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Sourabh JAIN Aix-Marseille Université Faculté de Médecine de Marseille Ecole Doctorale des Sciences de la Vie et de la Santé THÈSE DE DOCTORAT Présentée par Sourabh JAIN Date et lieu de naissance: 14-May-1984, Inde Comparative genomic study for identifying gene acquisitions in Megavirales Soutenance de la thèse le 06-JULY-2017 En vue de l’obtenir du grade de Docteur de l’Université d’Aix-Marseille Membres du jury de la thèse Docteur Pierre PONTAROTTI Directeur de Thèse Professeur Didier RAOULT Co-Directeur de Thèse Professeur Patrick FORTERRE Rapporteur Docteur Franck PANABIERES Rapporteur Professeur Jean Louis MEGE Examiner Laboratoire d’accueil URMITE Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UMR 6236, Faculté de Médecine 27, Boulevard Jean Moulin, 13385 Marseille, France I2M UMR-CNRS 7373, Evolution Biologique et Modélisation, Aix-Marseille Université 3, place V. Hugo case 19, 13331 Marseille Cedex 3 France 1 2 CONTENTS Abstract………………………………………...............5 Résumé …………………………………….…...............9 Avant-Propos……………………………………….....13 Chapter 1 Introduction…….…………...………...………......……15 Chapter 2 Megavirale diversity and evolution……………………25 Chapter 3 MimiLook: A Phylogenetic Workflow for Detection of Gene Acquisition in Major Orthologous Groups of Megavirales ………………………………….....……..79 Chapter 4 Contribution of horizontal gene transfers in evolution of family specific genome mosaicism of Megavirales ….127 Conclusions & Future Perspective ………………...183 Acknowledgements …………………………………189 3 4 Abstract Discovery of giant viruses with giant genome size and surprising genomic features raises different question about their origin and evolution. The diversity of Megavirales (MVs) imposes difficulties in collectively evaluating their phylogenetic relationships. While small subset of conserved core genes and phylogenomic analyses based on them, provide useful classification of MVs, but they give little insight on the remaining un- conserved and variable gene content of accessory genomes. Thus, many phylogenetic studies have pointed out decisive role of HGTs and genetic exchanges on evolution of MVs, but, majority of them are based on closely related MV families. However, exact proportion of instances of genes acquired horizontally varies greatly with the methodologies used for their detection of interpretation of phylogenies prepared. Therefore, it is necessary to adopt some systematic searching for detecting reticulate evolutionary events like HGT in MVs to decipher genomic composition and genome mosaicism of distantly related MV families. To investigate the contribution of HGTs in distantly related MV families, we have determined gene distributions and gene phylogenies for the 86 complete MV ORFomes classified in 6 defined and 4 putative families, in context of their homologs from other domains of life. At first, we prepared an automated phylogenetic workflow MimiLook, which deduces orthologous groups (OGs) 5 from ORFomes of MVs and constructs phylogeny by performing alignment generation, alignment editing and BLASTP searching across NCBI nr protein sequence database. Finally, this tool detects statistically validated events of gene acquisitions with the help of T-REX algorithm. We found 4577 clusters of orthologus groups (OGs), out of it, 91% of OGs are found to be family specific (i.e. represented by species classified in one MV family only), whereas, only 9% are represented by proteins from 2 or more MV families. In step 2 of our analysis, we found 414 OGs with detected HGT event. 174 were inferred to have transferred from eukaryotes, 106 to have transferred from bacteria and 9 gene families to have transferred from cellular domains other than eukaryotes or bacteria (archaea, and viruses, including phages). 52 OGs were detected as cases of sympatric transfers (gene transfer by association of MVs with more than one cellular domain). Interestingly, 129 gene families were identified to be involved in gene transfers from MVs to other cellular domains. We applied a similar procedure to the 7,898 non-orthologous proteins to detect transfer events and putative donors and identified 259 instances of HGT from non-orthologous proteins, of which 135 cases were from eukaryotes, 82 cases from bacteria, 11 cases from Phages and other viruses, 31 cases where MVs are transferring protein to other cellular domains. Instances of HGT were found to be depicting donor specificity, as viruses of vertebrates/invertebrates (Poxviridae, Ascoviridae and Iridoviridae) acquired genes from donors like 6 Euteleostomii, Eutheria, Baculoviridae and proteobacteria; algal viruses (Phycodnaviridae) and protozoan viruses (pandoravirus, Mimiviridae, pithovirus, and Marseilleviridae) were found to be acquiring genes majorly from cellular donors