Missouri University of Science and Technology Scholars' Mine Mathematics and Statistics Faculty Research & Creative Works Mathematics and Statistics 01 Jan 2010 Incorporating Genome Annotation in the Statistical Analysis of Genomic and Epigenomic Tiling Array Data Gayla R. Olbricht Missouri University of Science and Technology, [email protected] Follow this and additional works at: https://scholarsmine.mst.edu/math_stat_facwork Part of the Mathematics Commons, and the Statistics and Probability Commons Recommended Citation G. R. Olbricht, "Incorporating Genome Annotation in the Statistical Analysis of Genomic and Epigenomic Tiling Array Data," Purdue University, Jan 2010. This Book is brought to you for free and open access by Scholars' Mine. It has been accepted for inclusion in Mathematics and Statistics Faculty Research & Creative Works by an authorized administrator of Scholars' Mine. This work is protected by U. S. Copyright Law. Unauthorized use including reproduction for redistribution requires the permission of the copyright holder. For more information, please contact [email protected]. Graduate School ETD Form 9 (Revised 12/07) PURDUE UNIVERSITY GRADUATE SCHOOL Thesis/Dissertation Acceptance This is to certify that the thesis/dissertation prepared By Gayla Olbricht Entitled Incorporating Genome Annotation in the Statistical Analysis of Genomic and Epigenomic Tiling Array Data For the degree of Doctor of Philosophy Is approved by the final examining committee: Bruce A. Craig Rebecca W. Doerge Chair Mary Ellen Bock Michelle R. Lacey Yuan (Alan) Qi To the best of my knowledge and as understood by the student in the Research Integrity and Copyright Disclaimer (Graduate School Form 20) , this thesis/dissertation adheres to the provisions of Purdue University’s “Policy on Integrity in Research” and the use of copyrighted material. Approved by Major Professor(s): ___________________Rebecca W. Doerge _________________ ____________________________________Bruce A. Craig Approved by: Mary Ellen Bock 06/01/2010 Head of the Graduate Program Date Graduate School Form 20 (Revised 1/10) PURDUE UNIVERSITY GRADUATE SCHOOL Research Integrity and Copyright Disclaimer Title of Thesis/Dissertation: Incorporating Genome Annotation in the Statistical Analysis of Genomic and Epigenomic Tiling Array Data For the degree of _________________________________Doctor of Philosophy _______________________________ I certify that in the preparation of this thesis, I have observed the provisions of Purdue University Teaching, Research, and Outreach Policy on Research Misconduct (VIII.3.1) , October 1, 2008.* Further, I certify that this work is free of plagiarism and all materials appearing in this thesis/dissertation have been properly quoted and attributed. I certify that all copyrighted material incorporated into this thesis/dissertation is in compliance with the United States’ copyright law and that I have received written permission from the copyright owners for my use of their work, which is beyond the scope of the law. I agree to indemnify and save harmless Purdue University from any and all claims that may be asserted or that may arise from any copyright violation. Gayla Olbricht ______________________________________ Printed Name and Signature of Candidate ______________________________________07/14/2010 Date (month/day/year) *Located at http://www.purdue.edu/policies/pages/teach_res_outreach/viii_3_1.html INCORPORATING GENOME ANNOTATION IN THE STATISTICAL ANALYSIS OF GENOMIC AND EPIGENOMIC TILING ARRAY DATA A Dissertation Submitted to the Faculty of Purdue University by Gayla R. Olbricht In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2010 Purdue University West Lafayette, Indiana ii To my parents, who have provided a constant source of love and encouragement throughout my life, and to my husband Josh, whose loving support and belief in my potential to succeed continues to motivate me every day. iii ACKNOWLEDGMENTS During my time as a graduate student in the Department of Statistics at Purdue University, I have had the privilege of being surrounded by a wealth of talented, dedicated, and supportive individuals that have made my experience here exceptional. First and foremost, I would like to thank my two co-advisors, Professors Rebecca W. Doerge and Bruce A. Craig for their support, encouragement, direction, and friendship during my time as a Ph.D. student. I am very grateful to Rebecca for believing in me and offering a supportive ear from my first year of graduate school. The environment she creates for the students in her research group has helped me develop a breadth of professional skills and has exposed me to many new areas of scientific research. Her dedication to her students and profession is