of mutations, exhibited any predictive power over WS fitness. Overall, the findings in this study point towards an essential role for complex pleiotropic effects in strongly modulating the fitness effect of different mutations in wspF.
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Roh, Hyung-Keun. "Drug metabolic capacity in Koreans : CYP2D6 & CYP2C19 pheno- and genotype relationships in healthy volunteers and in patients /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-169-1.
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Duarte, Kévin. "Du génotype au phénotype : Analyse comparée de mutations du gène de déficience intellectuelle PAK3." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS511.
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La déficience intellectuelle (DI) est souvent associée à d’autres signes cliniques morphologiques et psychiatriques mais cette comorbidité est peu caractérisée pour la DI associée à un gène donné. Ainsi les mutations du gène p21-activated kinase 3 (PAK3) sont responsable d’un large spectre clinique, allant de la DI légère à des DI sévères associées parfois à des malformations du cerveau. Nous avançons l’hypothèse que les différentes mutations d’un même gène peuvent affecter divers paramètres biochimiques et affecter de manière différentielle les voies de signalisation impliquées dans la plasticité synaptique et dans le développement du cerveau. Pour valider notre hypothèse, nous avons caractérisé une nouvelle mutation responsable d’une déficience intellectuelle sévère associée à une agénésie du corps calleux et une microcéphalie. Cette mutation supprime l’activité kinase, n’affecte pas la stabilité de la protéine et augmente l’interaction avec un GEF de la famille PIX. Ces derniers résultats identifient une nouvelle voie de signalisation impactée par certaines mutations de PAK3. L’expression de ce variant modifie la morphologie cellulaire et la dynamique des adhésions focales, ainsi que les propriétés migratoires des cellules, ce qui pourraient relier les défauts biochimiques aux défauts de certaines fonctions cellulaires. De manière intéressante, ces caractéristiques sont aussi retrouvées pour un autre variant responsable d’une clinique également très sévère. Nous avons également caractérisé d’autres mutations associées à des phénotypes moins sévères. La synthèse de nos résultats nous permet ici de proposer un modèle explicatif de la relation génotype-phénotype pour les mutations de déficience intellectuelle liées au gène PAK3, intégrant des défauts neurodéveloppementaux et de plasticité synaptiqueIntellectual Disability (ID) is often associated with other morphological and psychiatric clinical signs, but this comorbidity is poorly characterized for ID associated with a given gene. Thus mutations of the p21-activated kinase 3 (PAK3) gene are responsible for a broad clinical spectrum, ranging from mild ID to severe ID, sometimes associated with brain malformations. We hypothesize that different mutations of the same gene may affect various biochemical parameters and differentially affect the signaling pathways involved in synaptic plasticity and brain development. To validate our hypothesis, we characterized a new mutation responsible for a severe intellectual disability associated with agenesis of the corpus callosum and microcephaly. This mutation suppresses kinase activity, does not affect protein stability and increases the interaction with a GEF of the PIX family. These latest results identify a new signaling pathway impacted by certain PAK3 mutations. The expression of this variant modifies the cellular morphology and the dynamics of the focal adhesions, as well as cell migratory properties, which could link the biochemical defects to those of certain cell functions. Interestingly, these features are also found for another variant responsible for a very similar severe clinical spectrum. We have also characterized other mutations associated with less severe phenotypes. The synthesis of our results allows us to propose an explanatory model of the genotype-phenotype relationship integrating neurodevelopmental and synaptic plasticity defects for intellectual disability and other clinical traits associated to the PAK3 gene mutations
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Pontius, Sarah E. "Genotype-Phenotype: Investigations in Typology." Cincinnati, Ohio : University of Cincinnati, 2007. http://www.ohiolink.edu/etd/view.cgi?acc%5Fnum=ucin1179414436.
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Thesis (Master of Architecture)--University of Cincinnati, 2007.Title from electronic theses title page (viewed July 16, 2007). Includes abstract. Keywords: architecture; typology; therapeutic; riding stable Includes bibliographic references.
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Sigwalt, Anastasie. "Origines génétiques de la variation de tolérance au stress au sein de populations naturelles de levures." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ024/document.
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Une question centrale de la génétique moderne est de mieux comprendre comment la variation génétique présente au sein d’individus d’une même espèce influence la diversité phénotypique et l’évolution. La levure modèle Saccharomyces cerevisiae offre une occasion unique d’apporter des éléments de réponse à cette question à travers la dissection de l’architecture génétique de la variation de tolérance à des stress environnementaux à l’échelle d’une population. Mon étude révèle un niveau supplémentaire de complexité de la relation génotype-phénotype où finalement les caractères supposés les plus simples, dits Mendéliens (déterminisme strictement monogénique) peuvent se révéler être complexes (déterminisme multigénique) selon le fond génétique en raison de l’action de gènes modificateurs, d’interactions épistatiques et/ou de suppresseurs. Toutefois, les processus évolutifs peuvent être bien différents en fonction des espèces. Afin de mieux les décrypter, je me suis également intéressée à Lachancea kluyveri, une levure phylogénétiquement distante de S. cerevisiae. Cette espèce présente une diversité génétique plus élevée et constitue une ressource encore peu exploitée. L’exploration de la diversité phénotypique et la détermination de leurs origines génétiques initiées dans cette étude sont extrêmement prometteuses et apportent de solides fondations pour l’étude à la fois de l’architecture génétique des caractères et de l’évolution de la relation génotype-phénotype au sein de diverses espèces de levuresA central issue of modern genetics is to better understand how genetic variations between individuals within a species influence the phenotypic diversity and the evolution. The budding yeast Saccharomyces cerevisiae as a model organism offers a unique opportunity to address this issue through the dissection of the genetic architecture of stress tolerance across a population. My study reveals an additional level of complexity of the genotype-phenotype relationship. Indeed, simple Mendelian traits (monogenic determinism) may become more complex (multigenic determinism) depending on genetic background due to the action of modifier genes, epistatic interactions and / or suppressors. However, evolutionary processes can be very different depending on the species. That is why a non-conventional yeast species namely Lachancea kluyveri (formerly S. kluyveri) was also studied. This species distantly related to S. cerevisiae has a higher genetic diversity and remains a relatively unexplored resource. The exploration of the phenotypic diversity and the determination of the genetic origins initiated in this study lay foundations for the analysis of the genetic architecture of traits and the evolution of the genotype-phenotype relationship within diverse yeast species
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Habib, Farhat Abbas. "Genotype-phenotype correlation using phylogenetic trees." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1187297400.
