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Exploration of Interaction Between Common and Rare Variants in Genetic Susceptibility to Holoprosencephaly Artem Kim

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Exploration of Interaction Between Common and Rare Variants in Genetic Susceptibility to Holoprosencephaly Artem Kim Exploration of interaction between common and rare variants in genetic susceptibility to holoprosencephaly Artem Kim To cite this version: Artem Kim. Exploration of interaction between common and rare variants in genetic susceptibility to holoprosencephaly. Human health and pathology. Université Rennes 1, 2020. English. NNT : 2020REN1B019. tel-03199534 HAL Id: tel-03199534 https://tel.archives-ouvertes.fr/tel-03199534 Submitted on 15 Apr 2021 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. THESE DE DOCTORAT DE L'UNIVERSITE DE RENNES 1 ECOLE DOCTORALE N° 605 Biologie Santé Spécialité : Génétique, génomique et bio-informatique Par Artem KIM « Prénom NOM » Exploration de l’interaction entre variants rares et communs dans la susceptibilité génétique à holoprosencéphalie Thèse présentée et soutenue à Rennes, le 30/09/2020 Unité de recherche : Institut de Génétique et Développement de Rennes (IGDR), UMR6290 CNRS, Université Rennes 1 Rapporteurs avant soutenance : Composition du Jury : Thomas BOURGERON Thomas BOURGERON Professeur des universités Professeur des universités, Université de Paris, CNRS UMR3571 Université de Paris, CNRS UMR3571 Gaël Nicolas Gaël Nicolas Maître de conférences des universités, Université de Rouen, Inserm U1079 Maître de conférences des universités Université de Rouen, Inserm U1079 Sylvain Lehmann Professeur des universités, Université de Montpellier, CNRS UMR1051 Président Sandrine Lagarrigue Professeur des universités, Agrocampus Ouest, UMR13448 Directeur de thèse Marie de Tayrac Maître de conférences des universités, Université Rennes 1, CNRS UMR6290 Co-directeur de thèse Véronique David Professeur des universités, Université Rennes 1, CNRS UMR6290 SUMMARY INTRODUCTION .............................................................................................................. 1 I. Mendelian and complex genetic disorders ....................................................................... 2 a. The human genome ................................................................................................................. 2 B. Genetic disorders and mutations ............................................................................................. 3 c. Mendelian disease era and single-gene disorders ..................................................................... 5 d. Complex non-Mendelian disorders .......................................................................................... 7 e. Towards the end of the Mendelian disease era ...................................................................... 11 II. Holoprosencephaly ....................................................................................................... 13 a. Definition ............................................................................................................................... 13 B. Clinical spectrum ................................................................................................................... 13 c. Etiology .................................................................................................................................. 17 d. Diagnostic and molecular testing ........................................................................................... 23 III. Molecular and genetic Basis of HPE ............................................................................. 25 a. ForeBrain and facial development .......................................................................................... 25 B. Molecular pathways of HPE ................................................................................................... 32 c. Genetic mechanisms of HPE ................................................................................................... 43 d. Non-mendelian HPE - Article I. ............................................................................................... 50 IV. Next Generation Sequencing in medical genomics ....................................................... 51 a. Main principles ...................................................................................................................... 52 B. Applications ........................................................................................................................... 53 c. DNA-Seq and identification of disease-causing variants .......................................................... 55 d. Novel strategies and future challenges for clinical variant interpretation ............................... 62 RESULTS ......................................................................................................................... 70 I. Implication of hypomorphic variants and oligogenic inheritance in HPE. ....................... 70 a. Background and oBjectives .................................................................................................... 70 B. Methods ................................................................................................................................ 70 c. Results - Article II ................................................................................................................... 78 II. Pathogenic impact of synonymous variants in SHH gene .............................................. 82 a. Background ............................................................................................................................ 82 B. Strategy ................................................................................................................................. 87 c. Results - Article III .................................................................................................................. 90 III. Autosomal recessive holoprosencephaly in consanguineous families .......................... 94 a. Background ............................................................................................................................ 94 B. Strategy ................................................................................................................................. 94 c. Results ................................................................................................................................. 100 DISCUSSION ................................................................................................................ 108 I. Oligogenic inheritance in complex genetic disorders .................................................... 108 II. Novel strategies for investigating the clinical impact of hypomorphic variants ........... 110 III. Autosomal recessive inheritance in HPE .................................................................... 113 IV. Perspectives .............................................................................................................. 113 Conclusion ...................................................................................................................... 117 REFERENCES ................................................................................................................ 120 ACKNOWLEDGEMENTS AND PERSONAL NOTES .................................................. 144 INTRODUCTION 1 I. Mendelian and complex genetic disorders a. The human genome The haploid human genome is composed of roughly 3 billion pairs of nucleotides. While a small amount of genetic information is found in the mitochondria (mitochondrial genome), the major part of human DNA is condensed within the nucleus as 23 pairs of chromosomes, one inherited from each parent. The nuclear genome encodes approximately 30,000 protein-coding genes consisting of coding (exonic) and non- coding (intronic) regions. The exonic regions are spliced and translated into ~100,000 different proteins containing ~6,000,000 amino acids, but compose less than 3 % of the human genome (Bohlander, 2013). The function is much less understood for the remaining, untranslated part of the genome. Sometimes referred to as the genomic ‘dark matter’, the non-coding part of the genome has been shown to play key roles in coordinating critical biological processes (Blaxter, 2010). More than 70% of the human genome is transcribed into RNA that does not encode proteins (ncRNA) but is involved in various regulatory processes of gene expression including splicing (lncRNA), post- transcriptional regulation (miRNA) and translational machinery (rRNA, tRNA) among others (Carcini et al., 2005; Romero-Barios et al., 2018). The non-coding genome also contains over 14,000 pseudogenes - copies of functional genes with coding-sequence alterations. Although considered as evolutionary relics, some pseudogenes have been shown to regulate their protein-coding counterparts (Jackson et al., 2018). In 2007, the authors of the Encyclopedia of DNA Elements (ENCODE) project claimed that a “biochemical function” could be assigned to 80% of the human genome (ENCODE Project Consortium, 2007; 2013). This statement was heavily debated afterwards, based on a loose definition of “function” by the authors and by invoking
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