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Functional genomics for discovery of new cell growth and immune resistance biomarkers

The main objective here was to characterize the impact of a deficient diet in fatty acids in the blue mussel Mytilus edulis. These fatty acids are pro-inflammatory eicosanoid precursors responsible of the molecular mechanisms behind larval fitness during early development. They confer further structural fluidity to cell membranes. A nutrigenomic approach provided us with essential information about modulators in marine adaptation and thorough knowledge of the ecological players during the progress of larval ontogenesis. Life cycle history of adult bivalves is strongly influenced by the quality and availability of food during the larval phase. Indeed, this dependency found amongst invertebrates and specifically in bivalves is central to the growing larvae. Several related concepts have been introduced in the first part of the thesis. In addition, we included detailed examples of the effect of eco-physiological interactions and genetic predisposition on the inclusive fitness of species. Energy reserves can vary greatly depending on the microalgal fatty acid composition. Microalgae constitute the main food source for the feeding larvae and are fundamental to their local adaptation. Moreover, they are nutrient-rich, which can contribute to the survival of larvae, their metamorphic success, and the duration of their transitional period to sexually mature adults. All these physiological hypotheses were tested using modern methods in developmental genomics. We thus identified a connection between the dynamical function of the genome and the fast-changing phenotype's inclusive fitness.

Furthermore, biometrics were measured at early larval development. We recorded the various transitions of a young, underdeveloped body and likely susceptible of high mortality, into a more resistant form. Next, larval transcriptome was RNA-sequenced. Consequently, the first chapter of the second part addresses the importance of whole-genome sequencing. Our strategy helped integrate various constituents of the genome for a more reliable physio-genetic assessment. For example, mechanisms known to be specifically activated during an immune defence in response to infections, can also be associated with cellular growth and development in the absence of exogenous perturbations. In addition, interactions between transcriptional regulators and their target genes were thoroughly investigated. This helped us define coordinated expressions between genes and the physiological changes underlying larval body-plan transitions. Supervised Machine Learning models were used to identify gene signatures from expression profiles during larval development, provided that the genomic response generated was assessed relatively to the impact of dietary fatty acids. Statistical modeling enabled us to map the whole transcriptome of M. edulis and to identify new genetic biomarkers. For example, we discovered new differentially regulated genes implicated in stress resistance and DNA repair using specialized supervised classifications. Therefore, data mining of the newly built transcriptome of M. edulis and notably the large-scale examination of gene expressions provided new insights on the existence of a direct environmental impact on the dynamic of larval transcriptome. Furthermore, pro-inflammatory fatty acids can activate depending on the stage of development, a newly discovered set of interrelated genes that promote defence and metabolic regulation. Lastly, these results confirm that the inclusive fitness of the identified GRNs can affect the local adaptation of larvae. For this reason, we were able to characterize 29 genetic markers that connect the effect of eicosanoid precursors with M. edulis larval growth and mortality. We have presented in this thesis an integrative approach of transcriptomic and behavioural data that brings a holistic understanding of systems biology. This will help to establish links between environmental assessment and functional development in marine bivalves.

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