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Burke, Georgina. "Genotype - phenotype correlations in congenital myasthenia." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437178.
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Ghasimi, Soma. "Genotype-phenotype studies in brain tumors." Doctoral thesis, Umeå universitet, Onkologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-83185.
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Meningioma and glioma are the most common primary brain tumors, but their etiologies are largely unknown. Although meningioma is usually benign, their intracranial location can lead to lethal consequences, and despite progress in surgery, radiotherapy, and chemotherapy the prognosis for patients with glioma remains poor. The only well-established environmental risk factor for meningioma and glioma is ionizing radiation. Evidence for inherited predisposition to meningioma and glioma is provided by a number of rare inherited syndromes where collectively these diseases account for only a small proportion of the twofold increased risk of brain tumors seen in first-degree relatives for meningioma and glioma patients. It is very possible that much of the excess familial risk is a consequence of co-inheritance of multiple low-risk genetic variations. With this in mind, the aims of the studies in this thesis were to discover genetic risk variants influencing the probability of acquiring the disease and to identify the association between risk variants on the tumor phenotype. To identify genetic variants influencing meningioma risk, a comprehensive tagging of the selected genes in a case-control study was performed. We identified nine risk variants in EGF, ERBB2, and LRIG2 genes. However, these findings could not be confirmed in another larger independent dataset. In addition, the study identified a correlation between LRIG2 protein expression and ER status when analyzed with different parameters. In a separate study with a larger sample of meningioma patients, the same correlation between LRIG2 and ER status was observed. To explore the potential association between reported germline risk variants and somatic genetic events, matched tumor and blood samples from glioma patients were analyzed by SNP array. The results identified correlations between EGFR gene variants and somatic aberrations within the EGFR locus and CDKN2A/B locus. To further study the relationship between germline risk variants and tumor phenotype, the same patient material was used and analyzed by three different techniques: SNP array, IHC, and FISH. The results revealed EGFR risk variants effecting copy number variation of the EGFR gene and the expression of the IDH1 and p53. Further comparison between different techniques such as SNP array and FISH analysis revealed the difficulty in achieving consistent results with different techniques. To summarize, the glioma studies show a link between genotype and phenotype where genetic risk variants in the EGFR gene were found to be associated with specific somatic aberrations. These associations are biologically interesting because EGFR is involved in multiple cellular processes. Additional studies of the direct functional role of these observations need to be conducted to elucidate the molecular mechanisms underlying the identified association between germline gene variants and somatic aberrations. For the meningioma studies, no significant risk variants influencing the disease were found but a correlation between LRIG2 and ER status was observed. This result suggests a potential role for the LRIG protein in the pathogenesis of meningioma, but more studies are needed to confirm this hypothesizes.Cancer research foundation in northern Sweden and Lions cancer research foundation at Umeå university
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Habib, Farhat. "Genotype-phenotype correlation using phylogenetic trees." The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1187297400.
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Jordan, Natasha Patricia. "Genotype-phenotype relations in lupus nephritis." Thesis, King's College London (University of London), 2014. http://kclpure.kcl.ac.uk/portal/en/theses/genotypephenotype-relations-in-lupus-nephritis(645d8e22-23b7-40d5-8c8d-23efeabf5d56).html.
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This thesis explores genotype-phenotype relations in lupus nephritis. Over the past decade, advances in genetic research have improved our understanding of the genes that contribute to lupus susceptibility. However a clear understanding of how these genetic factors interact with the immune system to produce disease in a given patient or group of patients with SLE is difficult to define at this time. Recent monogenic causes of SLE have provided valuable insights into lupus pathogenesis. A comprehensive clinical characterisation of 164 biopsy proven lupus nephritis patients was undertaken in the initial phase of this research. 27% of patients recruited were of juvenile onset, as defined by diagnosis of nephritis before 18 years of age. Non-European lupus nephritis patients had a younger age of onset and higher rate of progression to end-stage renal disease. Sixteen individuals had a first degree family history of lupus nephritis including five sibling pairs. Familial clustering of nephritis was associated with juvenile onset disease and a more severe clinical phenotype. The entire cohort was genotyped by ImmunoChip for known lupus susceptibility polymorphisms. Associations with lupus nephritis were found in polymorphisms in the HLA region, IRF5, ITGAM, STAT4, TNFAIP3, TNFSF4 and ETS1. Whole Exome Sequencing of familial lupus nephritis cases identified a large number of potential candidates for functional investigation. A promising short list of candidates was created using pedigree information, focusing on variants predicted to be damaging and by incorporating prior knowledge of the biologic pathways implicated in lupus. Candidates under consideration for functional testing include genes involved in activation of Ras pathways, genes involved in the antioxidant defence system, variants in ubiquitination pathways, mutations in serine/threonine protein kinases and genes involved in toll-like receptor and type I interferon signalling pathways.
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Dingle, Kamaludin. "Probabilistic bias in genotype-phenotype maps." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:eba8801e-182e-42f5-aa0a-d3d914fd7923.
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Among the most fundamental features shared by all organisms is the mapping of information encoded in genotypes (genetic material) to generate phenotypes (biological structures, functions, and traits). Hence, elucidating the structure of genotype-phenotype (GP) maps is important for understanding evolution and biology. While it is known that often GP maps are highly degenerate with many different genotypes adopting the same phenotype, the distribution of genotypes over phenotypes is less well studied. In this thesis we investigate the question of the distribution of genotypes over phenotypes, or put differently the distribution of neutral set sizes (NSS), where a neutral set is the collection of all genotypes in a GP map which map to the same phenotype. We focus on examining phenotypic bias in GP maps, where some phenotypes have disproportionally large NSS as compared to others. We find phenotypic bias to be ubiquitous in the broad range of GP maps that we analyse, from the genetic code up to molecular RNA to a model of neuronal connections, and hence we hypothesise bias to be a common property of GP maps. Further, we also consider the implications that this bias has for evolutionary outcomes, and we argue that bias is a significant influencing factor in determining evolutionary outcomes. Finally, we propose a method to predict a phenotype's NNS via estimating the phenotype's structural complexity, without using detailed knowledge about the specifics of the relevant GP map. We achieve this via a novel application of algorithmic information theory and especially Levin's coding theorem.
