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UNIVERSITY of CALIFORNIA SAN DIEGO Characterizing the Evolution UNIVERSITY OF CALIFORNIA SAN DIEGO Characterizing the Evolution of Epigenetic Clocks at Different Time Scales A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biomedical Sciences by Tina Wang Committee in charge: Professor Trey Ideker, Chair Professor Peter Ernst Professor Bing Ren Professor Elizabeth Winzeler Professor Kun Zhang 2019 Copyright Tina Wang, 2019 All Rights Reserved. SIGNATURE PAGE The Dissertation of Tina Wang is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California San Diego 2019 iii DEDICATION This dissertation is dedicated to my parents, Rong-Qi Wang and Shu Guang Xu, for their everlasting support of my professional endeavors. To Brandon Santos, my loving husband who has been the best thing that’s ever happened to my life. To Belli(ni), my dog, without whom, this work would have never occurred. iv TABLE OF CONTENTS SIGNATURE PAGE ................................................................................................................ iii DEDICATION........................................................................................................................... iv TABLE OF CONTENTS ............................................................................................................ v LIST OF SUPPLEMENTARY FILES .....................................................................................viii LIST OF FIGURES ................................................................................................................... ix LIST OF TABLES ..................................................................................................................... xi ACKNOWLEDGEMENTS ...................................................................................................... xii VITA ....................................................................................................................................... xiv ABSTRACT OF THE DISSERTATION ................................................................................. xvi INTRODUCTION ...................................................................................................................... 1 References .............................................................................................................................. 3 CHAPTER 1: Evidence for a common evolutionary rate in metazoan transcriptional networks ... 6 1.1 Abstract ............................................................................................................................. 6 1.2 Introduction ....................................................................................................................... 6 1.3 Results .............................................................................................................................. 8 1.4 Discussion ....................................................................................................................... 13 1.5 Methods .......................................................................................................................... 15 1.6 Figures ............................................................................................................................ 29 1.7 Supplementary figures ..................................................................................................... 35 1.8 Supplementary tables & files ........................................................................................... 44 1.9 Author contributions ....................................................................................................... 47 1.10 Acknowledgements ....................................................................................................... 47 1.11 References ..................................................................................................................... 47 v CHAPTER 2: Epigenetic aging signatures in mice are slowed by dwarfism, calorie restriction and rapamycin treatment.................................................................................................................. 57 2.1 Abstract ........................................................................................................................... 57 2.2 Introduction ..................................................................................................................... 58 2.3 Results ............................................................................................................................ 60 2.4 Discussion ....................................................................................................................... 64 2.5 Conclusions ..................................................................................................................... 65 2.6 Methods .......................................................................................................................... 66 2.7 Figures ............................................................................................................................ 74 2.8 Supplementary figures ..................................................................................................... 78 2.9 Supplementary tables and files ........................................................................................ 82 2.10 Author contributions...................................................................................................... 85 2.11 Acknowledgements ....................................................................................................... 85 2.12 References ..................................................................................................................... 85 CHAPTER 3: A conserved epigenetic progression aligns human and dog age ........................... 92 3.1 Abstract ........................................................................................................................... 92 3.2 Introduction ..................................................................................................................... 93 3.3 Results ............................................................................................................................ 94 3.4 Discussion ....................................................................................................................... 99 3.5 Methods .......................................................................................................................... 99 3.6 Figures .......................................................................................................................... 111 3.7 Supplementary Figures and Tables ................................................................................ 115 3.8 Author Contributions ..................................................................................................... 122 3.9 Acknowledgements ....................................................................................................... 122 vi 3.10 References ................................................................................................................... 123 CHAPTER 4: Discussion ........................................................................................................ 128 4.1 Summary ....................................................................................................................... 128 4.2 Limitations .................................................................................................................... 130 4.3 Outlook ......................................................................................................................... 131 4.4 References..................................................................................................................... 133 vii LIST OF SUPPLEMENTARY FILES Supplemental File S1.1: Accession numbers used in ChIP-seq analyses. Supplemental File S1.2: 648 segment-based ChIP analyses. Supplementary File S1.3: Influence of parameters choices when assessing GSTF binding divergence at segment resolution in mammals and insects. Supplemental File S2.1: Description of datasets used. Supplemental File S2.2: Sites used for mouse age model. Supplemental File S2.3: Treatment vs wild type stats. Supplementary File S3.1: Dogs used in study. Supplementary File S3.2: Mouse dataset description. viii LIST OF FIGURES Figure 1.1: Statistical framework to evaluate differences in evolutionary rates of change. ......... 29 Figure 1.2: Genomic sequences evolve more rapidly in mammals than in birds and insects. ...... 30 Figure 1.3: Gene expression levels diverge at a common rate in mammals, birds and insects..... 31 Figure 1.4: GSTF occupancy diverges at a common rate in mammals and insects. .................... 32 Figure 1.5: Regulatory sequences diverge at similar rates across lineages.................................. 34 Supplementary Figure S1.1: Comparative genomics platform for studying transcriptional network evolution across three metazoan lineages. ................................................................................. 35 Supplementary Figure S1.2: Power of the statistical framework to evaluate differences in evolutionary rates. ..................................................................................................................... 37 Supplementary Figure S1.3: Genomic segments retaining
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