In the next generation sequencing era many bioinformatics tools have been developed for assisting scientists in their studies on the molecular basis of genetic diseases, often with the aim of identifying the pathogenic variants. As a consequence, in the last decades more than one hundred new disease-gene associations have been discovered. Nevertheless, the genetic basis of many genetic diseases yet remains undisclosed. It has been shown that many diseases considered as monogenic with an imperfect genotype-phenotype correlation or incomplete penetrance are, on the contrary, caused or modulated by more than one mutated gene, meaning that they are in fact oligogenic. Current bioinformatics methods used for identifying pathogenic variants are trained and fine-tuned for identifying a single variant responsible of a disease. This monogenic-oriented approach cannot be used to explore the impact of combinations of variants in different genes on the complexity and genetic heterogeneity of rare diseases. Digenic diseases are the simplest form of oligogenic disease and thus they can provide a conceptual bridge between monogenic and the poorly understood polygenic diseases.The ambition of this thesis is to collect and analyse digenic data, introducing this topic in the bioinformatics field where digenic diseases are still an unexplored branch. This can be divided in two steps: the first consists in the creation of a central repository containing detailed information on digenic diseases; the second is an analysis of their peculiarities, using machine learning methods for studying subclasses of digenic effects.In the first step we developed DIDA (DIgenic diseases DAtabase), a novel database that provides for the first time a curated collection of genes and associated variants involved in digenic diseases. Detailed information related to the digenic mechanism have been manually mined from the medical literature. All instances in DIDA were also assigned to two sub classes of digenic effects, annotated as true digenic (both genes are required for developing the disease) and composite classes (one gene is sufficient to produce the disease phenotype, the second one alters it or change significantly the age of onset).In the second step, we hypothesized that the digenic effect may be related to some biological properties characterizing digenic combinations. Using machine learning methods, we show that a set of variant, gene and higher-level features can differentiate between the true digenic and composite classes with high accuracy. Moreover, we show that a digenic effect decision profile, extracted from the predictive model, motivates why an instance is assigned to either of the two classes.Together, our results show that digenic disease data generates novel insights, providing a glimpse into the oligogenic realm. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

<p>This thesis focuses on the identification of genetic factors underlying two inherited human phenotypes: hearing loss and monoamine oxidase activity. </p><p>Non-syndromic hearing loss segregating in a Swedish family was tested for linkage to 13 previously reported candidate loci for hearing disabilities. Linkage was found to two loci: DFNA12 (llq22-q24) and DFNA2 (lp32). A detailed analysis of the phenotypes and haplotypes shared by the affected individuals supported the hypothesis of digenic inheritance of hearing disability in the Swedish family. Mutation screening of α-tectorin, a gene residing within the DFNA12 region revealed a mutation of a conserved amino acid (Cys to Ser), that segregated with the disease. The identification of the mutation added support to the involvement of α-tectorin in hearing disabilities. In contrast, no mutations were identified in two candidate genes at the DFNA2 locus, that were reported to cause hearing loss in other families. It is possible that the DFNA2 locus contains a third, not yet identified, hearing loss gene. </p><p>Monoamine oxidase A (MAOA) and B (MAOB) catalyze the degradation of certain neurotransmitters in the central nervous system and are associated with specific behavioral and neuropsychiatric human traits. Activity levels of both monoamine oxidases (MAO) are highly variable among humans and are determined by unknown genetic factors. This study investigated the relationship of different MAO alleles with MAO mRNA levels and enzyme activity in human brain. Several novel DNA polymorphisms were identified in a group of Swedish individuals. Haplotypes containing several closely located MAOA polymorphisms were assessed in Asian, African, and Caucasian populations. The haplotype distribution and diversity pattern found among the three populations supported the occurrence of a bottleneck during the dispersion of modem humans from Africa. </p><p>Allelic association studies conducted on postmortem human brain samples, revealed the association between a SNP in the MAOB intron 13, and different levels of both MAO enzyme activities. This suggested that this SNP is in linkage disequilibrium with at least one novel functional DNA polymorphism that controls MAO enzyme activities in human brain. The identification of functional polymorphisms regulating the activity of these enzymes will help to elucidate the involvement of MAO in human behavior and neuropsychiatric conditions. </p>

