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PDF Hosted at the Radboud Repository of the Radboud University Nijmegen PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/76559 Please be advised that this information was generated on 2021-10-04 and may be subject to change. Phenotype-guided disease investigation using Bioinformatics Martin Oti Front cover image: Leonardo da Vinci’s Vitruvian Man, as an illustration of the systematic measurement of the human phenotype. Systematic representations are essential to fully exploit phenotype information in Bioinformatic disease analyses. Underlying the phenotype is the genome, represented by the fragment of DNA on which he is standing. Source : Wikimedia Commons ( http://commons.wikimedia.org/wiki/File:Vitruvian-Icon.png and http://commons.wikimedia.org/wiki/File:DNA_simple.svg ). Authors: Producer (Vitruvian Man) and Forluvoft (DNA); DNA image further modified by Leyo. License : Both images are licensed under the Creative Commons Attribution ShareAlike license (http://creativecommons.org/licenses/by-sa/3.0/) and the GNU Free Documentation License (http://commons.wikimedia.org/wiki/Commons:GNU_Free_Documentation_License). Printed by PrintPartners Ipskamp, Nijmegen. ISBN: 978-90-9024785-4 Phenotype-guided disease investigation using Bioinformatics Een wetenschappelijke proeve op het gebied van de Medische Wetenschappen Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. mr. S.C.J.J. Kortmann, volgens besluit van het college van decanen in het openbaar te verdedigen op vrijdag 23 april 2010 om 10.30 uur precies door Martin Okechukwu Oti geboren op 7 october 1974 te Kaduna (Nigeria) Promotors: Prof. dr. Han G. Brunner Prof. dr. Martijn A. Huynen Manuscriptcommissie: Prof. dr. Stan Gielen Prof. dr. Jan Smeitink Dr. Lude Franke (Rijksuniversiteit Groningen) Phenotype-guided disease investigation using Bioinformatics An academy essay in the Medical Sciences Doctoral thesis to obtain the degree of doctor from Radboud University Nijmegen on the authority of the Rector Magnificus prof. dr. S.C.J.J. Kortmann, according to the decision of the council of deans to be defended in public on Friday April, 23 2010 at precisely 10.30 hours by Martin Okechukwu Oti Born on 7 October 1974 in Kaduna (Nigeria) Supervisors: Prof. dr. Han G. Brunner Prof. dr. Martijn A. Huynen Doctoral Thesis Committee: Prof. dr. Stan Gielen Prof. dr. Jan Smeitink Dr. Lude Franke (Rijksuniversiteit Groningen) Table of Contents Chapter 1: General Introduction ............................................................................................ 11 1.1 Discovering disease genes......................................................................................... 12 1.2 Disease phenotypes.................................................................................................... 12 1.3 Genetic mapping........................................................................................................ 13 1.4 Functional candidate disease gene approaches using bioinformatics ............. 14 1.5 The importance of the phenotype ........................................................................... 16 1.6 Outline of the thesis ..................................................................................................... 17 References............................................................................................................................... 19 Chapter 2: The modular nature of genetic diseases ............................................................ 21 Abstract.................................................................................................................................... 22 Introduction ............................................................................................................................. 22 Relationship between genes and phenotypes.................................................................. 23 Formalizing phenotype descriptions .................................................................................... 32 Future prospects...................................................................................................................... 33 Acknowledgements............................................................................................................... 36 References............................................................................................................................... 36 Chapter 3: Predicting disease genes using protein-protein interactions ........................... 41 Abstract.................................................................................................................................... 42 Introduction ............................................................................................................................. 42 Methods ................................................................................................................................... 43 Results ....................................................................................................................................... 46 Discussion ................................................................................................................................. 55 Acknowledgements............................................................................................................... 57 References............................................................................................................................... 57 Chapter 4: Conserved co-expression for candidate disease gene prioritization............. 61 Abstract.................................................................................................................................... 62 Background ............................................................................................................................. 62 Results ....................................................................................................................................... 63 Discussion ................................................................................................................................. 69 Conclusions.............................................................................................................................. 70 Methods ................................................................................................................................... 71 Acknowledgements............................................................................................................... 77 References............................................................................................................................... 77 Chapter 5: The biological coherence of human phenome databases............................ 81 Abstract.................................................................................................................................... 82 Introduction ............................................................................................................................. 82 Methods ................................................................................................................................... 83 Results ....................................................................................................................................... 87 Discussion ................................................................................................................................. 92 Acknowledgements............................................................................................................... 93 References............................................................................................................................... 93 Chapter 6: General Discussion ................................................................................................. 95 6.1 Summary of findings .................................................................................................... 96 6.2 Moving from locus-based to genome-wide approaches..................................... 99 6.3 The importance of detailed phenotype characterization for genome-wide approaches........................................................................................................................... 104 6.4 The Future: Comprehensive elucidation of disease processes........................... 108 References............................................................................................................................. 116 Summary .................................................................................................................................... 123 Samenvatting............................................................................................................................ 127 Acknowledgements................................................................................................................. 131 Appendix I: Color Figures......................................................................................................... 133 Curriculum Vitae....................................................................................................................... 141 List of Publications....................................................................................................................
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