Analyse fonctionnelle de nouvelles mutations de l'aquaporine-2 responsable du diabète insipide néphrogénique

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mécanisme d'intégration des signaux RTK-dépendants par la protéine d'échafaudage CNK au sein de la voie de signalsiation RAS/MAPK chez la drosophile

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Identification des mutations responsables de la NHSA2 et de l'AOA2 dans la population canadienne-française : deux nouveaux exemples de maladies à effet fondateur au Québec

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Ataxie cérébelleuse avec mutations dans le gène senataxin : un nouvel effet fondateur canadien-français

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Functional Evaluation of Causal Mutations Identified in Human Genetic Studies

Human genetics has been experiencing a wave of genetic discoveries thanks to the development of several technologies, such as genome-wide association studies (GWAS), whole-exome sequencing, and whole genome sequencing. Despite the massive genetic discoveries of new variants associated with human diseases, several key challenges emerge following the genetic discovery. GWAS is known to be good at identifying the locus associated with the patient phenotype. However, the actually causal variants responsible for the phenotype are often elusive. Another challenge in human genetics is that even the causal mutations are already known, the underlying biological effect might remain largely ambiguous. Functional evaluation plays a key role to solve these key challenges in human genetics both to identify causal variants responsible for the phenotype, and to further develop the biological insights from the disease-causing mutations.

We adopted various methods to characterize the effects of variants identified in human genetic studies, including patient genetic and phenotypic data, RNA chemistry, molecular biology, virology, and multi-electrode array and primary neuronal culture systems. Chapter 1 is a broader introduction for the motivation and challenges for functional evaluation in human genetic studies, and the background of several genetics discoveries, such as hepatitis C treatment response, in which we performed functional characterization.

Chapter 2 focuses on the characterization of causal variants following the GWAS study for hepatitis C treatment response. We characterized a non-coding SNP (rs4803217) of IL28B (IFNL3) in high linkage disequilibrium (LD) with the discovery SNP identified in the GWAS. In this chapter, we used inter-disciplinary approaches to characterize rs4803217 on RNA structure, disease association, and protein translation.

Chapter 3 describes another avenue of functional characterization following GWAS focusing on the novel transcripts and proteins identified near the IL28B (IFNL3) locus. It has been recently speculated that this novel protein, which was named IFNL4, may affect the HCV treatment response and clearance. In this chapter, we used molecular biology, virology, and patient genetic and phenotypic data to further characterize and understand the biology of IFNL4. The efforts in chapter 2 and 3 provided new insights to the candidate causal variant(s) responsible for the GWAS for HCV treatment response, however, more evidence is still required to make claims for the exact causal roles of these variants for the GWAS association.

Chapter 4 aims to characterize a mutation already known to cause a disease (seizure) in a mouse model. We demonstrate the potential use of multi-electrode array (MEA) system for the functional characterization and drug testing on mutations found in neurological diseases, such as seizure. Functional characterization in neurological diseases is relatively challenging and available systematic tools are relatively limited. This chapter shows an exploratory research and example to establish a system for the broader use for functional characterization and translational opportunities for mutations found in neurological diseases.

Overall, this dissertation spans a range of challenges of functional evaluations in human genetics. It is expected that the functional characterization to understand human mutations will become more central in human genetics, because there are still many biological questions remaining to be answered after the explosion of human genetic discoveries. The recent advance in several technologies, including genome editing and pluripotent stem cells, is also expected to make new tools available for functional studies in human diseases.

Is Rapid Adaptation to New Environments Fueled by Old Mutations? A Case Study of Copper Tolerance on Mimulus guttatus

Rapid adaptation and tolerance is a phenomenon experienced by a variety of organisms typically because of new and harsh environments. Mimulus guttatus, a plant commonly seen on the west coast of the United States, is a prime example as it has rapidly evolved to soil contamination by copper due to mining in California in the last 150 years. There have been two hypotheses posed by researchers as to the genetic basis of how organisms have evolved so quickly which I set out to study: 1) There is a low frequency of tolerant genotypes in the ancestral population otherwise known as standing variation or 2) new mutations occurred once exposed to a new environment. In the past, researchers found it difficult to distinguish between the two because they lacked the technology we have today for DNA analysis. I used four different populations of M. guttatus from varying locations in order to address which hypothesis was valid. I conducted both survival assays of these populations and DNA analysis of known tolerant and non-tolerant lines using a copper oxidase gene. I found that there was at least some degree of tolerance in all populations in the survival assays, supporting the hypothesis of standing variation. I also found patterns within DNA analysis suggesting the copper oxidase gene would be useful for further study to verify the standing variation hypothesis. The results from this experiment helps in understanding rapid evolution not just in the context of soil contamination by metals but also ties back to why an alarming number of species are not able to adapt to our constantly changing world.

Les timbres amphoriques de Ras el Bassit

Sur le site de Ras el Bassit, durant les campagnes de fouilles menées de 1971 à 1984, 133 timbres amphoriques furent trouvés principalement dans le Tell du Meidan. Ces timbres sont des artefacts précieux. En effet, ce mémoire démontre comment les timbres amphoriques contribuent à l’élaboration de l’histoire d’un site, vue ici par l’analyse de ces 133 timbres amphoriques. Tout d’abord, les termes de base sont présentés pour expliquer ce que sont une amphore et un timbre. Par la suite, l’historiographie des recherches faites sur les timbres montre que, depuis le recueillement des informations sur les sites de production, certaines séries de timbres furent datés à l’année près, contribuant ainsi à améliorer les datations des autres sites. C’est de cette manière que les anses timbrées contribuent le plus souvent à améliorer un site. Il existe aussi d’autres apports. Par exemple, en localisant la production d’une série de timbres, les échanges commerciaux peuvent être aperçus. À travers l’analyse de ces 133 timbres, le site de Ras el Bassit pourra être mieux daté pendant l’époque hellénistique. En effet, les couches stratigraphiques en contexte pourront alors avoir un élément datable d’une grande précision, si tel est le cas. De plus, en connaissant la provenance de ces timbres amphoriques, elle démontrera que les échanges (avec des amphores timbrées) commencèrent dès le IVe siècle, ce qui correspond à une reprise des importations grecques. Ces importations dureront pendant toute l’époque hellénistique.

Les mutations socio-économiques de la Corse de 1957 à nos jours

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Effets de mutations dans le gène ldhA et dans la protéine FhlA ainsi que de la limitation en glucose ou en soufre sur la production d'hydrogène chez Escherichia coli

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Analyse fonctionnelle de nouvelles mutations de l'aquaporine-2 responsable du diabète insipide néphrogénique

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.