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Identification of Thrombosis Modifier Genes Using ENU Mutagenesis in the Mouse

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Identification of Thrombosis Modifier Genes Using ENU Mutagenesis in the Mouse Identification of Thrombosis Modifier Genes Using ENU Mutagenesis in the Mouse by Kärt Tomberg A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Human Genetics) in the University of Michigan 2016 Doctoral Committee: Professor David Ginsburg, Chair Associate Professor Patrick J. Hu Associate Professor Catherine E. H. Keegan Associate Professor Jun Li Assistant Professor Ryan E. Mills © Kärt Tomberg 2016 ACKNOWLEDGEMENTS First and foremost, I would like to thank my thesis mentor David Ginsburg. David has always been there for me throughout this process, either by challenging or encour- aging me, pushing or holding me back, all in good proportion. He sets a great example as a scientist, a mentor, and a human being, which I will strive to follow. Thank you to my dissertation committee (Patrick Hu, Katy Keegan, Jun Li, and Ryan Mills) for your time, great suggestions, intellectual input, encouraging support, and many helpful discussions. I would especially like to thank Ryan for letting me barge into his office, on several occasions, for advice ranging from data analysis to networking. I always left with new ideas! A special thank you to all the members of the Ginsburg lab. Each and every one of you has helped me at some point along the way. You are such great colleagues, good friends, and have provided me with a kind home away from home. I hope distance and time will not stop us from collaborating and supporting each other. A special shout-out to the amazing undergraduates that trained with me over the years. My sincere thank you to the faculty and my fellow students at Department of Hu- man Genetics. I have received a lot of encouragement, great ideas, and discussions from so many of you. All the emails, office visits, FAST talk questions, and chats at hap- py hours have helped me become a better scientist. I would also like to thank all the administrative staff of the Department of Human Genetics, PIBS, and Life Sciences In- stitute. Somehow I am always the troublemaker and without your kind, timely, and pro- fessional support, I would not be here today. In addition, I would like to thank the Ful- bright program and the American Heart Association for funding my training. My thanks to the University of Michigan basic science core facilities for excellent support and ac- cess to great technologies. Finally, I would like to thank my friends here in Ann Arbor and around the world, and my family back in Estonia for their constant love and support. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS ................................................................................................ii LIST OF TABLES ............................................................................................................ v LIST OF FIGURES ..........................................................................................................vi LIST OF APPENDICES ................................................................................................. viii ABSTRACT .....................................................................................................................ix CHAPTER I: Introduction ................................................................................................ 1 Venous thromboembolism ........................................................................................... 1 Mutagenesis screens ................................................................................................... 4 CHAPTER II: A sensitized mutagenesis screen in Factor V Leiden mice identifies novel thrombosis suppressor loci ............................................................................................ 20 Abstract ..................................................................................................................... 20 Introduction ................................................................................................................ 21 Materials and methods .............................................................................................. 22 Results ....................................................................................................................... 26 Discussion ................................................................................................................. 30 CHAPTER III: Spontaneous 8bp deletion in Nbeal2 recapitulates the gray platelet syndrome in mice .......................................................................................................... 51 Abstract ..................................................................................................................... 51 Introduction ................................................................................................................ 51 Materials and methods .............................................................................................. 52 Results ....................................................................................................................... 58 Discussion ................................................................................................................. 61 CHAPTER IV: ENU mutagenesis and whole exome sequencing to identify thrombosis modifier genes ............................................................................................................... 78 Abstract ..................................................................................................................... 78 iii Introduction ................................................................................................................ 79 Materials and methods .............................................................................................. 79 Results and discussion .............................................................................................. 85 CHAPTER V: Conclusions and future perspectives .................................................... 113 Limitations of traditional mapping strategies ............................................................ 113 Mutation burden approach in a dominant ENU screen ............................................ 114 Future perspectives for current screen .................................................................... 117 Opportunities beyond the current screen ................................................................. 119 APPENDICES ............................................................................................................. 127 REFERENCES ............................................................................................................ 167 iv LIST OF TABLES Table 1-1: Overview of genes used in the specific-locus test ........................................ 19 Table 2-1: Overview of linkage analysis ........................................................................ 39 Table 2-2: Distribution of genotypes from a cross of F5L/+ Tfpi+/- F8X+/X- to F5L/L............ 40 Table 2-3: Overview of all identified G1 F5L/L Tfpi+/- mice............................................... 41 Table 2-4: Overview of the ENU pedigrees ................................................................... 44 Table 2-5: Synthetic lethal phenotype on 129 genetic background ............................... 45 Table 2-6: Distribution of genotypes from a cross of F5L/+ Tfpi+/- F3+/- to F5L/L ............... 46 Table 2-7: Candidate ENU-induced mutations .............................................................. 47 Table 2-8: Overview of the WES data............................................................................ 49 Table 3-1: Overview of the exonic variants called from WES in 4 mice from the MF5L6 pedigree ........................................................................................................................ 73 Table 3-2: Expected and observed number of progeny in Nbeal2gps/+ crosses .............. 74 Table 3-3: CBC mean values and standard deviations by genotype in set 1 mice ........ 75 Table 3-4: Intensity of platelet staining and frequency of emperipolesis events in bone marrow megakaryocytes ............................................................................................... 76 Table 4-1: CRISPR-Cas9 alleles ................................................................................. 103 Table 4-2: Overview of rescue pedigrees .................................................................... 104 Table 4-3: Overview of candidate ENU-induced variants in pedigrees 1, 6, and 13 .... 105 Table 4-4: Overview of WES variants present in 2 or 3 G1 rescues ............................ 107 v LIST OF FIGURES Figure 1-1: Prevalence of FVL mutation ........................................................................ 13 Figure 1-2: Perinatal lethal thrombosis model ............................................................... 14 Figure 1-3: Mutagenetix database ................................................................................. 15 Figure 1-4: Screening strategies ................................................................................... 16 Figure 1-5: Sensitized screen for thrombosis modifiers................................................. 17 Figure 1-6: ENU gene space saturation ........................................................................ 18 Figure 2-1: F8 deficient thrombosuppression and design of the Leiden ENU mutagenesis screen .....................................................................................................
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