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Functional Analysis of Genomic Variations Associated with Emerging Artemisinin Resistant P Functional analysis of genomic variations associated with emerging artemisinin resistant P. falciparum parasite populations and human infecting piroplasmida B. microti Ankit Dwivedi To cite this version: Ankit Dwivedi. Functional analysis of genomic variations associated with emerging artemisinin resis- tant P. falciparum parasite populations and human infecting piroplasmida B. microti. Human health and pathology. Université Montpellier, 2016. English. NNT : 2016MONTT073. tel-01557492 HAL Id: tel-01557492 https://tel.archives-ouvertes.fr/tel-01557492 Submitted on 6 Jul 2017 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. Délivré par Université de Montpellier Préparée au sein de l’école doctorale CBS2 Et de l’unité de recherche Institut de Recherche en Cancérologie de Montpellier Spécialité : Bioinformatique et Parasitologie Présentée par Ankit Dwivedi Functional analysis of genomic variations associated with emerging artemisinin resistant P. falciparum parasite populations and human B. microti infecting piroplasmida populations Soutenue le 28 Septembre 2016 devant le jury composé de M. Emmanuel CORNILLOT , Professeur des universités, Directeur de Institut de Recherche en Cancérologie de Montpellier these Mme Christelle REYNES , Maître de conférences, Coencadrant de Faculté des sciences pharmaceutiques et biologiques these M. Thomas OTTO , Directeur de recherche, Rapporteur Wellcome Trust Sanger Institute M. Gordon LANGSLEY , Directeur de recherche, Rapporteur Institut Cochin Mme Rachel CERDAN , Professeur des universités, Examinateur Faculté des sciences M. Stéphane CRUVEILLER , Chargé de recherche, Examinateur Commissariat à l'énergie atomique (CEA) 2 Functional analysis of genomic variations associated with emerging artemisinin resistant P. falciparum parasite populations and human infecting piroplasmida B. microti populations PhD Thesis by Ankit Dwivedi September, 2016 Thesis Supervisors: Prof. Emmanuel Cornillot Asst. Prof. Christelle Reynes Institut de Recherche en Cancérologie de Montpellier Institut de Biologie Computationnelle Université de Montpellier Montpellier - FRANCE Certificate This is to certify that the thesis entitled "Functional analysis of genomic variations associated with emerging artemisinin resistant P. falciparum parasite populations and human infecting piroplasmida B. microti populations" submitted towards the fulfilment of the full-time Ph.D. degree programme at Université de Montpellier, represents the work carried out by Ankit Dwivedi at Bioinformatics and system biology of Cancer team of Institut de Recherche en Cancérologie de Montpellier (IRCM) and Institut de Biologie Computationnelle (IBC) Montpellier, France, during the academic year 2013-2016 under the supervision of Prof. Emmanuel Cornillot and Asst. Prof. Christelle Reynes. Ankit Dwivedi Thesis Jury Members: Prof. Emmanuel Cornillot - Thesis Supervisor Asst. Prof. Christelle Reynes - Thesis Co-Supervisor Dr. Thomas D. Otto - Reviewer Dr. Gordon Langsley - Reviewer Prof. Rachel Cerdan - Examiner Dr. Stéphane Cruveiller - Examiner Acknowledgments This project and associated achievements would not have been possible without the support and guidance of several people. First, I would sincerely like to express my gratefulness to Professor Emmanuel Cornillot for his guidance and encouragement throughout the project. His valuable discussion and ideas have helped in broadening my scope of thinking. His knowledge has helped me in understanding the fundamentals of parasite biology and associated functions. Being my guide and mentor for the last three years, he has patiently taught me many techniques and aspects of bioinformatics and functional analysis. Next, I would sincerely like to thank Asst. Prof. Christelle Reynes for guiding me, being my thesis co-supervisor. She has supported me throughout the project and has helped me in improving my presentation and technical skills. Her knowledge and guidance has played an important role in guiding me through mathematical and computational parts of the project. Her suggestions and valuable discussions have helped me a lot in understanding and improving various aspects of statistics. I am grateful to the team leader, Prof. Jacques Colinge, for the valuable discus- sions and guidance in the functional analysis stage of the project. He has provided inputs and guided me through the new techniques and trends in network analysis. The discussions with him has provided new aspects to the project. I am thankful to