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Fine Mapping Studies of Quantitative Trait Loci for Baseline Platelet Count in Mice and Humans

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Fine Mapping Studies of Quantitative Trait Loci for Baseline Platelet Count in Mice and Humans Fine mapping studies of quantitative trait loci for baseline platelet count in mice and humans A thesis submitted in fulfillment of the requirements for the degree of Doctor of Philosophy Melody C Caramins December 2010 University of New South Wales ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. This thesis is dedicated to my father. Dad, thanks for the genes – and the environment! ACKNOWLEDGEMENTS “Nothing can come out of nothing, any more than a thing can go back to nothing.” - Marcus Aurelius Antoninus A PhD thesis is never the work of one person in isolation from the world at large. I would like to thank the following people, without whom this work would not have existed. Thank you firstly, to all my teachers, of which there have been many. Undoubtedly, the greatest debt is owed to my supervisor, Dr Michael Buckley. Michael, without your rich intellect, endless encouragement and supremely agreeable manner, I doubt whether I would have ever started, or finished. I would also like to thank Professors Robert Lindeman, Peter Thomson, and Chris Moran for your guidance, and ability to face any challenge with grace, humour, understanding and wisdom. I cannot imagine success without your counsel. A great thanks also to Dr Ian Martin for the breeding of the AIL. Thank you to all the laboratory staff at the Molecular and Cytogenetics department at Prince of Wales Hospital, and especially Dr Peter Taylor. You have all walked the fine line of allowing me to go about this project with independence and support. A special thanks to my family, who have always been encouraging and proud of my academic achievements. A special mention must go to my uncle Norik, who passed away suddenly and unexpectedly during the course of this PhD. And finally, a very special thanks to my exceptional husband, Alex Johnson for giving more kinds of support than I ever imagined existed. Alex, you have always allowed me to take my work very seriously without taking myself too seriously. TABLE OF CONTENTS ABSTRACT …………………………………………………………….......................................................................1 1 CHAPTER ONE – LITERATURE REVIEW…………………………….......................................……2 1.1 INTRODUCTION………………………………………………………………………………………......................……….2 1.2 PLATELET BIOGENESIS..........................................................................................................5 1.2.1 INTRODUCTION.................................................................................................................5 1.2.2 STAGES OF MEGAKARYOPOIESIS........................................................................................6 1.3 PATHWAYS AND CYTOKINES IN PLATELET BIOGENESIS........................................................9 1.3.1 THE THPO DEPENDENT PATHWAY....................................................................................10 1.3.2 THE THPO INDEPENDENT PATHWAY.................................................................................16 1.4 THE CONTRIBUTION OF GENETICS TO UNDERSTANDING THROMBOPOIESIS......................19 1.4.1 CONTRIBUTION OF MONOGENIC AND SYNDROMIC DISORDERS........................................19 1.4.2 CONTRIBUTION OF COMPLEX GENETIC METHODOLOGIES AND ANIMAL MODELS.............28 2 CHAPTER TWO – MATERIALS AND METHODS........................................................32 2.1 HUMAN TWIN ASSOCIATION ANALYSIS STUDY………………………...........……………………………….32 2.1.1 SUBJECT RECRUITMENT AND SAMPLE COLLECTION…………………………….........................…..32 2.1.2 PHENOTYPES....................................................................................................................33 2.1.3 GENOTYPES......................................................................................................................34 2.1.4 GENOTYPING...................................................................................................................34 2.1.5 DATA CLEANING………………………………………………………………………................................……….35 2.1.6 SAMPLE HOMOGENEITY……………………………………………………………………...............……………….35 2.1.7 STATISTICAL ANALYSIS………………………………………………………………………………………..............…36 2.2 MOUSE AIL STUDY………………………………………………………………………………………………........……….38 2.2.1 MOUSE AIL RESOURCE MAINTENANCE AND BREEDING……………………………………….........…..38 2.2.2 SAMPLE COLLECTION AND PHENOTYPING…………..............……………………………………………….40 2.2.3 SELECTION OF MICE FOR GENOTYPING……………………………………………..........……………………..41 2.2.4 DNA EXTRACTION……………………………………………………………………………………………...............….42 2.2.5 GENOTYPING…………………………………………………………………………………………………….................42 2.2.6 ASSOCIATION ANALYSIS FOR THE AIL REPLICATION EXPERIMENT…………..............……………44 2.2.7 AIL QTL MAPPING METHODS………………………………………………………………………………..............46 2.2.8 LINKAGE MAP CONSTRUCTION……………………………………………………...............……………………..47 2.3 MOUSE IN SILICO STUDY………………………………...........………………………………………………………….52 2.3.1 DATABASE INFORMATION………………………………………………………………………………….............…52 2.3.2 MOUSE STRAINS…………………………………………………………………………………………….............…….53 2.3.3 HAPLOTYPE BLOCK STRUCTURE GENERATION…………………………………………..............………….53 2.3.4 STRAIN RELATEDNESS…………………………….............……………………………………………………………..54 3 CHAPTER THREE – FINE MAPPING OF PLTCT1 AND PLTCT2 BY CROSS SPECIES COMPARISON WITH HUMANS…………..........................................................57 3.1 INTRODUCTION……………………………………………...............................………………………………………57 3.1.1 QUANTITATIVE TRAIT MAPPING – FROM MICE TO MEN……………………………………………………57 3.1.2 QTL AND PLT………………………………………………………………………………………………………………………62 3.2 MATERIALS AND METHODS…………………………………………………………………………………………………65 3.3 RESULTS………………………………………………………………………………………………………………………….……67 3.4 DISCUSSION……………….………………………………………………………………………………………………………..77 4 CHAPTER FOUR– REPLICATION OF F2 RESULTS AND F11 QTL MAPPING.......82 4.1 INTRODUCTION..................................................................................................................82 4.1.1 QTL MAPPING AS A STRATEGY..........................................................................................82 4.1.2 REPRODUCTION OF F2 GENERATION RESULTS IN F11 GENERATION..................................84 4.2 MATERIALS AND METHODS................................................................................................86 4.2.1 REPLICATION OF F2 RESULTS............................................................................................86 4.2.2 QTL INTERVAL MAPPING..................................................................................................87 4.3 RESULTS.............................................................................................................................87 4.3.1 PHENOTYPIC CHARACTERISTICS OF THE AIL......................................................................87 4.3.2 REPLICATION STUDY RESULTS..........................................................................................88 4.3.3 F11 AIL QTL FINE MAPPING RESULTS................................................................................90 4.4 DISCUSSION.......................................................................................................................94 5 CHAPTER FIVE – FINE MAPPING USING IN SILICO ANALYSIS.............................99 5.1 INTRODUCTION................................................................................................................100 5.2 MATERIALS AND METHODS..............................................................................................104 5.3 RESULTS AND DISCUSSION...............................................................................................105 6 CHAPTER SIX – CANDIDATE GENE SEQUENCING.................................................115 6.1 INTRODUCTION................................................................................................................115 6.2 MATERIALS AND METHODS..............................................................................................122 6.3 RESULTS...........................................................................................................................126 6.4 DISCUSSION.....................................................................................................................138 7 CHAPTER SEVEN – DISCUSSION................................................................................145 LIST OF COMMON ABBREVIATIONS adenosine diphosphate ADP advanced intercross line AIL autosomal dominant AD autosomal recessive AR burst forming megakaryocytes BFU-MK calmodulin-dependent kinases CaMK cluster of differentiation CD colony forming megakaryocytes CFU-MK common deleted region CDR comparative genomic hybridization CGH
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