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Southward, Katie Hannah. "Genotype, phenotype and outcomes in colorectal cancer." Thesis, University of Leeds, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713695.
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Stage II/III CRCs are currently treated by surgery, then stage III and stage II patients exhibiting high-risk pathological features undergo a course of 5-FUbased adjuvant chemotherapy, often with oxaliplatin added. Improved characterisation of stage 11/111 tumours is required in order to improve their treatment and to ensure that drugs are only given to patients where there is evidence of a likely response. This will reduce the unnecessary and costly overtreatment of these patients, as well as the associated unpleasant side effects. Pyrosequencing, immunohistochemistry, FISH, and next-generation sequencing were used in order to assess a number of molecular markers of high-risk stage 11 CRCs in two cohorts. Of the markers tested, only mutation in KRAS was prognostic in stage 11/11I CRC (HR = 1.4). Mutation of BRAF, NRAS, PIK3CA and overexpression/amplification of HER-2 were not prognostic or predictive of response to 5-FU chemotherapy in the QUASAR-1 trial. TOP2A was coamplified with HER-2 in 28% cases. Copy number profiles produced from this cohort showed the differences between dMMR and pMMR, and the effect of high stromal content on CNV. Cases from the QUASAR-1 fit into one of three groups regarding CNV which need further characterisation and their relationship to prognosis needs to be established. KRAS mutation is a prognostic marker in stage 11/11I disease and could be tested for routinely. Importantly none of the other markers tested predicted a worse outcome with 5-FU-based chemotherapy. TOP2A is frequently coamplified with HER-2 suggesting that a subset of these cases may respond to anthracycline therapy.
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Brais, Bernard. "Oculopharyngeal muscular dystrophy : from phenotype to genotype." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0002/NQ44369.pdf.
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Wu, Chuang. "Phenotype Inference from Genotype in RNA Viruses." Research Showcase @ CMU, 2014. http://repository.cmu.edu/dissertations/457.
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The phenotype inference from genotype in RNA viruses maps the viral genome/protein sequences to the molecular functions in order to understand the underlying molecular mechanisms that are responsible for the function changes. The inference is currently done through a laborious experimental process which is arguably inefficient, incomplete, and unreliable. The wealth of RNA virus sequence data in the presence of different phenotypes promotes the rise of computational approaches to aid the inference. Key residue identification and genotype-phenotype mapping function learning are two approaches to identify the critical positions out of hitchhikers and elucidate the relations among them. The existing computational approaches in this area focus on prediction accuracy, yet a number of fundamental problems have not been considered: the scalability of the data, the capability to suggest informative biological experiments, and the interpretability of the inferences. A common scenario of inference done by biologists with mutagenesis experiments usually involves a small number of available sequences, which is very likely to be inadequate for the inference in most setups. Accordingly biologists desire models that are capable of inferring from such limited data, and algorithms that are capable of suggesting new experiments when more data is needed. Another important but always been neglected property of the models is the interpretability of the mapping, since most existing models behave as ’black boxes’. To address these issues, in the thesis I design a supervised combinatorial filtering algorithm that systematically and efficiently infers the correct set of key residue positions from available labeled data. For cases where more data is needed to fully converge to an answer, I introduce an active learning algorithm to help choose the most informative experiment from a set of unlabeled candidate strains or mutagenesis experiments to minimize the expected total laboratory time or financial cost. I also propose Disjunctive Normal Form (DNF) as an appropriate assumption over the hypothesis space to learn interpretable genotype-phenotype functions. The challenges of these approaches are the computational efficiency due to the combinatorial nature of our algorithms. The solution is to explore biological plausible assumptions to constrain the solution space and efficiently find the optimal solutions under the assumptions. The algorithms were validated in two ways: 1) prediction quality in a cross-validation manner, and 2) consistency with the domain experts’ conclusions. The algorithms also suggested new discoveries that have not been discussed yet. I applied these approaches to a variety of RNA virus datasets covering the majority of interesting RNA phenotypes, including drug resistance, Antigenicity shift, Antibody neutralization and so on to demonstrate the prediction power, and suggest new discoveries of Influenza drug resistance and Antigenicity. I also prove the extension of the approaches in the area of severe acute community disease.
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Correia, Annapaula. "Linking phenotype to genotype in Pseudonas aeruginosa." Thesis, University of East Anglia, 2016. https://ueaeprints.uea.ac.uk/65369/.
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The global transcriptional regulator mexT, is a mutational hotspot; the sequence variants commonly seen to co-exist within the P. aeruginosa population are: drug susceptible (e.g. PAO1) and chloramphenicol and norfloxacin non-susceptible (nfxC mutant). The nfxC phenotype, selected for on chloramphenicol agar is characterised by reduced virulence. The conversion between PAO1 and nfxC phenotypes is associated with an 8-bp repeat sequence in mexT. To investigate the effects of the 8-bp repeat on the adaptive mode of survival of P. aeruginosa, isogenic mutants were generated: PA (8-bp, two copies) and PAdel (8-bp, one copy). The mutants were characterised using phenotypic microarrays (PM), motility, antibiotic susceptibility, Galleria virulence models and RNA-seq in defined media. PM revealed differences in central metabolism indicating that PAdel/PAnfxC were associated with a biological metabolic cost. Strains with the single copy of the 8-bp sequence showed reduced motility and virulence. Transcriptome analysis revealed that mexT, in PA, consists of two regulatory elements defined by an intact helix-turn-helix motif (across the repeat region) which is capable of regulating the downstream LysR region via repressor and autoregulative mechanisms. Whole genome sequencing identified regions of compensatory mutations that were associated with differences in phenotype between PAdel (genetically modified) and PAnfxC (selected). To link phenotype and genotype and to understand the metabolic effects of this mutation, a genome wide metabolic reconstruction was performed. This revealed differences in key metabolic pathways such as glycolysis, gluconeogenesis and oxidative phosphorylation. This study has shown that an 8-bp repeat in mexT is a driver of genetic diversity. Regulatory elements linked to the effect of the 8-bp sequence on antibiotic resistance, central metabolism, chemotaxis, motility and virulence have also been identified. These methods can be used to define phenotype in any pair of isogenic mutants, at the genome level, and to investigate the clinical risk of strains.
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Okoro, Chinyere Kyna. "Invasive Salmonella typhimurium : linking phenotype to genotype." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607714.