Dr. Axel Kuehn for helping me through the technical part of the network analysis. I am thankful to the other members of the team, Dr. Patrice ravel, Dr. Rasha E Boulos and Sabine Chabalier, for valuable discussions and technical support. I would like to thank Dr. Didier Menard and Dr. Nimol Khim for valuable discussions and data input. The data was made available by them for the barcode approach. I would also sincerely like to acknowledge Dr. Maxime Hebbard and Sylvain Milanesi for helping me with the technical part of the project. Their support v vi in the beginning of the project has played a crucial role in completing the variant calling analysis. I would like to sincerely thank Dr. Eric Rivals and Prof. Patrick Bastien for being the thesis committee members and providing me valuable inputs and critics to improve the analysis, results and presentation skills. I would sincerely like to acknowledge the Erasmus Mundus Action 2 Svaagata.eu project and European commission for granting me the scholarship for pursuing full time Ph.D. program for the duration of 36 months at the University of Montpellier, France. Also, I am grateful to Institut de Biologie Computationnelle (IBC) for pro- viding me all the financial and technical support and services. IBC has provided me opportunities to participate in international conferences which has helped me in growing professionally. I am very grateful to and would sincerely like to thank Ankita Jha for all the moral, emotional and professional support. In the last very importantly, I would like to thank my family for showing belief in me and supporting me in every possible way. - Ankit Dwivedi Abstract Functional analysis of genomic variations associated with emerging artemisinin resistant P. falciparum parasite populations and human infecting piroplasmida B. microti populations by Ankit Dwivedi The undergoing WHO Malaria elimination program is threatened by the emer- gence and potential spread of the Plasmodium falciparum artemisinin resistant par- asite. Recent reports have shown (a) SNPs in region of chromosome 13 to be under strong recent positive selection in Cambodia, (b) presence of P. falciparum para- site resistant and sensitive subpopulations in Cambodia, (c) the evidence that mu- tations in the Kelch propeller domain of the k13 gene are major determinants of artemisinin resistance in Cambodian parasite population and (d) parasite subpopula- tions in Northern Cambodia near Thailand and Laos with mefloquine drug resistance and carrying R539T allele of the k13 gene. Identifying the genetic basis of resistance is important to monitor and control the transmission of resistant parasites and to understand parasite metabolism for the de- velopment of new drugs. This thesis focuses on analysis of P. falciparum population structure in Cambodia and description of metabolic properties of these subpopula- tions and gene flow among them. This could help in identifying the genetic evidence associated to transmission and acquisition of artemisinin resistance over the country. First, a barcode approach was used to identify parasite subpopulations using small number of loci. A mid-throughput PCR-LDR-FMA approach based on LUMINEX technology was used to screen for SNPs in 537 blood samples (2010 - 2011) from 16 health centres in Cambodia. Based on successful typing of 282 samples, subpopula- tions were characterized along the borders of the country. Gene flow was described based on the gradient of alleles at the 11 loci in the barcode. The barcode success- fully identifies recently emerging parasite subpopulations associated to artemisinin and mefloquine resistance. In the second approach, the parasite population structure was defined based on 167 parasite NGS genomes (2008 - 2011) originating from four locations in Cambodia, recovered from the ENA database. Based on calling of 21257 SNPs, eight parasite vii viii subpopulations were described. Presence of admixture parasite subpopulation could be supporting artemisinin resistance transmission. Functional analysis based on sig- nificant genes validated similar background for resistant isolates and revealed PI3K pathway in resistant populations supporting acquisition of resistance by assisting the parasite in ring stage form. Our findings question the origin and the persistence of the P. falciparum sub- populations in Cambodia, provide evidence of gene flow among subpopulations and describe a model of artemisinin resistance acquisition. The variant calling approach was also implemented on the Babesia microti genome. This is a malaria like syndrome,
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