This thesis focuses on the identification of genetic factors underlying two inherited human phenotypes: hearing loss and monoamine oxidase activity. Non-syndromic hearing loss segregating in a Swedish family was tested for linkage to 13 previously reported candidate loci for hearing disabilities. Linkage was found to two loci: DFNA12 (llq22-q24) and DFNA2 (lp32). A detailed analysis of the phenotypes and haplotypes shared by the affected individuals supported the hypothesis of digenic inheritance of hearing disability in the Swedish family. Mutation screening of α-tectorin, a gene residing within the DFNA12 region revealed a mutation of a conserved amino acid (Cys to Ser), that segregated with the disease. The identification of the mutation added support to the involvement of α-tectorin in hearing disabilities. In contrast, no mutations were identified in two candidate genes at the DFNA2 locus, that were reported to cause hearing loss in other families. It is possible that the DFNA2 locus contains a third, not yet identified, hearing loss gene. Monoamine oxidase A (MAOA) and B (MAOB) catalyze the degradation of certain neurotransmitters in the central nervous system and are associated with specific behavioral and neuropsychiatric human traits. Activity levels of both monoamine oxidases (MAO) are highly variable among humans and are determined by unknown genetic factors. This study investigated the relationship of different MAO alleles with MAO mRNA levels and enzyme activity in human brain. Several novel DNA polymorphisms were identified in a group of Swedish individuals. Haplotypes containing several closely located MAOA polymorphisms were assessed in Asian, African, and Caucasian populations. The haplotype distribution and diversity pattern found among the three populations supported the occurrence of a bottleneck during the dispersion of modem humans from Africa. Allelic association studies conducted on postmortem human brain samples, revealed the association between a SNP in the MAOB intron 13, and different levels of both MAO enzyme activities. This suggested that this SNP is in linkage disequilibrium with at least one novel functional DNA polymorphism that controls MAO enzyme activities in human brain. The identification of functional polymorphisms regulating the activity of these enzymes will help to elucidate the involvement of MAO in human behavior and neuropsychiatric conditions.

Le corpus interroge des œuvres désancrées, décentrées, mouvantes : loin d’être des unités séparées et indépendantes, les romans quoique singuliers entre en relation les uns avec les autres sur le plan thématique narratif. On peut donc identifier un univers romanesque, à la fois spécifique et commun. Les romans rayonnent à partir d’un lieu et d’une histoire commune et s’articulent autour de trois îles créant une véritable géographie scripturale : trois romans, trois îles de la Caraïbe, trois auteurs. L’archipel géographique comme l’archipel littéraire apparaissent comme le résultat d’une géographie malléable et/ou d’une écriture sans limite. L’espace dessiné et l’œuvre sont en perpétuelle construction. L’archipélité géographique mais aussi littéraire est, dans cette étude, à percevoir comme une façon de retrouver et rassembler les morceaux d’histoires, de mémoires. La Traite est proprement un « parler indicible » et ne donne lieu à aucun récit. C’est donc sur ce fond d’absence de mythe et d’épopées que s’inscrivent les œuvres du corpus. Elles tentent de retranscrire également la dimension lacunaire fragmentée, mettant en avant une pensée du vide, de l’absence, de l’indicible et de l’ineffable. Le « non-monde » initial laisse la place à l’émergence d’un nouveau lieu digénique narratif. Il s’agit d’une dématérialisation du lieu géographique dans l’espace narratif. Le lien archipélique retranscrit l’indicible et l’invisible des mémoires et des histoires oubliées par l’acte d’écriture. Non contente d’en décrire la vacance, les romans transforment la béance géographique, historique et mémorielle en atout littéraire et poétique. Ce qui était une carence pourrait s’avérer aujourd’hui un atout pour la pensée et, paradoxalement pour la création littéraire. / The body of texts examined in this study deals with disanchored, decentred, shifting literary works. Far from being separate and independent units, the novels, though singular, are constantly overlapping in terms of narrative themes. Therefore we can identify a fictional landscape that is both specific and common. The novels take pride of place from within a common history and focus on three islands, thereby creating a real scriptural geography. Three novels, three Caribbean islands and three authors are under consideration. The geographical archipelity and the literary one appear to be the result of a malleable geography and/or of a boundless creativity. The designated space and the works are in perpetual construction. In this study, both the geographical and literary archipelagos are conceptualized as a way to identify and bring together small portions of history and memories. The slave trade is a truly “unspeakable language” which does not provide any narrative. Against the backdrop of an absence of epic tales and myths, the texts that are considered for study have been highlighted. They are seeking to reproduce the fragmented and incomplete nature of life, thereby emphasizing the importance of nothingness, absence, the unspeakable and the ineffable. The initial “non-world” evolves into an emerging new digenic narrative space. Hence a geographical dematerialization within the narrative. The archipelago itself reproduces the unspeakable and invisible memories that are related to forgotten stories. Thus, the novels are not only describing geographical and historical nothingness, they are also transforming it into an asset for literature and poetry. What was once considered a fundamental flaw has become an asset for literary and creative thought.

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