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O'Connor, Timothy. "Detecting evolutionary dynamics of genotype-phenotype associations." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609119.
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Gardner, Catherine Joanne. "Genotype-phenotype correlation in sickle cell disease." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/genotypephenotype-correlation-in-sickle-cell-disease(07a190be-c88a-41f2-8e74-e063d85919a3).html.
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Sickle cell disease (SCD) has a complex pathophysiology initiated by the polymerisation of deoxy-sickle-haemoglobin. The single nucleotide change underpinning SCD does not account for the vast range and severity of SCD complications. This clinical heterogeneity is only partly explained by the genetic variability of fetal haemoglobin gene levels and co-inheritance of α- thalassemia. Although environmental factors also contribute to the clinical complexity of SCD, further genetic modifiers of SCD severity exist but are yet to be determined. Genetic association studies have been boosted recently not only with the advent of new genotyping tools, but also with the development of increasingly sophisticated analytical methods. New developments in phenotyping, genotyping and genotype-phenotype association approaches allow us to disentangle true genetic associations from hits due to chance. This thesis seeks to investigate biomarkers of sickle severity and to use these clinical markers in genotype-phenotype correlation studies. I have investigated three key markers of disease severity: haemolysis, frequency of acute pain episodes and mortality. Estimated median survival of 67 years in HbSS disease in our UK cohort is a significant improvement in survival compared to other recent estimates in the USA and Jamaica. I have undertaken genome-wide micro-array scanning and created an imputed genotype dataset of over 15,000,000 genetic variants. I have used these phenotype and genotype datasets to conduct genetic association studies, both genome-wide and candidate gene association studies. These analyses are based on linear mixed modelling to account for relatedness (including population stratification) within the cohort. In addition to the severity outcomes, I have also evaluated the known genetic loci for HbF and created a genetic “summary statistic” to quantify the effects of these three loci. Finally, I have also assessed the role of the erythroid regulator KLF1 in HbF levels in SCD with two laboratory-based projects.
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Adam, Laura. "Mapping Genotype to Phenotype using Attribute Grammar." Diss., Virginia Tech, 2013. http://hdl.handle.net/10919/51768.
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Over the past 10 years, several synthetic biology research groups have proposed tools and domain-specific languages to help with the design of artificial DNA molecules. Community standards for exchanging data between these tools, such as the Synthetic Biology Open Language (SBOL), have been developed. It is increasingly important to be able to perform in silico simulation before the time and cost consuming wet lab realization of the constructs, which, as technology advances, also become in themselves more complex. By extending the concept of describing genetic expression as a language, we propose to model relations between genotype and phenotype using formal language theory.
We use attribute grammars (AGs) to extract context-dependent information from genetic constructs and compile them into mathematical models, possibly giving clues about their phenotypes. They may be used as a backbone for biological Domain-Specific Languages (DSLs) and we developed a methodology to design these AG based DSLs. We gave examples of languages in the field of synthetic biology to model genetic regulatory networks with Ordinary Differential Equations (ODEs) based on various rate laws or with discrete boolean network models.
We implemented a demonstration of these concepts in GenoCAD, a Computer Assisted Design (CAD) software for synthetic biology. GenoCAD guides users from design to simulation. Users can either design constructs with the attribute grammars provided or define their own project-specific languages. Outputting the mathematical model of a genetic construct is performed by DNA compilation based on the attribute grammar specified; the design of new languages by users necessitated the generation on-the-fly of such attribute grammar based DNA compilers.
We also considered the impact of our research and its potential dual-use issues. Indeed, after the design exploration is performed in silico, the next logical step is to synthesize the designed construct's DNA molecule to build the construct in vivo. We implemented an algorithm to identify sequences of concern of any length that are specific to Select Agents and Toxins, helping to ensure safer use of our methods.Ph. D.
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Al, Maani Noor Walid Salem. "Refining genotype-phenotype correlation in epidermolysis bullosa." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/refining-genotypephenotype-correlation-in-epidermolysis-bullosa(0efb4606-e7eb-422c-9402-28c29de6ebfc).html.
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Dystrophic epidermolysis bullosa results from mutations in COL7A1 that encodes collagen VII, the major component of anchoring fibrils. General paradigms have emerged attributing dominant DEB to heterozygous glycine substitutions and recessive DEB to nonsense, frameshift or splice site mutations on both COL7A1 alleles. Several aspects of the genotype-phenotype heterogeneity encountered in DEB remain unexplained, although genetic, epigenetic and environmental modulators have been implicated. In this thesis, various aspects of DEB were studied, in a bid to refine genotype-phenotype correlation. A detailed analysis of missense GS and non-GS mutations identified 57 novel mutations and was in-keeping with the general established paradigms. Unique clinical entities such as EB-pr and BDN were studied. The role of the matrix metalloproteinase-1 promoter polymorphism, -1607 1G/2G, on disease modification in EB-pr was explored, but was shown to be an unlikely modulator. A large study of BDN, highlighted that intracytoplasmic retention of collagen VII and stellate bodies were not exclusive to BDN and can be associated with various subtypes of DEB, non-EB cases and normal skin. The first case of revertant mosaicism in DEB was studied revealing intragenic cross-over as the underlying mechanism. Finally, intradermal injection of allogeneic fibroblasts was shown to result in increased and sustained expression of COL7A1 possibly through the upregulation of HB-EGF. Recognition of disease modifiers in DEB and refinement of genotype–phenotype correlation will not only further our understanding of DEB but will have implications on diagnosis, counselling and prognosis through patient specific and targeted therapy.
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Luu, Tien Dao. "Développement d'une infrastructure d'analyse multi-niveaux pour la découverte des relations entre génotype et phénotype dans les maladies génétiques humaines." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00866371.
