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Anne-Ruxandra Carvunis Des protéines et de leurs interactions aux principes évolutifs des systèmes biologiques Anne-Ruxandra Carvunis To cite this version: Anne-Ruxandra Carvunis. Des protéines et de leurs interactions aux principes évolutifs des sys- tèmes biologiques. Médecine humaine et pathologie. Université de Grenoble, 2011. Français. NNT : 2011GRENS001. tel-00586614 HAL Id: tel-00586614 https://tel.archives-ouvertes.fr/tel-00586614 Submitted on 18 Apr 2011 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. THÈSE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITÉ DE GRENOBLE Spécialité : MODELES, METHODES ET ALGORITHMES EN BIOLOGIE, SANTE ET ENVIRONNEMENT Arrêté ministériel : 7 août 2006 Présentée par Anne-Ruxandra CARVUNIS Thèse dirigée par Laurent TRILLING et codirigée par Nicolas THIERRY-MIEG et Marc VIDAL préparée au sein du Laboratoire du Professeur Marc Vidal et du laboratoire Techniques de l’Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications de Grenoble dans l’Ecole Doctorale Ingénierie pour la Santé, la Cognition et l’Environnement Des protéines et de leurs interactions aux principes évolutifs des systèmes biologiques Thèse soutenue publiquement le 26 janvier 2011 devant le jury composé de : Mr Jacques DEMONGEOT Professeur, Grenoble, Président Mr Vincent LOTTEAU DR INSERM, Lyon, Rapporteur Mr David SHERMAN DR INRIA, Bordeaux, Rapporteur Mr François KEPES 1 DR CNRS, Evry, Membre LABORATOIRES DE THESE Laboratoire TIMC-IMAG, équipe TIMB Techniques de l’Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications de Grenoble Équipe Traitement de l’Information et Modélisation en Bio-médecine Unité Mixte de Recherche CNRS Université Joseph Fourier UMR 5525 Domaine de la Merci 38706 La Tronche Cedex France Laboratory of Dr. Marc Vidal, Professor Department of Cancer Biology, Dana-Farber Cancer Institute Department of Genetics, Harvard Medical School 44 Binney Street, Smith Building 858 Boston MA 02115 USA 2 Aux Nicolas qui m’ont aidée et inspirée, À mes parents. REMERCIEMENTS Je remercie vivement Marc Vidal pour la confiance dont il a fait preuve en m’accueillant dans son laboratoire et la qualité de son encadrement. L’enthousiasme scientifique de ce visionnaire est communicatif. Il m’a appris l’indépendance et la rigueur, le travail d’équipe et la nécessité de faire des sacrifices à l’autel de la science. Il m’a poussée à aller bien plus loin que ce dont je me croyais capable. Grâce à Marc, le vif intérêt que je portais à la biologie s’est transformé en passion de la recherche. Je remercie sincèrement Nicolas Thierry-Mieg et Laurent Trilling pour leur soutien sans faille tout au long de ma thèse et leur aide précieuse à la rédaction de ce manuscrit. Je remercie du fond du cœur les scientifiques talentueux avec qui travailler fut un pur plaisir : Kavitha Venkatesan, Denis Dupuy, Benoît Charloteaux, Jean-François Rual, Nicolas Bertin, Cesar Hildalgo, Murat Tasan, Ilan Wapinski, Muhammed Yildirim, Michael Cusick, Shahid Mukhtar, Matija Dreze, et tout spécialement mon « jeune mentor » Nicolas Simonis. Je remercie toute ma famille pour leur soutien et leur compréhension, et spécialement ma petite sœur Solange, qui partage ma conviction que l’art et la science sont deux exercices de curiosité et créativité qui émanent du même amour de la vie. Merci Amélie, Benoit, Elisa, et les autres copines et copains qui non seulement m’ont beaucoup aidée moralement, mais surtout qui m’aiment assez pour lire cette page ! Thanks to my boyfriend Andy, probably the most patient man on this planet. 3 RESUME Darwin a révélé au monde que les espèces vivantes ne cessent jamais d’évoluer, mais les mécanismes moléculaires de cette évolution restent le sujet de recherches intenses. La biologie systémique propose que les relations entre génotype, environnement et phénotype soient sous-tendues par un ensemble de réseaux moléculaires dynamiques au sein de la cellule, mais l’organisation de ces réseaux demeure mystérieuse. En combinant des concepts établis en biologie évolutive et systémique avec la cartographie d’interactions protéiques et l’étude des méthodologies d’annotation de génomes, j’ai développé de nouvelles approches bioinformatiques qui ont en partie dévoilé la composition et l’organisation des systèmes cellulaires de trois organismes eucaryotes : la levure de boulanger, le nématode Caenorhabditis elegans et la plante Arabidopsis thaliana. L’analyse de ces systèmes m’a conduit à proposer des hypothèses sur les principes évolutifs des systèmes biologiques. En