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TURNER-DISSERTATION-2014.Pdf Elucidating the Etiology of Autism Using Genomic Methods by Tychele Naomi Turner A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy in Human Genetics and Molecular Biology Baltimore, Maryland November, 2013 © 2013 Tychele Naomi Turner All Rights Reserved ABSTRACT In 1943, Dr. Leo Kanner, at the Johns Hopkins Hospital, identified the childhood neuro-psychiatric disorder called autism. However, it was not until the 1970s that there was even one article mentioning both the words gene and autism. In 1989, a twin study provided the first evidence for a genetic element to this disorder. The 1990s brought about the initial comprehension of autism at a molecular level, in particular, through the identification of FMR1 in Fragile X Syndrome and MECP2 in Rett Syndrome. By 2003, when the human genome project was completed, the study of genetics in autism began to rapidly advance not only in the number of publications but also in the diversity of researchers involved around the world. Herein, I present my findings, at the Johns Hopkins University School of Medicine 70 years after Kanner's original discovery, on the genetics of autism etiology through a large epidemiological study and a detailed molecular genetic study of female-enriched multiplex families (FEMFs) with a particular focus on the gene delta catenin (CTNND2). In this dissertation, I show that second borns in families are more often affected then others, female affected containing families show linkage to 19p and Xq (encompassing the FMR1 gene), females cases are enriched for mutations in 18 different “candidate” autism genes, and CTNND2 is an autism gene based on genetics, gene expression, dysregulation of its function, and pathway analyses. Advisor: Aravinda Chakravarti, Ph.D. Reader: Sarah Wheelan, M.D., Ph.D. (Chair of Dissertation Committee) Other Thesis Committee Members: Dr. Edwin H. Cook, Jr., M.D. Dr. Richard Huganir, Ph.D. Dr. Victor Velculescu, M.D., Ph.D. ii PREFACE There are many people to recognize and thank for their contribution to my Ph.D. expedition. The largest and most significant thanks goes to my dissertation mentor Dr. Aravinda Chakravarti. Thanks Aravinda for taking a chance on the girl who wanted to investigate the etiology of autism. I’ll never forget the first time we met, which was during my Hopkins interview. At that time you discussed your perspective on research and as I recall you said you were like a mechanic who examines all the parts of a car and figures out how to work with and improve them. You utilized this example as an analogy for your own labor in genetics and this was the most unique response I remember from my graduate school interviews. Upon arrival at Johns Hopkins, I assimilated more knowledge about your lab and thought it would be beneficial to rotate there during my second rotation. Your encouragement during this rotation was fantastic as I did an entire copy number variation (CNV) project using excel and pencil and paper for the “computation” and a PCR based genotyping assay as a follow up at the bench. Thankfully my inexpertise with computation at the time did not prevent you from saying “yes” when I asked to join your laboratory. In my early days in the lab, you set forth a path for me to work towards your primary goal for me and my time in the lab. The goal was for me to master sequencing from both a bench and computational perspective and it was a very exciting endeavor. Over the past few years it has been intriguing to learn more about how you think of scientific questions; seemingly contrary to “popular” opinion. I’ve definitely learned how to be a skeptic and to require an immense amount of evidence before deeming something robust from a scientific point of view. I am very grateful for the opportunities you have given me to learn from a wide array of scientists both within iii their laboratories and also through attendance at conferences. In addition, I have enjoyed the chances I have had to improve my writing by working on grants, manuscripts, and through reviewing the research of other investigators. Thank you for always encouraging me to present aspects of this dissertation in various places, in particular, in Italy which was the first international trip of my life. Overall, I have had an amazing experience as a part of this awesome lab and I look forward to a notable future in the study of human disease thanks to you as my great mentor. Next, I acknowledge all the members of my doctoral dissertation committee: Dr. Aravinda Chakravarti, Dr. Edwin Cook, Dr. Richard Huganir, Dr. Victor Velculescu, and Dr. Sarah Wheelan. Thank you Dr. Cook for agreeing to be on my dissertation committee and for flying from Chicago to Baltimore for every one of my yearly meetings. From a scientific perspective, I have truly valued all of your advice especially on the utilization of phenotypic features to parse autism at a genetic level. I have also truly appreciated the guidance you have given me over the years regarding my graduate education as a whole. Thank you Dr. Huganir for opening your lab for me to come and acquire more knowledge about neuroscience. The ability to perform experiments using rat hippocampal neurons and ultimately advanced neuron imaging techniques and analysis was a real boon to my dissertation. Dr. Velculescu thank you for helpful discussions on next generation sequencing, in particular in strategies for improving bench (wet lab) and statistical analysis of the resulting data. To the chair of my committee, Dr. Wheelan, thank you for providing useful input on statistical and computational analysis including details on how to license software! Also, I’m very grateful for positive feedback on my yearly reviews and for you allowing me to come to the Next Generation Sequencing Center at the Sidney iv Kimmel Comprehensive Cancer Center to prepare the libraries and perform the exome capture as part of my exome sequencing experiments. Finally, thank you kindly for agreeing to be the reader of this dissertation and for many beneficial comments. I am very appreciative of all the members of the Chakravarti lab who made my experience a fantastic one over the last 5 years. Thank you to Dr. Ashish Kapoor for giving a splendid presentation on hearing loss at one of our departmental journal clubs, during my first year, reaffirming my excitement to rotate in the Chakravarti lab. In addition, I am thankful to you and Betty for being the only 2 people in the lab to take me to lunch on the last day of my rotation. Riding in Betty’s Lexus made me think it might be the standard in the Chakravarti lab. It’s not as I found out (!) but this was definitely a good recruiting strategy. Discussing my dissertation with you has been one of the joys of my Ph.D. I really treasure you making me learn protocols and experiments in detail and for performing your own experiments with such care and excellence. You lead by example in the lab. Thank you Dr. Vasyl Pihur for teaching “this kid” how to program. I started knowing nothing of this foreign universe called “computation” and frankly the command line at first seemed like only something people use in those really impressive spy movies (I’m thinking Q in James Bond here!). I’ll never forget when Hopkins only had the “yellow school buses” running as their daily shuttle and we sat the whole ride with you trying to explain a for loop to me. I don’t know why this was so difficult at first but I’m so happy that you were able to help me figure it out. Thank you for always encouraging me and for being on my first paper and also for you and Ashok Sivakumar for taking me to Ruth’s Chris to celebrate this accomplishment. Thanks also for working at Google. I try to drop that line as much as I can: “I have a friend who works at Google.” v Look I’m even doing it in my dissertation. Thank you to Dr. Betty Doan for finally saying “hi” to me in the lab after about a month of rotation where I would say “hi” and bug you about your project. Your helpful advice during the first few years of my Ph.D. has been very beneficial during my time in the lab. Thank you to Dr. KD Nguyen for being my friend and fellow graduate student in the lab for almost the entire duration of my Ph.D. I delighted in our lunches together at work and occasional excursions to the movies, for frozen yogurt, or dinner. It has been very fun and thanks also for inviting me to attend your Miami Beach wedding. Thank you to Dr. Qian Jiang for involving me in your 454 project and for offering me a job in China someday. Thank you to Maria X. Sosa for working on some aspects of the autism projects in the lab. Thank you to Dallas Auer for daily conversations and for taking care of those new delta-catenin mice. I think they really like you and they couldn’t ask for a better “parent” to take care of them. Thank you also to all the laboratories that let me come and visit their labs to learn new techniques. First, thanks to Dr. Nicholas Katsanis at Duke University for allowing me to visit and pick up some experience in zebrafish experiments as well as in their application to the understanding of human disease.
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