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研究生:鄭煜輝
研究生(外文):Yu-Huei Cheng
論文名稱:引子設計及單一核苷酸多型性於生物資訊之研究與應用
論文名稱(外文):Studies and Applications of Primer Design and Single Nucleotide Polymorphisms in Bioinformatics
指導教授:楊正宏楊正宏引用關係
指導教授(外文):Cheng-Hong Yang
學位類別:博士
校院名稱:國立高雄應用科技大學
系所名稱:電子工程系
學門:工程學門
學類:電資工程學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:英文
論文頁數:301
中文關鍵詞:引子設計單一核苷酸多型性聚合酶鏈鎖反應限制酵素片段長度多型性
外文關鍵詞:primer designsingle nucleotide polymorphism (SNP)polymerase chain reaction (PCR)restriction fragment length polymorphism (RFLP)
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本研究論文主要為開發引子設計(primer design)方法及發展使用者需要的單一核苷酸多型性(single nucleotide polymorphism, SNP)系統以輔助生物學者及研究人員進行關聯性研究。於引子設計問題上,遺傳演算法(Genetic Algorithm, GA)、瀰集演算法(Memetic Algorithm, MA)及粒子族群最佳化(Particle Swarm Optimization, PSO)被應用至專一聚合酶鏈鎖反應(Polymerase Chain Reaction, PCR)引子設計以挑選適當的引子集。此外,以模糊調適慣性權重的粒子族群最佳化(Fuzzy Adaptive inertia weight of PSO, FAPSO)及以混沌慣性權重的粒子族群最佳化(Chaotic Inertia Weight of PSO, CIWPSO)的方法也促進了專一聚合酶鏈鎖反應引子設計。對於聚合酶鏈鎖反應-酵素片段長度多型性(Restriction Fragment Length Polymorphism, RFLP)之引子設計,本研究論文使用遺傳演算法並整合SNP-RFLPing程式的更新核心設計自然及誘導突變的PCR-RFLP引子,為SNP定型上(SNP genotyping)提供適當的引子集及限制酶。特別地,本研究論文引進了遺傳演算法及瀰集演算法設計出時間減少及成本低廉的聚合酶鏈鎖反應-對抗的兩對引子(Confronting Two-Pair Primers, CTPP)。於發展使用者需要的單一核苷酸多型性系統方面,SNP-RFLPing 2提供很多有關於SNP定型所需之PCR-RFLP資訊,如RFLP酵素及引子集。SNP-Flankplus提供16個物種可用的樣版序列以輔助PCR試驗上適當引子集的設計。Prim-SNPing提供自然的引子設計、誘導突變的引子設計、對抗的兩對引子設計及一般的引子設計。由BLAST及品質控制增強設計的引子於PCR上之效率,避免了二級結構影響。Methyl-Typing為改良的COBRA (Combined Bisulfite Restriction Analysis)軟體,提供了限制酶探勘及甲基化胞嘧啶包含序列(methyl-cytosine-containing)於重亞硫酸鹽改變(bisulfite-conversion)之視覺化。Drug-SNPing連結及整合藥物與SNPs相關的資源及工具以輔助藥物基因體學的個人化醫學研究。
The dissertation focuses on the works of developing primer design methods and single nucleotide polymorphism (SNP) user-friendly systems to assist biologists and researchers performing association studies. In the primer design, genetic algorithm (GA), memetic algorithm (MA) and particle swarm optimization (PSO) are applied to specific polymerase chain reaction (PCR) primer design for selection of feasible primer pairs. Furthermore, fuzzy adaptive inertia weight of PSO (FAPSO) and chaotic inertia weight of PSO (CIWPSO) also facilitate the specific PCR primer design. For PCR-restriction fragment length polymorphism (RFLP) primer design, the dissertation uses the GA and integrated the updated core of SNP-RFLPing to design natural and mutagenic PCR-RFLP primers to provide feasible primers and restriction enzymes for SNP genotyping. Specially, this dissertation introduces the GA-based and MA-based methods to design time- and cost-effective PCR-CTPP (Confronting Two-Pair Primers) primers. In the SNP user-friendly systems, SNP-RFLPing 2 is developed to provide PCR-RFLP information such as the RFLP enzymes and their primer set for SNP genotyping in many comprehensive fields related to the SNP. SNP-Flankplus provides an available template sequence to assist the design of feasible primer sets in a PCR assay for SNP genotyping with sixteen organisms. Prim-SNPing provides natural-primer design (PD), mutagenic-PD, and CTPP-PD as well as general-PD. The PCR efficiency for the designed primers is enhanced by BLAST and quality control, thus avoiding secondary structures. Methyl-Typing, an improved COBRA (combined bisulfite restriction analysis) software providing restriction enzyme mining and visualization of methyl-cytosine-containing sequences after bisulfite-conversion. Drug-SNPing connects and integrates between drug- and SNPs-related resources and tools to assist personalized medicine studies of pharmacogenomics.
