Discovering the associations between genetic variables and disease status can help reduce the burden of disease on society. This thesis focuses on the methods required to detect maternal genetic effects (an effect where the genes of the mother affect the disease risk of the child) and interaction effects between these maternal genes and environmental variables in trio data consisting of parents and an affected child. A simulation study was conducted to determine the extent to which testing for these effects is affected by violations to the mating symmetry assumption required for two current methods when control parents are not available.. This study showed that methods for maternal effect estimation are not robust to these violations; however, the interaction test is robust to the violation. Finally, a candidate gene study on orofacial clefts was conducted to evaluate maternal gene-environment interactions in international consortium data. Significant effects were found but the large magnitude of the effect estimates raises concerns about the validity of the results. This thesis tries also discusses the lack of methods and software available to estimate maternal gene environment interactions.

Les vitréorétinopathies (VRPs) héréditaires constituent un groupe de maladies cécitantes englobant des formes exsudatives résultant d’un arrêt développemental de la vascularisation rétinienne, et des formes dégénératives associant des anomalies du vitré, de la vascularisation rétinienne et une dégénérescence choriorétinienne. L’analyse par séquençage haut-débit d’une cohorte de 182 patients-VRPs nous a permis d’élargir le spectre des anomalies moléculaires de ces pathologies et d’identifier pour la première fois des délétions hétérozygotes de l’exon 8 du gène VCAN dans la maladie de Wagner, une vitréorétinopathie autosomique dominante très sévère, non syndromique. VCAN code pour la versicane, qui joue un rôle prépondérant dans l’angiogenèse, la migration/prolifération/adhésion/différenciation cellulaire. Tous ces rôles sont sous la dépendance de quatre isoformes, produites par épissage alternatif des exons 7/8, et dont le rapport quantitatif est déséquilibré chez les patients atteints de la maladie de Wagner. Afin de mieux comprendre ces mécanismes, nous avons généré une délétion d’environ 10-kb incluant l’exon 8 de Vcan chez la souris grâce à la technologie Crispr/Cas9. Les analyses moléculaires de ces souris VcanΔ8, indiquent que le déséquilibre quantitatif d’expression des isoformes de la versicane dans les tissus oculaires est similaire à celui retrouvé à partir des fibroblastes des patients Wagner. L’exploration phénotypique ophtalmologique indique que les souris souris VcanΔ8 présentent dès 3 mois une altération de l’ERG similaire à celle observée chez les patients Wagner. Nous avons pu réaliser une analyse du transcriptome oculaire des souris VcanΔ8 par RNA-Seq dont les résultats indiquent des différences d'expression du gène Rp1l1, jouant un rôle au niveau du cil connecteur des photorécepteurs, et de gènes majeurs impliqués dans des voies de signalisation contrôlant l'inflammation choriorétinienne. Ces différentes pistes sont pertinentes pour expliquer en partie les processus physiopathogéniques de la maladie de Wagner. Nous avons également réalisé une étude d'expression des différents isoformes de la versicane au cours du développement oculaire à partir des souris sauvages et transgéniques. Le modèle murin VcanΔ8 offre, pour la première fois, un modèle oculaire qui semble reproduire le modèle humain de la maladie de Wagner. Par conséquent, il offre des perspectives prometteuses vers une meilleure compréhension des mécanismes physiopathologiques de la maladie de Wagner. Mais au-delà de la maladie de Wagner, ce modèle pourrait avoir des retombées dans d'autres processus pathologiques. En effet, la versicane est une glycoaminoglycane à chondroïtine sulfate qui suscite une attention toute particulière dans le domaine de la cancérogénèse car c'est une molécule qui semble fortement moduler le phénotype du microenvironnement de nombreuses tumeurs à pronostic défavorable. / Pas de résumé

