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Application of Genomic Technologies to Study Infertility Nicholas Rui Yuan Ho Washington University in St

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Application of Genomic Technologies to Study Infertility Nicholas Rui Yuan Ho Washington University in St Washington University in St. Louis Washington University Open Scholarship Arts & Sciences Electronic Theses and Dissertations Arts & Sciences Spring 5-15-2016 Application of Genomic Technologies to Study Infertility Nicholas Rui Yuan Ho Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/art_sci_etds Part of the Bioinformatics Commons, Genetics Commons, and the Molecular Biology Commons Recommended Citation Yuan Ho, Nicholas Rui, "Application of Genomic Technologies to Study Infertility" (2016). Arts & Sciences Electronic Theses and Dissertations. 786. https://openscholarship.wustl.edu/art_sci_etds/786 This Dissertation is brought to you for free and open access by the Arts & Sciences at Washington University Open Scholarship. It has been accepted for inclusion in Arts & Sciences Electronic Theses and Dissertations by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN ST. LOUIS Division of Biology and Biomedical Sciences Computational and Systems Biology Dissertation Examination Committee: Donald Conrad, Chair Barak Cohen Joseph Dougherty John Edwards Liang Ma Application of Genomic Technologies to Study Infertility by Nicholas Rui Yuan Ho A dissertation presented to the Graduate School of Arts & Sciences of Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2016 St. Louis, Missouri © 2016, Nicholas Rui Yuan Ho Table of Contents List of Figures ............................................................................................................................... v List of Tables .............................................................................................................................. vii Acknowledgements .................................................................................................................... viii Abstract ........................................................................................................................................ iv Introduction: Application of Genomic Technologies to Study Infertility .................................... 1 0.0 Title Page ............................................................................................................................ 1 0.1 Introduction Body .............................................................................................................. 2 0.2 References .......................................................................................................................... 4 Chapter 1: Computational Fertility Gene Candidate Identification .............................................. 5 1.0 Title Page ............................................................................................................................ 5 1.1 Introduction ........................................................................................................................ 6 1.1 Results ................................................................................................................................ 9 1.1.1 Mouse Prediction Model ........................................................................................ 10 1.1.2 Human Prediction Model ........................................................................................ 12 1.1.3 Model Predictions ................................................................................................... 15 1.1.4 Using Model Predictions in Studying Human Fertility Associated CNVs ............. 15 1.2 Discussion ......................................................................................................................... 16 1.3 Methods ............................................................................................................................. 22 1.3.1 Training Gene Sets .................................................................................................. 22 1.3.2 Gene Similarity Features......................................................................................... 24 1.3.3 Linear Discriminant Analysis Model ...................................................................... 25 1.3.4 Human Infertility Gene Deletion Analysis ............................................................. 26 1.4 Supplemental Figures ........................................................................................................ 28 ii 1.5 References ......................................................................................................................... 50 Chapter 2: Experimental in vivo Genetics Screen for Spermatogenesis Function ..................... 52 2.0 Title Page ........................................................................................................................... 52 2.1 Introduction ....................................................................................................................... 53 2.2 Results ............................................................................................................................... 58 2.2.1 Pilot shRNA Screen ............................................................................................... 58 2.2.2 Performance Benchmarks ....................................................................................... 63 2.2.1 Predicted Genes’ shRNA Screen ............................................................................ 65 2.3 Discussion ......................................................................................................................... 69 2.4 Methods ............................................................................................................................. 73 2.4.1 Gene Selection ....................................................................................................... 73 2.4.2 shRNA Pool Preparation ........................................................................................ 73 2.4.3 Mouse Testis Transfection ..................................................................................... 74 2.4.4 Cell Line Transfection ........................................................................................... 74 2.4.5 Illumina Sequencing Library Preparation .............................................................. 74 2.4.6 Statistical Analysis ................................................................................................. 75 2.4.7 Network Analysis ................................................................................................... 76 2.5 Supplemental Protocols, Figures, and Tables ................................................................... 77 2.5.1 Supplementary Protocol 2.1: Mouse Testis Transfection ...................................... 77 2.5.2 Supplementary Protocol 2.2: shRNA Pool DNA Preparation (For Injection) ....... 78 2.5.2 Supplementary Protocol 2.2: shRNA Pool Sequencing Library Preparation ........ 80 2.5.2 Supplementary Tables and Figures ........................................................................ 81 2.6 References ......................................................................................................................... 92 Chapter 3: Genetic Engineering to Rescue Fertility .................................................................. 94 3.0 Title Page ........................................................................................................................... 94 iii 3.1 Introduction ....................................................................................................................... 95 3.2 Results ............................................................................................................................... 96 3.2.1 Transgene Delivery ................................................................................................ 96 3.2.2 Endogenous Gene Repair ........................................................................................ 98 3.3 Discussion ....................................................................................................................... 103 3.4 Methods ........................................................................................................................... 104 3.4.1 Plasmid Cloning ................................................................................................... 104 3.4.2 Cell Line Transfection ......................................................................................... 104 3.4.3 DNA Library Preparation .................................................................................... 105 3.4.4 Data Analysis ....................................................................................................... 105 3.5 Supplemental Data and Tables ........................................................................................ 107 3.5 References ....................................................................................................................... 114 Summary: Application of Genomic Technologies to Study Infertility ..................................... 115 4.0 Title Page ......................................................................................................................... 115 4.1 Summary Body ...............................................................................................................
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