Phylodynamic Patterns in Pathogen Ecology and Evolution by Daniel Zinder A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Bioinformatics) in the University of Michigan 2015 Doctoral Committee: Professor Mercedes Pascual, Co-Chair Assistant Professor Stephen A. Smith, Co-Chair Associate Professor Aaron A. King Assistant Professor Adam S. Lauring Associate Professor Patricia J. Wittkopp A common ancestor, proto-Sinaitic (or proto-Canaanite) script (16th-17th century BC). One of the earliest known relatives of the common ancestor of alphabetic scripts, including amongst many others English, Hebrew, and Bengali. Principles of inheritance and its correlation with phenotypic similarity, have long been used outside the context of biology in philological research and are likely to have inspired early ideas of evolution in biology. Copyright © 2015 Daniel Zinder Acknowledgments I have been very fortunate to conduct research with highly skilled and insightful colleagues and with inspirational mentors. I would first like to thank my dissertation committee: Aaron King, Stephen Smith, Adam Lauring, Patricia Wittkopp and my advisor Mercedes Pascual. Their guidance and instruction have profoundly shaped and improved my dissertation. They have likewise influenced my approach to research, and I am grateful for their stimulating questions and insightful suggestions over the past several years. It has been the greatest privilege to have the opportunity to learn science from one of the most inspiring people in the field, Mercedes. I have been very fortunate to work with someone who combines an incredible talent for research and science, together with radiating enthusiasm and an enticing personality. Our lab, has been my home away from home for the last several years, and I am thankful to Mercedes for generating such a stimulating environment for her students. I am also deeply grateful for her support, patience and encouragement. I would also like to give special thanks to my coauthors within our lab: Bob Woods, Ed Baskerville, Trevor Bedford, Manojit Roy, Molly Rorick (and Maria Riolo). None of the chapters here would have existed without their teamwork and help, and I am thankful to be able to work with such professional, ethical and gifted scientists. Many thanks are appropriate for specific chapters. Mercedes originally posed the idea of incorporating evolution into the study of ‘strain theory’ and studying how ii phylogenetic patterns may correspond to its different regimes (Chapter 2). She also forged the collaboration with Sunetra Gupta, who commented and improved on the paper considerably. Trevor was first to suggest that the results should be framed within the context of two basic components of evolution: mutation and competition, and is also responsible for giving me access to his well-written code. Chapter 3 was inspired by this same major theme, but Bob Woods has been the motivation behind many of the types of dynamics we eventually decided to choose. My knowledge of rotavirus comes directly from his guidance and literature references. Although not in this text, a stronger connection to data in this chapter, will be achieved with the aid of Maria who has been a recent and incredible addition to our lab as a postdoc. My exposure to phylogenetic inference (Chapter 4 and 5) has been facilitated by Trevor Bedford. Trevor has a canny talent for neat science generated by few magical lines of code in Mathematica or Java. In Chapter 4, originally the intent was to study evolutionary patterns of influenza through changing weather, a project which I may yet re-approach. In its current form, an analysis of the patterns of migration was stimulated by ideas inspired from both Robert Woods and my committee advisor Stephen Smith. Bob has also been the big driver behind our project on the rotavirus population described in Chapter 5. The machinery for inference has been generated with the help of numerous lines of elegant code and theoretical support by Ed Baskerville. Ed has a talent for computational science which exceeds anything I have seen. iii Molly and Yael represent collaborations on the part of my work which was not included in this dissertation, yet are part of my PhD nonetheless. I’m grateful to Yael for the many methods and tools she has taught me, and for the initiation into the field of theoretical disease ecology. Molly has introduced me to the molecular world of var genes, and I hope our collaboration will continue and flourish. Similarly, I would like to thank Prof. Oliver He and Dr. Andrew Hodges for a great and highly valuable experience during my rotation project. I would also like to thank all my friends and colleagues in the lab throughout the years. I’m listing Manojit here first for both guiding me scientifically and encouraging my bottom up understanding of knowledge from basic principles, but also as a true friend in times of need. Not listed before, I’m grateful for many stimulating conversations with my lab-mates Qixin He, Xiangjun Du, Richard Zinck, Bobby Reiner, Tony Golubski, Andrew Strayer, Andres Baeza, Kevin Baker, Pamela Martinez and Mauricio (Oscar) Santos Vega, all of whom I have learned a lot from, and hope to continue and do so in years to come. I am also grateful for the support of people and staff in the Bioinformatics, PIBS and Ecology departments, who have made arranging research, travel and collaboration much easier, including Julia Eussen, Sonja Botes, Katia Kitchen and Michelle Melis. I would also like to thank Margit Burmeister and Dan Burns for their help and academic guidance throughout my graduation process. I am thankful for my core financial support through Mercedes’ appointment at the Howard Hughes Medical Institute, and to Rackham and the Bioinformatics department for providing additional funding. iv Finally, I would like to thank my family, with a mix of English, Hebrew and some my dearest ,דפנה Michael and ,אבא היקר ,Bengali (which I do not speak): Mom שתי מלחמות grandmother who helped raise me and brought together a fantastic family মিমি সুন্দরীSudeshna who is always সবসিয় 膿ক, but .עולם לא עצרו אותה והכוחות שלה איתנו עד היום more importantly, very dear to me. v Table of Contents Acknowledgments .................................................................................................................... ii List of tables .............................................................................................................................. ix List of figures ............................................................................................................................. x Chapter 1. Introduction ............................................................................................................ 1 1.1 Background ...................................................................................................................... 1 1.2 Phylodynamic patterns in rotavirus and influenza ................................................... 4 1.3 Phylodynamic patterns of multiple serotypes .......................................................... 10 1.4 Overview of the thesis .................................................................................................. 13 Section I....................................................................................................................................16 Chapter 2. The role of competition and mutation in shaping antigenic and genetic diversity in H3N2 influenza .................................................................................................. 16 2.1 Abstract ........................................................................................................................... 16 2.2 Introduction ................................................................................................................... 17 2.3 Results ............................................................................................................................. 20 2.4. Discussion ...................................................................................................................... 28 2.5. Methods ......................................................................................................................... 36 2.6. Acknowledgments ....................................................................................................... 40 2.7. Summary ....................................................................................................................... 40 2.8 Figures ............................................................................................................................. 42 2.9 Supporting Information ............................................................................................... 50 Chapter 3. Antagonism between reassortment and antigenic niche partitioning in a model of strain dynamics motivated by rotavirus ............................................................. 56 3.1 Abstract ........................................................................................................................... 56 3.2 Introduction ................................................................................................................... 57 vi 3.3 Methods .......................................................................................................................... 60 3.4 Results ............................................................................................................................