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Development of Evolutionary Knowledge Extraction Methods and Their Application in Biological Complex Systems Benjamin Linard

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Development of Evolutionary Knowledge Extraction Methods and Their Application in Biological Complex Systems Benjamin Linard Development of evolutionary knowledge extraction methods and their application in biological complex systems Benjamin Linard To cite this version: Benjamin Linard. Development of evolutionary knowledge extraction methods and their application in biological complex systems. Biochemistry, Molecular Biology. Université de Strasbourg, 2012. English. NNT : 2012STRAJ044. tel-00766182 HAL Id: tel-00766182 https://tel.archives-ouvertes.fr/tel-00766182 Submitted on 17 Dec 2012 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITÉ DE STRASBOURG Ecole Doctorale des Sciences de la Vie et de la Santé IGBMC - CNRS UMR 7104 - Inserm U 964 THÈSE présentée par : Benjamin LINARD soutenue le : 15 octobre 2012 pour obtenir le grade de : Docteur de l’université de Strasbourg Discipline/ Spécialité : Bioinformatique Développement de méthodes évolutionnaires d’extraction de connaissance et application à des systèmes biologiques complexes (Development of evolutionary knowledge extraction methods and their application in biological complex systems) THÈSE dirigée par : Mme THOMPSON Julie Directeur de recherche, Université de Strasbourg RAPPORTEURS : M VANDEPOELE Klaas Directeur de recherche, VIB / Ghent University M GIBRAT Jean-François Directeur de recherche, MIG-INRA EXAMINATEURS : Mme DESPONS Laurence Maître de conférences, Université de Strasbourg Remerciements Je tiens à exprimer ma sincère reconnaissance à M. VANDEPOELE Klaas, M. GIBRAT Jean-François et Mme DESPONS Laurence pour l’honneur qu’ils me font de juger cette thèse. Cette section est sûrement la plus difficile à écrire car elle concrétise en quelque sorte la fin d’une aventure… Je vais essayer de n’oublier personne, mais j’ai tellement de personnes à remercier. Commençons par le laboratoire. Merci à tous de m’avoir si bien accueillis durant toutes ces années. J’ai toujours été motivé pour venir travailler au laboratoire, ce n’est pas seulement grâce au sujet mais aussi grâce à la bonne ambiance qui a toujours régné dans les bureaux et aux petites blagues qui fusaient régulièrement... Merci Luc, Raymond et Laëtitia pour tout le temps que vous m’avez consacré pour m’expliquer les méandres des serveurs de l’institut. Merci Wolfgang, Nicolas et Nicodème pour vos conseilles avisés sur divers outils statistiques. Merci Odile et Fréderic pour avoir été les premiers à me permettre d’intégrer ce labo et pour avoir initié la petite étincelle qui m’a donné l’envie de continuer. Merci Jean pour tous tes conseils et les petites références star wars du quotidien. Merci Hoan pour ton aide sur DB2 et pour toutes les nouvelles mondiales bizarres que tu dénichais régulièrement. Merci Laurent et Véronique pour tous vos conseils. Merci Dao pour m’avoir montré ce qu’est vraiment la persévérance et pour tous les plats vietnamiens louches que j’ai goûté. Merci à Alexis, Raphaël, Can et Marc pour leurs contributions respectives à OrthoInspector. Merci également à Alin, Xavier et Vincent pour toutes les discussions autour de nos repas au RU. Enfin il reste deux personnes du laboratoire pour qui les mots de remerciement me manquent. Olivier et Julie, je pense que beaucoup vous ont déjà remercié pour tout ce que vous avez fait pour eux scientifiquement et professionnellement parlant. Alors c’est pour un autre point que je vais vous remercier. Je ne sais pas si vous vous en rendez toujours compte, mais vous avez un don que peu de gens possèdent et ça, je l’ai compris en commençant à discuter avec d’autres personnes dans le monde scientifique et en particulier en observant d’autres « chefs ». Vous savez motiver les troupes, vous savez partager votre passion et vous êtes capable de tirer le meilleur des compétences de chacun en rendant globalement tout le monde satisfait après les efforts. J’ai vu trop peu de personnes capables de réaliser ça durant ces trois ans et c’est pourtant tellement important pour donner à des débutants comme moi l’envie de persévérer et d’aller plus loin. C’est pour celà que je veux avant tout vous remercier et pour ce sourire que vous avez toujours affiché en regardant mes arcs-en-ciel de barcodes. ;) Quelques mots également pour tous les gens de l’institut ou d’ailleurs qui ont eu beaucoup d’influence sur ma thèse. Merci à Serge, Guillaume et Damien pour leur aide sur les serveurs et leur disponibilité. Merci aux membres du service communication pour les fêtes de la science que nous avons menés ensemble. Merci à Georges Labouesse et Laurence Drouard pour m’avoir choisi pour les enseignements d’OpenLAB et merci à toute l’équipe d’OpenLAB pour les inoubliables souvenirs que l’on s’est forgé lors