||Systems Biology Approaches for Analysis of High-Throughput Genome-Wide Data
||Institute of Computer Science and Information Engineering
Kinome Regulatory Network
The two main challenges from the biological complexity and high data dimensionality are to understand how biological systems function and to determine how enormous data can be dealt with, respectively. The objective of this dissertation is to propose a systems biology framework and aims to target the problem with the purpose of exploring the biological complexity and high data dimensionality. This framework that contains two systems biology approaches is a constantly evolving loop with three elements: biology, computation, and network. In our research, we first have proposed a systems network that can analyze big data, build a kinome network from huge datasets, and uncover the complex regulation by phosphorylation. Secondly, we have developed a systems analysis that can decipher nuclear pore complexes (NPCs) mechanism by analyzing tremendous data and providing feedback to biology. In conclusion, our research contributes to the development of systems biology framework in four ways: 1) it creates new models in order to address new biological questions, 2) it summarizes and describes the data through statistical tests to validate the hypothesis, 3) it gives visualization of the analyzed results effectively to break down the biological complexity, and 4) it provides an evolving cycle framework to address biological issues and to advance in computation.
CHAPTER 1 INTRODUCTION 1
1.1 OVERVIEW 1
1.2 OBJECTIVE 2
1.3 ORGANIZATION OF DISSERTAION 4
CHAPTER 2 WHY WE NEED SYSTEMS BIOLOGY? 5
2.1 WHY IS SYSTEMS BIOLOGY IMPORTANT? 5
2.2 NETWORK ANALYSIS IN SYSTEMS BIOLOGY 7
2.3 SYSTEMS BIOLOGY FOR DISEASE AND MEDICINE 8
2.4 SYSTEMS BILOGY FOR BIG DATA 9
CHAPTER 3 A SYSTEMAS NETWORK TO BUILD THE KINOME NETWORK 11
3.1 RELATED WORK 12
3.2 MATERIALS AND METHODS 16
3.2.1 Datasets used to predict Phosphorylation networks 21
3.2.2 Data Processing 21
3.2.3 Model Learning 25
3.3 RESULTS 27
3.2.1 PhosphoChain evaluation 28
3.2.2 Reconstruction of MAPK Pathways 34
3.2.3 Predicting Phosphorylation Sites 40
3.2.4 Reconstruction of the Genome-wide Kinome Network 47
3.4 SUMMARY 54
CHAPTER 4 A SYSTEMS ANALYSIS IN DECIPHERING THE NUCLEAR PORE COMPLEXES MECHANISM 56
4.1 RELATED WORK 57
4.2 MATERIALS AND METHODS 60
4.2.1 Telomeric enrichment model 60
4.2.2 Nucleosome fluctuation model 62
4.2.3 Subtelomeric association model 65
4.2.4 Visualization 67
4.3 RESULTS 68
4.3.3 Detection of the enrichment pattern of subtelomeric genes silencing 68
4.3.4 Identification of subtelomeric chromatin changes in nucleosome positioning and occupancy 71
4.3.5 Measurement of the physical interactions of NPC protein with RP genes and subtelomeric DNA 76
4.4 SUMMARY 83
CHAPTER 5 CONCLUSION AND FUTURE WORK 84
5.1 REMARKS 84
5.2 FUTURE WORK 86
5.2.1 Extending PhosphoChain and improvement of kinome network building 86
5.2.2 Extending NPCparser and providing feedback to biology 88
5.2.3 Multi-scale visualizations in multiple levels for big data 89
5.2.4 New statistical and mathematical methods for big data 90
APPENDIX FIGURES 105
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