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Role of Transcription in Mammalian Copy Number Variant Formation By Role of Transcription in Mammalian Copy Number Variant Formation by So Hae Park A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Human Genetics) in the University of Michigan 2018 Doctoral Committee: Professor Thomas W. Glover, Co-Chair Professor Thomas E. Wilson, Co-Chair Assistant Professor Shigeki Iwase Professor Mats E. Ljungman Associate Professor JoAnn M. Sekiguchi So Hae Park [email protected] ORCID iD: 0000-0002-7076-9152 © So Hae (Irene) Park 2018 Dedication I dedicate this dissertation to my parents, whose selflessness and courage opened numerous doors of opportunities for me. They are the biggest reasons why I was even able to consider graduate school as a possible option after college. They are the living, breathing examples of the American Dream, and I owe them a debt that I don’t think I can ever fully pay back. ii Acknowledgements Getting a PhD is a team effort. Without these people I would not have gotten to where I am. First and foremost, I want to express my gratitude for both of my advisors, Tom and Tom, for their mentorship and patience. The last six years have been an unprecedented adventure for all three of us in navigating co-mentorship, attending multiple lab meetings, discussing different strategies, and keeping everyone in the loop. But at the end, the tug of war between different ideas and perspectives raised the quality of the research, and I am forever grateful. I also will always be impressed by their unending optimism, curiosity, and desire to still get their hands dirty (sometimes quite literally!) with research. I want to also thank the rest of my thesis committee members, Mats, JoAnn, and Shigeki, and the past and the present members of the Wilson and Glover labs for creating a welcoming and supportive environment to discuss science. In particular, Martin has been extremely kind and patient with my never-ending questions about experiment setup, results, and interpretation and with my antics and complaints. Sountharia has taught me so many lab skills in the first three years of graduate school. During the rare times I was physically at the Wilson lab, Sham was a great person to talk to about everything, ranging from science to religion. And many thanks to my undergraduate mentor, Melanie Filiatrault, who first instilled in me the joy of independently seeking answers via scientific experiments. For the times I was not motivated in the lab or doubted myself about my capabilities, writing helped a lot. Wudan Yan is singlehandedly responsible for getting me started in science iii writing. It is amazing how someone I met during an interview weekend (for a school I ended up not attending) has such a profound influence in my life. I got my first taste in science writing at The Michigan Daily, and I thank for Ian, Amabel, and Katie for being such fantastic research beat editors during my three years there as a news reporter. Also, a shout-out to Lydia, Brandon, Brian, and Riyah for working with me during the time I was the summer research/hospital/campus life beat editor. I of course need to thank everyone I had the pleasure of working with for Michigan Science Writers (MiSciWriters) — Ada, Bryan, Shweta, Alisha, Kevin, Sarah, David, Melissa, Whit, and Scott — for providing me an opportunity to explore my career interests outside academia and for letting my creative juices flow. Scott especially has been a fearless champion in students’ well-being and intellectual growth, and he always made time for the students, no matter how small the problems were. I cannot thank him enough for his guidance and leadership for MiSciWriters and PIBS. I want to thank all other people who helped me with my science communication and outreach efforts, including (but not limited to) Elyse and Katherine for the excellent RELATE workshops and being great collaborators on number of science communication projects, Joe Palca and Maddie Sofia at NPR for their tireless efforts toward making science more accessible for the public and establishing FOJBI, and Steve Benowitz for being a great mentor since the AAAS meeting. What I did during graduate school (research or otherwise) would not have been possible without the supportive staff members. The Human Genetics Department administrative staff members were such a joy to work with, and I am convinced they are the most patient people for dealing with our problems every day. Likewise, the PIBS staff members were incredibly iv supportive and caring. Brooke and I especially had many conversations about potential projects, and she has been supportive of my career-exploring and outreach efforts since day one. My family members and friends have shown me unconditional love and support, and I thank them for my sanity. My sister Anna was always there when I needed to rant about life and when I wanted to share yet another funny meme I found on the Internet at two o’clock in the morning. The “9A” girls have taught me the value of friendship, especially one that spans across different geographical locations, goals, and values. To the “Le Bear” group — Joe, Linda, Susana, Tom, and Chris — we have made so many precious memories over the years, and I really hope one day we can open a nice restaurant/distillery that only serves the best steak and whiskey. I specifically want to thank Susana for being a reliable, sincere friend, someone who I can count on having my back when I need help or when I need to assuage my guilty pleasure of looking at cute Shiba pictures and videos. And a thousand thank you’s for Erika, for the deep conversations during our Sunday brunches and all the times we watched superhero movies and your teaching me how the individual movies fit in the bigger Marvel or DC universe. Last but not certainly not least, I thank Chris Miles for being the best partner and confidante for a graduate student who went through intense quarter-life crises. He and Kuma have been with me through all of my ups-and-downs, and I am truly lucky. With him by my side, I am confident that I can face whatever life throws at me next. v Table of Contents Dedication ...................................................................................................................................... ii Acknowledgements ...................................................................................................................... iii List of Figures ................................................................................................................................ x List of Tables .............................................................................................................................. xiii List of Abbreviations .................................................................................................................. xv Abstract ...................................................................................................................................... xvii Chapter 1 — Introduction............................................................................................................ 1 Overview of Dissertation ............................................................................................................ 1 Common Fragile Sites................................................................................................................. 2 Copy Number Variants ............................................................................................................... 3 Studying CNVs Using a Cell Culture System .............................................................................. 7 Paucity of Replication Origins at CFSs and CNV Hotspots ....................................................... 8 Dormant Origins to the Rescue................................................................................................... 9 Different Manifestations of Stalled and Collapsed Forks......................................................... 11 CFS Gaps and Breaks ........................................................................................................... 11 Ultrafine Anaphase Bridges .................................................................................................. 12 Incorrect Fork Start and DNA Repair Resulting in CNVs ................................................... 13 Importance of Transcription in CFSs and CNV Hotspots ........................................................ 14 Transcription-Replication Collisions........................................................................................ 15 Bacteria ................................................................................................................................. 16 Yeast ..................................................................................................................................... 17 Humans ................................................................................................................................. 18 Role of R-Loops in Transcription-Replication Conflict ............................................................ 18 CFS and CNV Hotspot Genes Are Clinically Relevant ............................................................ 20 Rationale for Dissertation......................................................................................................... 23 vi Figures ...................................................................................................................................... 25 Tables
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