like Dictyostellium, Mammeillales, Firmicutes, Clostridiales, Klebsormidium, Rozella allomycis, Ooomycetes and Phytophthora. In conclusion, clear distinction can be seen in the genome mosaicism of distantly related Megavirale families, where they evolved via genome specificity and family specific gene acquisitions from their respective ecological niche. Evolution of Megavirale families can be evidently based on phylogenetic analysis of few core genes as well as similarities of their gene contents, but, knowing that the horizontal gene transfer play a major role on the gene contents of Megavirales, it could be unforeseen to decipher the evolution of all Megavirale families by this approach. Keywords: Megavirales; Horizontal gene transfer; MimiLook; Comparative genomics; phylogeny 7 8 Résumé La diversité de Megavirales (MV) impose des difficultés à évaluer collectivement leurs relations phylogénétiques. Bien qu'un petit sous-ensemble de gènes de base conservés et des analyses phylogénomiques basés sur eux, fournissent une classification utile des MV, mais ils donnent peu de perspicacité sur le reste du contenu génétique non conservé et variable des génomes accessoires. Ainsi, de nombreuses études phylogénétiques ont souligné le rôle décisif des HGT et des échanges génétiques sur l'évolution des MV, mais la plupart d'entre eux sont basés sur des familles MV étroitement liées. Cependant, la proportion exacte des cas de gènes acquis horizontalement varie considérablement avec les méthodologies utilisées pour leur détection de l'interprétation des phylogénies préparées. Par conséquent, il est nécessaire d'adopter une recherche systématique de la détection d'événements évolutifs réticulés comme HGT dans les MV pour déchiffrer la composition génomique et la mosaïque du génome de familles MV à distance. Pour étudier la contribution des HGT dans les familles de MV éloignées, nous avons déterminé les distributions de gènes et les phylogénies de gènes pour les 86 ORFomes complets de MV classés dans 6 familles définies et 4 putatives, dans le cadre de leurs homologues d'autres domaines de la vie. Au début, nous avons préparé un flux de travail phylogénétique automatisé MimiLook, qui détermine les groupes 9 orthologues (OG) des ORFomes des MV et construit la phylogénie en effectuant une génération d'alignement sur les homologues BLASTP. Enfin, cet outil détecte des événements statistiquement validés d'acquisitions de gènes avec l'aide de T-REX. Nous avons trouvé 4577 groupes de groupes d'orthologues, hors de celui-ci, 91% des OG se révèlent spécifiques à la famille, alors que seulement 9% sont représentés par des protéines de 2 familles de MV ou plus. À l'étape 2 de notre analyse, nous avons trouvé 414 OG avec événement HGT détecté. On a déduit que 174 ont été transférés des eucaryotes, 106 pour avoir transféré des bactéries et 9 familles de gènes pour avoir transféré des domaines cellulaires autres que les eucaryotes ou les bactéries. 52 OG ont été détectés comme des cas de transferts sympatriques. Notons que 129 familles de gènes ont été identifiées comme impliquées dans le transfert de gènes de MV à d'autres domaines cellulaires. Similairement, 7898 protéines non orthologues pour détecter les événements de transfert et les donneurs putatifs et identifié 259 cas de HGT à partir de protéines non orthologues, dont 135 cas proviennent d'earyaryotes, 82 cas de bactéries, 11 cas de Phages et autres Virus, 31 cas où les MV transfèrent des protéines sur d'autres domaines cellulaires. Les exemples de HGT ont révélé la spécificité des donneurs, car les virus des vertébrés/invertébrés (Poxviridae, Ascoviridae et Iridoviridae) ont acquis des gènes de donneurs comme Euteleostomii, Eutheria, Baculoviridae et proteobactéries; Les virus des algues (Phycodnaviridae) et les virus des 10 protozoaires (pandoravirus, Mimiviridae, Pithovirus et Marseilleviridae) ont été en train d'acquérir des gènes principalement auprès de donneurs cellulaires comme Dictyostellium, Mammeillales, Firmicutes, Clostridiales, Klebsormidium, Rozella allomycis, Ooomycetes et Phytophthora. En conclusion, une distinction claire peut être observée dans le mosaïque du génome des familles de Megavirale éloignées, où elles ont évolué par spécificité génomique et acquisitions de gènes spécifiques à la famille de leur créneau écologique respectif. L'évolution des familles de Megavirale peut évidemment être basée sur l'analyse phylogénétique de quelques gènes de noyau ainsi que sur les similitudes de leur contenu génétique, mais, sachant que le transfert de gène horizontal joue un rôle majeur sur le contenu des gènes de Megavirales, il pourrait être imprévisible de déchiffrer Évolution de toutes les familles Megavirale par cette approche. Mots-clés: Megavirales; Horizontal
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