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Répondant au besoin de mieux comprendre les relations qui lient un génotype aux phénotypes moléculaires et cliniques associés, nous avons développé une nouvelle infrastructure bioinformatique qui unit, dans un même système, la collecte, la gestion, la maintenance et le traitement de multiples données ou informations. La première contribution de cette thèse est SM2PH Central et sa capacité de générer des instances. SM2PH Central constitue notre centre de référence en ligne pour toutes les protéines humaines intégrant des niveaux d'informations qui vont des aspects génomiques, structuraux, fonctionnels ou évolutifs aux aspects de transcriptomique, interactomique, protéomique ou métabolomique. La deuxième contribution est MSV3d, une ressource d'annotation multi-niveau (propriétés physico-chimiques, fonction, évolution, structure) des mutations humaines connues. MSV3d fournit l'ensemble des connaissances exploitées par la troisième contribution de cette thèse à savoir KD4v, notre base d'extraction de connaissances pour prédire l'impact phénotypique d'une mutation. La base de connaissances de KD4v induite par la Programmation Logique Inductive contient des règles exploitables par un humain ou un ordinateur et des facteurs prédictifs caractérisant les mutations neutres ou délétères. Enfin, l'ultime contribution de cette thèse est liée au développement de GEPeTTO, un prototype de priorisation de gènes. Une application biologique a été réalisée. Nous avons étudié la cécité nocturne en utilisant SM2PH Central, en combinaison avec le service d'annotation de MSV3d et la méthode de prédiction KD4v pour analyser le gène GPR179 et ses deux mutations nouvellement identifiées.
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Ibáñez, Marcelo Esther. "Evolutionary dynamics of populations with genotype-phenotype map." Doctoral thesis, Universitat Politècnica de Catalunya, 2014. http://hdl.handle.net/10803/284931.
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In this thesis we develop a multi-scale model of the evolutionary dynamics of a population of cells, which accounts for the mapping between genotype and phenotype as determined by a model of the gene regulatory network. We study topological properties of genotype-phenotype networks obtained from the multi-scale model. Moreover, we study the problem of evolutionary escape and survival taking into account a genotype-phenotype map.
An outstanding feature of populations with genotype-phenotype map is that selective pressures are determined by the phenotype, rather than genotypes. Our multi-scale model generates the evolution of a genotype-phenotype network represented by a pseudo-bipartite graph, that allows formulate a topological definition of the concepts of robustness and evolvability.
We further study the problem of evolutionary escape for cell populations with genotype-phenotype map, based on a multi-type branching process. We present a comparative analysis between genotype-phenotype networks obtained from the multi-scale model and networks constructed assuming that the genotype space is a regular hypercube. We compare the effects on the probability of escape and the escape rate associated to the evolutionary dynamics between both classes of graphs.
We further the study of evolutionary escape by analysing the long term survival conditioned to escape. Traditional approaches to the study of escape assume that the reproduction number of the escape genotype approaches infinity, and, therefore, survival is a surrogate of escape. Here, we analyse the process of survival upon escape by taking advantage of the fact that the natural setting of the escape problem endows the system with a separation of time scales: an initial, fast-decaying regime where escape actually occurs, is followed by a much slower dynamics within the (neutral network of) the escape phenotype. The probability of survival is analysed in terms of topological features of the neutral network of the escape phenotype.En aquesta tesi es desenvolupa un model multi-escala de la dinàmica evolutiva d'una població de cèl·lules, tenint en compte la correspondència entre el genotip i el fenotip determinat per un model de la xarxa de regulació genètica. Estudiem les propietats topològiques de les xarxes genotip-fenotip obtingudes a partir del model multi-escala. D'altra banda, s'estudia el problema de la fugida evolutiva i la supervivència, tenint en compte una aplicació entre genotip i fenotip. Una característica destacable de les poblacions amb aplicació genotip-fenotip és que les pressions selectives actuen sobre els fenotips, en lloc dels genotips. El nostre model multi-escala genera l'evolució d'una xarxa genotip-fenotip representada per un graf pseudo-bipartit, el qual permet formular una definició topològica dels conceptes de robustesa y capacitat evolutiva. A més a més, estudiem el problema de fugida evolutiva de poblacions de cèl¿lules amb una aplicació genotip-fenotip, basat en en un procés de ramificació multi-tipus. Presentem un anàlisi comparatiu entre les xarxes de genotip-fenotip obtingudes a partir del model multi-escala i les xarxes construïdes assumint un espai de genotips de tipus hipercub regular. Comparem els efectes de la probabilitat de fugida i la freqüència d'escapament associades a la dinàmica evolutiva entre ambdues classes de grafs. Anem més enllà de l'estudi de fugida evolutiva mitjançant l'anàlisi de la supervivència a llarg plaç condicionat a fugir. Els enfocaments tradicionals per a l'estudi de la fugida o escapament suposen una taxa de reproducció en el genotip de fugida propera a infinit. Per tant, la supervivència és equivalent a la fugida. Aquí analitzem el procés de supervivència suposant fugida aprofitant el fet que l'entorn natural del problema de fugida dota al sistema amb una separació d'escales de temps: un règim inicial, de temps ràpid, on la fugida realment es produeix; seguit d'una dinàmica molt més lenta dins de la (xarxa neutra del) fenotip de fugida. La probabilitat de supervivència s'analitza en termes de les característiques topològiques de la xarxa neutra del fenotip de fugida
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Efremov, Dimitar Georgi. "Correlation of genotype and phenotype in [beta]-thalassemia." [Maastricht : Maastricht : Rijksuniversiteit Limburg] ; University Library, Maastricht University [Host], 1994. http://arno.unimaas.nl/show.cgi?fid=6614.
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Bessant, avid Alfred Roger. "Genotype-phenotype correlation in the related retinal dystrophies." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406179.
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Saville, Robert Jack. "Understanding DELLA in wheat : linking genotype to phenotype." Thesis, University of East Anglia, 2011. https://ueaeprints.uea.ac.uk/32675/.
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Chinoy, Hector. "A correlation of genotype and phenotype in myositis." Thesis, University of Manchester, 2007. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:141949.