inspiring. I would like to thank Bruce for his helpful guidance, starting with my time as a consultant in the Statistical Consulting Service. He has always challenges me to think about things in new ways and I am grateful for his invaluable support. I would also like to gratefully acknowledge my committee members, Professors Alan Qi, Mary Ellen Bock, and Michelle Lacey for their insights and helpful dis- cussions. A special thanks to former department head Mary Ellen Bock, who has fostered an atmosphere within the Department of Statistics conducive to developing sound statistical skills, while encouraging respectful and positive interactions between faculty, students, and staff. I would like to thank the staff members in the depart- ment for their kindness and helpfulness as I navigated through graduate school. I would especially like thank Regina Becker, Teena Erwin, and Cheryl Crabill for gen- erously giving of their time when I was a leader in the Statistics in the Community (STATCOM) program. I am also very grateful to system administrators, Doug Cra- bill and My Truong, who have helped me on numerous occasions with their invaluable computing expertise. iv I am grateful to Dr. Jolena Waddell and Professor Christopher Bidwell in the An- imal Sciences Department who provided my first opportunity as a consultant to learn about microarray data analysis. Thanks to Jolena for her friendship and teaching me many biological concepts about gene expression data. I would like to acknowledge Professor Stanton Gelvin and Dr. Nagesh Sardesai in the Biological Sciences Depart- ment for collaborating with me on a tiling array analysis and allowing me to use their data in Chapter 3 of this dissertation. I am also grateful to Dr. Jody Riskowski and Jennifer Wilson, whose creative insights during my time as a GK-12 Fellow at Wea Ridge Middle School have helped me become a better teacher. I am also indebted to Professor George Mathew at Missouri State University for encouraging me to pursue a career in statistics and for providing helpful advice along the way. The friendships I have developed as a graduate student have made my time here rewarding and enjoyable. In particular, I am fortunate to have had the opportunity to work with current and past members of the RWD research group: Tilman Achberger, Lingling An, Paul Livermore Auer, Doug Baumann, Martina Muehlbach Bremer, Riyan Cheng, Kyunga Kim, Alex Lipka, Cherie Ochsenfeld, Andrea Rau (and the UWN), Sanvesh Srivastava, and Suk-Young Yoo. The camaraderie and fruitful dis- cussions with this group has been one of the highlights of my time as a graduate student. I am also grateful for the friendship of Tina Alexander, Nilupa Gunaratna, Amy Wozniak, Andrew Lewandowski, and Amanda Bean who I have had the privilege of sharing valuable study time, STATCOM experiences, and many fond memories. Finally, I would like to express my heartfelt gratitude for the love and support of my family, which has always been a source of strength and inspiration for me. I would especially like to thank my parents, Randal and Linda Hobbs, and my parents- in-law, Ted and Barbara Olbricht, for their love, patience, and encouragement, which have been particularly uplifting during my time in graduate school. Thanks to my sister, Rhonda, for her friendship throughout life. To my husband Josh, thank you for taking this adventure in life with me. Your companionship and unwaivering belief in me has inspired me more than you will ever know. v TABLE OF CONTENTS Page LIST OF TABLES ................................ vii LIST OF FIGURES ............................... viii ABSTRACT ................................... xv 1 Introduction .................................. 1 1.1 Basics of Genetics ............................ 1 1.1.1 DNA Structure and Central Dogma of Molecular Biology . 1 1.1.2 Genetic Variation ........................ 3 1.2 Epigenetics ............................... 4 1.2.1 DNA Methylation ........................ 6 1.2.2 Histone Modifications ...................... 8 1.3 Genomics and Epigenomics ...................... 9 1.4 Microarray Technology and Applications ............... 11 1.4.1 Gene Expression Microarrays and Differential Expression Stud- ies ................................ 11 1.4.2 Tiling Arrays and Applications ................ 15 1.5 Genomic Annotation and Tiling Array Experiments ......... 19 2 Genomic Annotation of Tiling Arrays .................... 20 2.1 Genomic Annotation and Differential Expression Analysis ...... 21 2.2 Genomic Annotation and DNA Methylation Profiling ........ 22 2.3 Arabidopsis thaliana Tiling Arrays .................. 24 2.3.1 Custom-designed Chromosome 4 Tiling Array ........ 25 R 2.3.2 Affymetrix Whole Genome Tiling Array .......... 26 3 Using Genomic