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Conservation biologists are interested in maintaining genetic variation in small populations, with a view to maintaining fitness and the ability of the species to adapt to changing environmental conditions. The most important type of genetic variation is therefore that which affects fitness and reproduction, and is therefore subject to natural selection. Such fitness traits are often quantitative, i.e. are the result of a suite of loci, and are continuously variable. Microsatellite markers are a popular method of determining the level of variation present in a species??? genome. The assumption is made that microsatellites, which are neutral markers, behave in the same manner as quantitative traits. If this assumption were proved incorrect, then the use of neutral markers in conservation monitoring would have to be re-evaluated. In this study, experiments have been conducted using Drosophila melanogaster to test the assumption that variation in quantitative traits under stabilising selection declines at the same rate as heterozygosity in microsatellite markers, during a population bottleneck. Experimental population bottlenecks were of two effective population sizes (Ne), Ne=2 for one generation and Ne=60 for 35 generations. Based on the effective population size, we expected both types of bottlenecks to lose 25% of neutral genetic variation. Ten replicates of each bottleneck were maintained, along with four large control populations with Ne=320. In each population, heterozygosity (He) for eight microsatellite loci was compared with the heritability and additive genetic variance of two quantitative traits subject to balancing selection: fecundity and sternopleural bristle number. Microsatellite heterozygosity decreased in accordance with neutral predictions, whereas additive genetic variation in quantitative traits altered more than expected in both large and in bottlenecked populations relative to the initial sampling values, indicating that variation in quantitative traits was not being lost at the same rate as predicted by neutral theory. For most traits, the changes in additive genetic variance were congruent in all populations, large or bottlenecked. This congruence suggests that a common process was affecting all populations, such as adaptation. A mite infestation in early generations is a possible source of selective pressure. When bottlenecked populations were compared to the contemporaneous large populations (Ne = 320), the additive genetic variance of most traits was seen to have been lost in accordance with predictions from the loss of microsatellite heterozygosity. Loss of variation in microsatellites can thus be used to predict the loss of variation in quantitative traits due to bottlenecks, but not to predict the potentially much larger changes due to other processes such as adaptation. The effects of concurrent environmental stress and reduced population size were also evaluated. Endangered populations are often subject to environmental stress in addition to reduced population size, but the effect of stress on the additive genetic variance of fitness traits in organisms undergoing population bottlenecks is unknown. If the presence of stress alters the level of additive genetic variance in fitness traits, the viability of such populations could be substantially affected. The loss of microsatellite heterozygosity was not affected by the presence of a stress agent during a bottleneck. I found some significant effects of stress on the additive genetic variance of sternopleural bristles and fecundity; there was also a significant interaction between stress and the response to directional selection in sternopleural bristles. There was also an increase in the coefficient of variation of VA for sternopleural bristles. Stress may therefore affect the manner in which populations respond to selective pressures.

The debate on genetic testing for Huntington???s disease has been dominated heavily by the bioethical and biomedical discourses. Yet upon analysis, both discourses are highly inadequate for understanding the complexity of the difficult choices people are faced with, and the inter-personal relations that are central to decisions regarding the uptake of genetic tests. The purpose of this thesis is two-fold. Firstly, to conduct a theoretically-informed critical analysis of the existing bioethical discourse on genetic testing for Huntington???s disease, that draws primarily on the work of contemporary feminist thinkers. Secondly, to explore how people with a genetic risk for Huntington???s disease negotiate the available choices between certainty and uncertainty; how they experience the liminality of ???being at risk??? in everyday life; how they manage their social environments; and how they interpret their own situation. The matter of ???choice??? is heightened because of the ready availability of genetic testing for Huntington???s disease, and the moral rhetoric that accompanies the provision of genetic services. Empirically, the research draws on the narratives by eleven people with a family history of Huntington???s disease, through which they discuss their fears of living in the shadow of the fatal disease, and consider their choices on reproduction and genetic testing. Their narratives will be analysed through the work of Foucault and Goffman, as well as a wide range of contemporary sociologists.The thesis being proposed is that decisions on genetic testing cannot be said to be ???individual???, but are instead dispersed among the social relations between the self and others, reflecting and transforming the values, competing desires, and the discourses that are prevalent in their social worlds. This is achieved through the discursive production of a web of narratives through which both individuals and institutions attempt to govern, with varying degrees of success, the implications of this relatively new field of knowledge.

Amendements: leaves 252-254. Copies of author's previously published articles inserted. Bibliography: leaves 226-251. The CYP2C19 and CYP2D6 genetic polymorphisms control the oxidative metabolism of many different drug classes. Populations are separated into groups of extensive metabolisers (EM), poor metabolisers (PM), and in the case of CYP2D6, ultra-rapid metabolisers (UM). In vitro studies using human liver microsomes were conducted to examine the kinetics of the oxidative metabolism of flunitrazepam, and which CYP450 enzymes mediate the oxidative metabolism of flunitrazepam, (S)-mephenytoin and proguanil.

Copy of author's previously published work inserted. Bibliography: leaves 193-216. Thesis which examines in detail the genetics of congental ataxias, and early and late onset ataxias.

Bibliography: leaves 116-129.