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Aims: To elucidate the aetiopathological mechanisms underlying the IIMs, through a combination of genotyping, serotyping and clinical phenotyping in a large cohort of Caucasian idiopathic inflammatory myopathy (IIM) patients. Methods: A cross-sectional study of prevalent IIM cases, ascertained through the Adult Onset Myositis Immunogenetic Collaboration, was performed. Cases were confirmed as possessing myositis according to Bohan and Peter (Bohan and Peter 1975a; Bohan and Peter 1975b). IIM clinical subtypes studied included polymyositis (PM), dermatomyositis (DM) and myositis associated with other connective tissue disease (myositis/CTD-overlap). Genotyping of major histocompatibility complex genes, including HLA-B, -DR, -DQ, tumour necrosis factor alpha (TNF-α), was performed using commercial kits. Serotyping of a comprehensive range of myositis specific/associated antibodies (MSA/MAAs) was undertaken. Results: Clinical subsets are described within the serological groupings, suggesting that the classification of the IIMs appears to be better served by the serotype than by the clinical subgrouping of disease. The IIMs possess HLA class I and II haplotype associations and genetic differences observed between PM and DM are accounted for by serological differences. The TNF-308A association is not independent of HLA class I, due to the strong LD within the MHC, but does form part of a haplotype with these factors. An absence of routinely tested for MSA/MAAs makes cancer associated myositis (CAM) more likely, especially in the DM subgroup. An antibody against a 155 and 140kDa doublet is associated with the development of CAM. Outcome measures in the IIMs show construct validity. HLA-DRB1*07 appears to predict a milder clinical phenotype with less disability. No convincing gene-environmental interaction was found capable of altering disease susceptibility or clinical phenotype. Conclusions: Myositis disease subtypes therefore appear to be defined by specific haplotypes acting as risk factors for the development of various MSAs and MAAs.
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Matthews, E. L. "The skeletal muscle channelopathies : phenotype, genotype and pathogenesis." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1446912/.
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The skeletal muscle channelopathies are a group of inherited disorders due to the dysfunction of voltage gated channels in the sarcolemma resulting in abnormal membrane excitability. Simplistically they are broadly divided into those that result froman “over excited” membrane (the non-dystrophic myotonias) and those due to an inexcitable one (the periodic paralyses). Skeletal muscle channelopathies were describedclinically long before they were genotyped or hypotheses regarding pathogenesis fullyevolved. This thesis explores all three, the phenotype, the genotype and recent insightsinto the pathogenesis. Detailed clinical and neurophysiologic examination of a large group of patients identifiednew aspects of the phenotype including neonatal presentations with importantimplications for early life care. Morphological findings are also expanded with thepresence of inflammatory infiltrates, not previously described in the channelopathies. Extensive DNA sequencing of causative genes was undertaken in a carefully genotypedcohort. In hypokalaemic periodic paralysis an exclusive relationship between mutationsand the channel voltage sensor emerged which relates closely to recentelectrophysiological evidence of a “gating pore” disease mechanism. A small butsignificant minority of cases remain however where no mutation is found. The implication of other potential genetic mechanisms or even undescribed genes in thesecases is discussed. Current drug therapies are also examined in three separate cohorts and evidence suggests acetazolamide, a commonly prescribed treatment, may only be effective in 50-60% of those with hypokalaemic periodic paralysis. A tentative relationship between efficacy and genotype also emerges. Patch clamp studies show significant loss of function of the main alpha pore of the sodium channel in periodic paralysis but the implications of this in light of the “gating pore” hypothesis are discussed. Tentative explorations are made as to the viability of performing future studies in myoctes as opposed to the traditional HEK cell model with early experiments illustrating limitations.
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Gordon, Kristiana. "Refining the phenotype and genotype of primary lymphoedema." Thesis, St George's, University of London, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.676101.
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The background to this research is the primary lymphoedema clinic held at St George's Hospital, London. This is a multidisciplinary clinic run by the combined expertise of dermatology and genetic teams, and is the only one of its kind in the UK. The aim of the service is to diagnose, investigate and manage patients with primary lymphoedema. To date, 7 genes are known to cause a phenotype where lymphoedema predominates. The main aim of my MO(Res) project was to use and refine Connell et aI's diagnostic classification pathway (Connell, Brice et al. 2010) for patients with primary lymphoedema in order to identify phenotypically similar groups of patients who could then be the subject of molecular investigation. This, in turn, would hopefully lead to the discovery of new genotypes responsible for subtypes of primary lymphoedema . Lymphangiogenesis, lymphoedema, its clinical features, diagnosis and investigation modalities, and the well -established phenotypes of primary lymphoedema are discussed in the introduction. The laboratory techniques that have been used (including Sanger sequencing and next generation sequencing) are described. Subsequent chapters describe the individual projects that have been carried out in an effort to phenotype and genotype cohorts of patients with primary lymphoedema, including the discovery of a new causal gene for primary lymphoedema. One chapter is dedicated to the development of magnetic resonance lymphangiography (MRL) as an investigative tool in patients with lymphoedema to improve accurate phenotyping of the subgroups, as current imaging techniques are limited. Finally, Connell et aI's diagnostic pathway has been updated on the basis of new findings.
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Sailer, Zachary. "Predicting Phenotypes in Sparsely Sampled Genotype-Phenotype Maps." Thesis, University of Oregon, 2019. http://hdl.handle.net/1794/24231.
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Naturally evolving proteins must navigate a vast set of possible sequences to evolve new functions. This process depends on the genotype-phenotype map. Much effort has been directed at measuring protein genotype phenotype maps to uncover evolutionary trajectories that lead to new functions. Often, these maps are too large to comprehensively measure. Sparsely measured maps, however, are prone to missing key evolutionary trajectories. Many groups turn to computational models to infer missing phenotypes. These models treat mutations as independent perturbations to the genotype-phenotype map. A key question is how to handle non-independent effects known as epistasis. In this dissertation, we address two sources of epistasis: 1) global and 2) local epistasis. We find that incorporating global epistasis improves our predictive power, while local epistasis does not. We use our model to infer unknown phenotypes in the Plasmodium falciparum chloroquine transporter (PfCRT) genotype-phenotype map, a protein responsible for conferring drug resistance in malaria. From these predictions, we uncover key evolutionary trajectories that led high resistance. This dissertation includes previously published and unpublished co-authored material.2020-01-11
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Groth, Philip. "Knowledge management and discovery for genotype/phenotype data." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät II, 2009. http://dx.doi.org/10.18452/16033.