premier lieu, je propose une théorie selon laquelle la traduction fortuite de régions intergéniques produirait des peptides sur lesquels la sélection naturelle agirait pour aboutir occasionnellement à la création de protéines de novo. De plus, je montre que l’évolution de protéines apparues par duplication de gènes est corrélée avec celle de leurs profils d’interactions. Enfin, j’ai mis en évidence des signatures de la co-évolution ancestrale hôte-pathogène dans l’organisation topologique du réseau d‘interactions entre protéines de l’hôte. Mes travaux confortent l’hypothèse que les systèmes moléculaires évoluent, eux aussi, de manière darwinienne. Mots clés : réseaux d’interactions entre protéines, interactions hôte-pathogène, annotation de génomes, duplications de gènes. 4 FROM PROTEINS AND THEIR INTERACTIONS TO EVOLUTIONARY PRINCIPLES OF BIOLOGICAL SYSTEMS ABSTRACT Darwin exposed to the world that living species continuously evolve. Yet the molecular mechanisms of evolution remain under intense research. Systems biology proposes that dynamic molecular networks underlie relationships between genotype, environment and phenotype, but the organization of these networks is mysterious. Combining established concepts from evolutionary and systems biology with protein interaction mapping and the study of genome annotation methodologies, I have developed new bioinformatics approaches that partially unveiled the composition and organization of cellular systems for three eukaryotic organisms: the baker’s yeast, the nematode Caenorhabditis elegans and the plant Arabidopsis thaliana. My analyses led to insights into the evolution of biological systems. First, I propose that the translation of peptides from intergenic regions could lead to de novo birth of new protein-coding genes. Second, I show that the evolution of proteins originating from gene duplications and of their physical interaction repertoires are tightly interrelated. Lastly, I uncover signatures of the ancestral host-pathogen co-evolution in the topology of a host protein interaction network. My PhD work supports the thesis that molecular systems also evolve in a Darwinian fashion. Key words: protein interaction networks, host-pathogen interactions, genome annotation, gene duplications. 5 TABLE DES MATIERES AVANT-PROPOS ............................................................................................................................... 7 INTRODUCTION ................................................................................................................................ 8 La bioLogie systémique représente un important changement de paradigme scientifique par rapport à La bioLogie moLécuLaire des cinquante dernières années. .................................................................. 8 La bioLogie systémique est L’étude des interactions dynamiques entre composants d’un système bioLogique. ...................................................................................................................................... 8 bioLogie systémique : des concepts historiques … ........................................................................... 9 … remis à jour grâce au déveLoppement de technoLogies expérimentaLes et de nouveaux outiLs d’anaLyse ........................................................................................................................................11 Biologie synthétique : reconstruire un système pour mieux le comprendre .............................11 Génomique fonctionnelle : expérimentation à l’échelle de la cellule entière ............................11 Gestion des données et modélisation : transfert de savoir des « sciences dures » et apparition de nouvelles problématiques ................................................................................................... 12 La science des réseaux, une branche prometteuse de La bioLogie systémique. ................................. 14 mesurer expérimentaLement Les réseaux d’interactions protéiques ................................................ 16 probLématique ............................................................................................................................... 18 présentation du pLan ..................................................................................................................... 20 document joint 1 .................................................................................................................. 21 CHAPITRE 1 : A LA RECHERCHE DES NŒUDS
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