UNIVERSITY OF CALIFORNIA, IRVINE Computational Biology of RNA: The Messenger and The Regulator DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Computer Science by Elmira Forouzmand Dissertation Committee: Professor Xiaohui Xie, Chair Professor Michael Dillencourt Professor Yongsheng Shi 2019 © 2019 Elmira Forouzmand DEDICATION To MAMAN BABA SIAVASH ALI SAMIRA ii TABLE OF CONTENTS List of Figures ............................................................................................................................................................. v List of Tables ..............................................................................................................................................................vi Acknowledgements ................................................................................................................................................ vii Curriculum Vitae ........................................................................................................................................................ x Publications ...............................................................................................................................................................xi Abstract of the Dissertation .................................................................................................................................. xii Chapter 1 : Introduction ............................................................................................................................................. 1 Chapter 2 : Bioinformatics for Next Generation Sequencing .................................................................................. 8 Background .............................................................................................................................................................. 8 Bioinformatics in application ................................................................................................................................ 16 Chapter 3 : Developmentally regulated long non-coding RNAs in Xenopus tropicalis ....................................... 20 Introduction ........................................................................................................................................................... 20 Data ......................................................................................................................................................................... 23 Method .................................................................................................................................................................... 23 Gaussian Processes ............................................................................................................................................ 24 Detection Pipeline .............................................................................................................................................. 28 Weak lncRNA candidates’ detection approach .............................................................................................. 32 Expression Dynamics......................................................................................................................................... 36 Gene-LnRNAs Correlations ............................................................................................................................. 39 cell-type specific expression .............................................................................................................................. 41 Conclusion .............................................................................................................................................................. 41 Chapter 4 : Exon Size and Sequence Conservation for Identification of Splice Altering Nucleotides ............... 43 Introduction ........................................................................................................................................................... 43 Method and Results ............................................................................................................................................... 45 Exon Matching ................................................................................................................................................... 45 Splice Altering Mutations ................................................................................................................................. 50 Conclusion .............................................................................................................................................................. 55 Chapter 5 : PASARNA: A Tool for polyadenylation analysis using RNA-Seq Data ........................................... 56 Introduction ........................................................................................................................................................... 56 Background ............................................................................................................................................................ 61 Method .................................................................................................................................................................... 62 RNA-Seq vs PAS-Seq ........................................................................................................................................ 62 Module 1. Pre-Processor ................................................................................................................................... 64 Module 2. Candidate identifier with Change Point Detection Techniques ................................................... 67 Module 3. Basic Filter........................................................................................................................................ 75 Module 4. Sequence Model with Convolutional Neural Network ................................................................. 76 Module 5. Quantifier. ........................................................................................................................................ 79 iii Data ......................................................................................................................................................................... 80 Implementation ...................................................................................................................................................... 81 Results ..................................................................................................................................................................... 81 Future work............................................................................................................................................................ 84 Chapter 6 : Cells that record their own history ...................................................................................................... 86 Introduction ........................................................................................................................................................... 86 Framework and Methods ...................................................................................................................................... 87 CHRYON technology ........................................................................................................................................ 87 Lineage Tracing ................................................................................................................................................. 88 Bulk Experiment ................................................................................................................................................ 89 Simulation and Lineage Tracing ...................................................................................................................... 91 Forward process - Simulation ........................................................................................................................... 91 Reverse Process – Reconstruction (Greedy and Probabilistic) ...................................................................... 92 Future work.......................................................................................................................................................... 106 References ................................................................................................................................................................ 108 iv LIST OF FIGURES Figure 2-1 General Schematics of pre-mRNA processing ...................................................................................... 10 Figure 2-2 Typical RNA-Seq Experiment................................................................................................................ 12 Figure 3-1 Time-Scale ............................................................................................................................................... 27 Figure 3-2 Signal to Noise Ratio ............................................................................................................................... 28 Figure 3-3 LncRNA Discovery Pipeline ..................................................................................................................