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Die Untersuchung des Phänotyps bringt z.B. bei genetischen Krankheiten ein Verständnis der zugrunde liegenden Mechanismen mit sich. Aufgrund dessen wurden neue Technologien wie RNA-Interferenz (RNAi) entwickelt, die Genfunktionen entschlüsseln und mehr phänotypische Daten erzeugen. Interpretation der Ergebnisse solcher Versuche ist insbesondere bei heterogenen Daten eine große Herausforderung. Wenige Ansätze haben bisher Daten über die direkte Verknüpfung von Genotyp und Phänotyp hinaus interpretiert. Diese Dissertation zeigt neue Methoden, die Entdeckungen in Phänotypen über Spezies und Methodik hinweg ermöglichen. Es erfolgt eine Erfassung der verfügbaren Datenbanken und der Ansätze zur Analyse ihres Inhalts. Die Grenzen und Hürden, die noch bewältigt werden müssen, z.B. fehlende Datenintegration, lückenhafte Ontologien und der Mangel an Methoden zur Datenanalyse, werden diskutiert. Der Ansatz zur Integration von Genotyp- und Phänotypdaten, PhenomicDB 2, wird präsentiert. Diese Datenbank assoziiert Gene mit Phänotypen durch Orthologie über Spezies hinweg. Im Fokus sind die Integration von RNAi-Daten und die Einbindung von Ontologien für Phänotypen, Experimentiermethoden und Zelllinien. Ferner wird eine Studie präsentiert, in der Phänotypendaten aus PhenomicDB genutzt werden, um Genfunktionen vorherzusagen. Dazu werden Gene aufgrund ihrer Phänotypen mit Textclustering gruppiert. Die Gruppen zeigen hohe biologische Kohärenz, da sich viele gemeinsame Annotationen aus der Gen-Ontologie und viele Protein-Protein-Interaktionen innerhalb der Gruppen finden, was zur Vorhersage von Genfunktionen durch Übertragung von Annotationen von gut annotierten Genen zu Genen mit weniger Annotationen genutzt wird. Zuletzt wird der Prototyp PhenoMIX präsentiert, in dem Genotypen und Phänotypen mit geclusterten Phänotypen, PPi, Orthologien und weiteren Ähnlichkeitsmaßen integriert und deren Gruppierungen zur Vorhersage von Genfunktionen, sowie von phänotypischen Wörtern genutzt.In diseases with a genetic component, examination of the phenotype can aid understanding the underlying genetics. Technologies to generate high-throughput phenotypes, such as RNA interference (RNAi), have been developed to decipher functions for genes. This large-scale characterization of genes strongly increases phenotypic information. It is a challenge to interpret results of such functional screens, especially with heterogeneous data sets. Thus, there have been only few efforts to make use of phenotype data beyond the single genotype-phenotype relationship. Here, methods are presented for knowledge discovery in phenotypes across species and screening methods. The available databases and various approaches to analyzing their content are reviewed, including a discussion of hurdles to be overcome, e.g. lack of data integration, inadequate ontologies and shortage of analytical tools. PhenomicDB 2 is an approach to integrate genotype and phenotype data on a large scale, using orthologies for cross-species phenotypes. The focus lies on the uptake of quantitative and descriptive RNAi data and ontologies of phenotypes, assays and cell-lines. Then, the results of a study are presented in which the large set of phenotype data from PhenomicDB is taken to predict gene annotations. Text clustering is utilized to group genes based on their phenotype descriptions. It is shown that these clusters correlate well with indicators for biological coherence in gene groups, such as functional annotations from the Gene Ontology (GO) and protein-protein interactions. The clusters are then used to predict gene function by carrying over annotations from well-annotated genes to less well-characterized genes. Finally, the prototype PhenoMIX is presented, integrating genotype and phenotype data with clustered phenotypes, orthologies, interaction data and other similarity measures. Data grouped by these measures are evaluated for theirnpredictiveness in gene functions and phenotype terms.
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Tian, Liang. "Metabolic characterization of an adaptively evolved cell factory for continuous production of 1.3-propanediol and development of a new catalyst for 1.3 propanediol and acetone co-productions." Thesis, Compiègne, 2014. http://www.theses.fr/2014COMP2132.
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Les micro-organismes ont la capacité de s'adapter rapidement aux différentes contraintes environnementales ou métaboliques, mais le mécanisme détaillé et les principes de cette réponse adaptative en micro-organisme sont mal compris aux niveaux génétiques, biochimiques et métaboliques. Ici, une souche de E. coli a évolué avec un titre élevé de 1,3-propanediol a été sélectionné et cette souche a été analysée comme un exemple pour la découverte de ce processus d'évolution adaptative. La technologie de séquençage comparatif du génome entier a été utilisée pour identifier les mutations génétiques dans le chromosome et le plasmide portant les gènes codant pour la voie de production de 1,3-propanediol a également été séquencée. Quatre mutations ont été trouvées dans le chromosome et ils sont Ipd, glpR, dhak, nagD - promoteur. Une mutation a été trouvée dans le gène GGP2, qui est situé dans le plasmide. Toutes les mutations ont été en outre caractérisées par analyse génétique et inverse biochimique et leur influence dans le réseau métabolique sont aussi découverts. Nous avons démontré que tous les cinq mutations individuellement peuvent augmenter le taux de croissance et la production de 1,3 -propanediol. Selon le profil de fermentation de la souche évolué, l’accumulation d'acétate entravé la croissance de la souche et de l'augmentation de 1,3-propanediol titre. Pour optimiser la production de 1,3- propanediol, un nouveau catalyseur a été développé pour la co-production de 1,3-propanediol avec de l'acétone au lieu de l'acétate, parce que l'acétone a une plus grande valeur et est moins toxique que l'acétate. Les deux voies de l'acétate, dépendantes et indépendantes, ont été testées pour la co-production de 1,3-propanediol et l'acétone dans des conditions anaérobies. Pour la voie de l'acétate dépendante, en modifiant le niveau d'expression de l'acétate kinase cette voie était active dans des conditions anaérobies dans E. coli. Pour la voie de l'acétate indépendant, une courte chaîne acyl-CoA thioestérase candidat a été sélectionné et caractérisé, mais son activité doit encore être améliorée en utilisant l'évolution adaptative ou la sélection in vitro. Pour l'évolution adaptative, le réseau métabolique était rationnel conçu pour forcer de flux de carbone à la production d'acétone, ce qui va augmenter la possibilité et l'efficacité de la sélection d'une thioestérase avec une affinité et une activité élevée à l'acétoacétyl -CoA au cours du processus d’évolution adaptative. Pour la sélection in vitro, un système de bio-sensor a été développé afin de simplifier la méthode de sélection d'une thioestérase mutant avec une grande capacité de catalyser l'acétoacétyl -CoA in vitroMicroorganisms have the ability to adapt rapidly to different environmental or metabolic constraints, but the detailed mechanism and the principles of this adaptive response in microorganism is poorly understood at the genetic, biochemical, and metabolic levels. Here, the glycerol pathway from S. cerevisiae and the B12-independent C. butyricum 1,3-PD pathways were introduced into E. coli and its central metabolic network was restructured to couple the production of 1.3-propanediol to the growth of the microorganism. This strain was grown in conditions favouring adaptive evolution for around 1000 hours. An evolved population was selected under optimal conditions in mineral medium. Comparing with the original strain, it can convert glucose to 1.3-PD at high molar yield (94 %) and its productivity was also significantly increased. Comparative whole genome sequencing technology was used to identify the genetic mutations and five mutating genes lpd, glpR, dhaK, nagD and GPP2 were discovered. All the mutations were further analysed and characterized to disclose their changes after the evolution and to elucidate their influence in the whole metabolic engineering network. To optimize the production of 1.3-PD further, we plan to convert the co-production of acetate to acetone. Indeed, the 1.3 propanediol production was hampered by the acetate inhibition on growth, and acetone is a valuable product which is less toxic thyan acetate. Both the acetate-dependent and independent pathways were tested to produce acetone and some modifications to adapt the global metabolic network were performed. Several strategies were applied to ameliorate the performance of acetone production. Finally, the bottleneck of the acetate-dependent acetone pathway under anaerobic condition was indentify and the acetate-independent acetone pathway still need to be improve with the selection of an evolved or mutant enzyme with high short-chain acyl-CoA thioesterase activity
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Johansson, Camilla. "Exploring genotype to phenotype correlations in Duchenne muscular dystrophy." Thesis, KTH, Skolan för bioteknologi (BIO), 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-215302.