de nos interventions (ah là là, ces ados…). Une pensée aussi pour tous les membres du SPB, vous êtes nombreux, il me faudrait 1 page rien que pour vous remercier. On a monté une association super en à peine 1 an et on a réussi à convaincre beaucoup de hautes instances que c’est une chose utile ! Je pense que rien que pour ça, on a gagné notre pari. Enfin un petit mot plus personnel pour certaines personnes… Merci à Nicolas, Ismail, Tao et Claire R. Je n’ai pas à les écrire, vous savez toutes les choses pour lesquelles vous avez compté. Mickaël et Damien, c’est la même chose. En plus grâce à moi vous êtes célèbres à l’IGBMC maintenant ! Un petit mot également pour Lena, Claire B., Ebe, Florianna, Deepika, Thomas, Jérôme, Adrien, Rose-Marie, Justine, Sara, Laure, Caroline, Morgane, Isabelle, Mélanie, Nadia, Terrence, Twix, Firas, Anna, Iskander et Katarzyna pour les tous les bon moments que l’on a partagé ensemble autour d’un café, d’une bière fraîche ou en allant au sport. Pour finir, merci à ma famille et surtout à Jonathan et Marjolaine et vous deux papa et maman. Cette réussite est aussi la vôtre et rien de tout cela n’existerait si vous n’aviez pas toujours été là pour tant donner et pour m’aider à réaliser mes projets. Résumé de la thèse ( version française) La biologie des systèmes, une opportunité pour les études évolutionnaires L’évolution, principe inhérent à toute forme de vie, est un aspect fondamental de la biologie. La vie ne connaît pas la stabilité et la fixité, toute espèce se transforme subtilement avec le temps. Les indices de ces transformations peuvent s’observer à tous les niveaux. Tout d’abord au niveau moléculaire, avec la fixation de mutations génétiques, la conservation/la modification de structure protéiques 3D, l’apparition/la perte de gènes ou de familles entières de gènes… Mais les principes de l’évolution ne s’appliquent pas qu’au niveau moléculaire, l’évolution induit des remodelages qui s’opèrent à tous les niveaux biologiques. La biologie des systèmes s’est beaucoup développée ces dix dernières années, confrontant plusieurs niveaux biologiques (molécule, réseau, tissu, organisme, écosystème…). Elle a démontré que le gène n’est pas seul responsable de l’apparition d’un phénotype. Notre compréhension du vivant s’est étendue au rôle des phénomènes épigénétiques, au rôle de la dynamique des processus intra et inter cellulaires jusqu’à une modélisation des interactions tissulaires. Toutes ces études se sont réalisés dans un contexte couramment appelé la biologie des systèmes, qui tente de décrire et de prédire le comportement d’un phénomène biologique en tenant compte de tous les niveaux biologiques. Nucleo- Amino Sugars Lipids Metabolomics tides acids Glycomics Lipidomics Genomics DNA Exomics Epigenomics Metagenomics tRNA, rRNA, siRNA, Transcriptomics mRNA snoRNA, microRNA … RNomics Phenomics Proteomics Proteins Interactomics Networks, pathways… Figure 1. Vue générale des principaux omics utilisés en biologie des systèmes. Pour comprendre ces phénomènes, ce domaine en plein essor produit de très nombreuses données à haut- débit, multipliant l’apparition de nouveaux « omics » et plaçant la bioinformatique comme une discipline indispensable à l’ère post-génomique (figure 1). Du point de vue de l’étude de l’évolution, la biologie des systèmes offre de nombreuses possibilités. Les études évolutionnaires peuvent enfin ne plus se restreindre à la seul variation du gène mais s’étendre à la variation des systèmes cellulaires. Ce contexte a tout récemment donné naissance à un nouveau domaine, encore balbutiant, mais riches en opportunités : la « biologie évolutionnaire des systèmes » (evolutionary systems biology). Son but est de réunir la mécanistique détaillée de la biologie des systèmes avec le domaine plus ancien de l’évolution pour comprendre comment un organisme répond à des perturbations. En effet, ce qui est conservé par l’évolution est généralement essentiel pour le fonctionnement d’un organisme et les variations sont autant d’innovations potentielles. Etudier l’évolution d’un système biologique permet donc de comprendre la façon dont s’exercent les pressions évolutives au niveau des éléments d’un processus, les variations induisant ou non des transformations au niveau d’un organisme. La biologie évolutionnaire des systèmes Les premières études de « biologie évolutionnaire des systèmes » ont permis de mettre en évidence plusieurs tendances évolutives au niveau d’un organisme. Concernant la diversité inter-espèce, la plasticité des réseaux biologiques a été mise en évidence : l’inactivation d’un gène peut être compensée par d’autres processus biologiques et les gènes d’un processus peuvent être recrutés dans de nouvelles voies selon les espèces considérées. A l’inverse il a été démontré que certains modules d’interactions biologiques sont conservés par l’évolution, indépendamment des mutations génétiques.
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