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Sousa, Ribeiro Maria Leticia de. "ß-Thalassemia and HB lepore heterozygotes: phenotype-genotype correlation." [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 1997. http://arno.unimaas.nl/show.cgi?fid=5822.
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Ma, Shiu-kwan Edmond, and 馬紹鈞. "Genotype phenotype correlation of {221}-thalassaemia in the Chinese." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B29532656.
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Dev, Borman Arundhati. "A genotype-phenotype study of childhood onset retinal dystrophies." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1476347/.
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Introduction The childhood onset retinal dystrophies comprise a clinically and molecularly heterogeneous group of disorders. To date, sixteen genes have been implicated in the pathogenesis of the spectrum of disorders comprising Leber Congenital Amaurosis (LCA) and Early Onset Retinal Dystrophy (EORD), accounting for approximately 70% of cases. Although a wide range of phenotypes have been observed within this spectrum, some genotype – phenotype associations are reported. Further detailed genotype – phenotype studies will be important for expanding our understanding of the effects of mutations in these genes on patients and their families. Our knowledge of the phenotypic effects of mutations in other genes implicated in childhood onset retinal dystrophies, such as the bestrophinopathies, continues to expand. Purpose To undertake detailed phenotypic studies into subjects with molecularly identified childhood onset retinal dystrophies, and to describe novel phenotypes. Methods Affected subjects and their families were recruited from Moorfields Eye Hospital to an ongoing Study into childhood onset retinal dystrophies. Subjects were examined clinically and those that were historically recruited to the Study were invited back for further phenotypic analyses, if their molecular cause was identified. Genetic analysis was performed using a variety of methods including DNA microarray analysis, autozygosity mapping, direct sequencing and whole exome sequencing. Results Between August 2008 and August 2011, 201 subjects from 186 families were recruited into the Childhood Onset Retinal Dystrophy Study, and categorised into 2 cohorts: cohort 1 - the generalised retinal dystrophies, comprising 177 subjects (166 families); and cohort 2 – subjects with a macular phenotype, comprising 24 subjects (20 families). The molecular cause was identified in 34.5% of subjects in cohort 1 and 25% of subjects in cohort 2. RDH12 accounted for 28% of mutations in cohort 1, 18% had mutations in CEP290, and 13% had mutations in RPE65. The subjects in cohort 2 with autosomal recessive bestrophinopathy all had bi-allelic mutations in BEST1. The phenotype associated with the different genes identified was expanded, and focused on those genes with limited reports of the phenotype, such as SPATA7, LRAT, RGR and BEST1. The phenotype associated with a gene not previously identified in human EORD, TUB, was studied, and the features associated with a novel macular phenotype named Benign Yellow Dot Dystrophy were characterised. Conclusions This study has expanded and refined our understanding of the phenotypes associated with mutations in genes that cause childhood onset retinal dystrophies, and has identified a novel phenotype. This work will allow accurate prognostic and genetic counselling to affected families, and provides phenotypic information that will be important in ascertaining disorders that may be suitable for clinical trials of novel therapies.
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Anderson, Craig. "Mechanistic bases of metal tolerance : linking phenotype to genotype." Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/43776/.
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Ecotoxicology is currently undergoing a revolution as the result of new technological advances in molecular biology, capable of finely resolving metabolic mechanisms associated with exposure. These high-throughput analyses can detail the evolutionary and ecological implications of exposure in non-model organisms, such as the earthworm, Lumbricus rubellus. This terrestrial sentinel has been observed across former mine sites that are highly contaminated with arsenic and have been found to mitigate toxicity at soil concentrations that cause mortality in unadapted individuals. This is indicative of the adaptive capacity of natural populations recently exposed to persistent and strong selection pressure. However, mechanisms surrounding adaptation to arsenic in L. rubellus have yet to be characterised, and so the effects of exposure are broadly reported with the aim of distinguishing resistance from phenotypic plasticity in natural populations. Unadapted earthworms were initially used to derive basal phenotypic variation associated with arsenic exposure. Variation in life-history parameters was observed among adult and juvenile L. rubellus, establishing relative sensitivity and population-level inferences. A systems biology approach was employed to describe molecular mechanisms associated with arsenic metabolism, encompassing transcriptomic and metabolomic analyses, underpinned by arsenic speciation. Insight into the genetic bases of arsenic resistance, which enable persistence of L. rubellus at highly contaminated sites, was sought. Recombinant inbred lineages derived from adapted populations, were cultivated and their phenotypes relative to arsenic exposure determined. Phylogeographic analyses were used to interrogate genetic variation among populations inhabiting former mine sites as well as proximal control sites. A mitochondrial marker defined cryptic species across the UK, but did not establish soil chemical profiles relative to clade occurrence. RADseq better resolved genetic variation at these sites, determining that soil geochemistry is strongly associated with genetic variation. Furthermore, genomic markers inferred genetic erosion, found to selectively reduce variation at sites relative to a single clade.