ABSTRACT IN CHINESE i
ABSTRACT iii
ACKNOWLEDGEMENT v
LIST OF TABLES i
LIST OF FIGURES vi
I. INTRODUCTION 1
1.1 Motive of study 1
1.2 Purpose of study 1
1.3 Organization of the dissertation 3
II. BACKGROUND 5
2.1 Polymerase Chain Reaction (PCR) and primer design 5
2.1.1 Polymerase Chain Reaction (PCR) 5
2.1.2 Primer design 8
2.2 Single Nucleotide Polymorphism (SNP), Restriction Fragment Length Polymorphism (RFLP) and Methylation 11
2.2.1 Single Nucleotide Polymorphism (SNP) 11
2.2.2 Restriction Fragment Length Polymorphism (RFLP) 12
2.2.3 Methylation 13
2.3 Biological databases and bioinformatics tools 15
2.3.1 Biological databases 15
2.3.2 Bioinformatics tools 18
2.4 Algorithms 20
2.4.1 Genetic Algorithm (GA) 20
2.4.2 Memetic Algorithm (MA) 20
2.4.3 Particle Swarm Optimization (PSO) 21
2.4.4 Fuzzy adaptive inertia weight of PSO (FAPSO) 22
2.4.5 Chaotic inertia weight of PSO (CIWPSO) 22
III. PRIMER DESIGN 24
3.1 Specific PCR primer design 24
3.1.1 Problem definition 24
3.1.2 Fitness evaluation 26
3.1.3 GA for specific PCR primer design 30
3.1.4 MA for specific PCR primer design 36
3.1.5 PSO for specific PCR primer design 44
3.1.6 FAPSO for specific PCR primer design 46
3.1.7 CIWPSO for specific PCR primer design 52
3.2 PCR-RFLP primer design 59
3.2.1 Problem definition 59
3.2.1.1 Definition of natural PCR-RFLP primer design 59
3.2.1.2 Definition of mutagenic PCR-RFLP primer design 61
3.2.2 GA for natural PCR-RFLP primer design 64
3.2.3 GA for mutagenic PCR-RFLP primer design 71
3.3 PCR-Confronting Two-Pair Primer (CTPP) design 79
3.3.1 Problem definition 79
3.3.2 Fitness evaluation 82
3.3.3 GA for PCR-CTPP primer design 88
3.3.4 MA for PCR-CTPP primer design 93
IV. SNP RELATED APPLICATIONS AND IMPLEMENTATIONS 99
4.1 SNP-RFLPing 2 99
4.1.1 System structure and functions 99
4.1.2 Database description 103
4.2 SNP-Flankplus 104
4.2.1 System overview 104
4.3 Prim-SNPing 107
4.3.1 System structure and functions 107
4.4 Methyl-Typing 110
4.4.1 System structure and functions 110
4.5 Drug-SNPing 115
4.5.1 System structure and functions 115
V. RESULTS AND DISCUSSION 119
5.1 Specific PCR primer design 119
5.1.1 Datasets and environment 119
5.1.2 Parameter settings for specific PCR primer design 119
5.1.3 Results comparison among the primer design methods 120
5.1.4 Summary of GA, MA and PSO primer design 130
5.1.5 SPD tool and wet-laboratory validation for specific primer design 132
5.2 PCR-RFLP primer design 137
5.2.1 Datasets and environment 137
5.2.2 Parameter settings for PCR-RFLP primer design 137
5.2.3 In silico simulation results 138
5.2.3.1 Results for GANPD 138
5.2.3.2 Results for GAMPD 166
5.3 PCR-CTPP primer design 194
5.3.1 Datasets and environment 194
5.3.2 Parameter settings for PCR-CTPP primer design 194
5.3.3 Results for computational simulated experiments of PCR-CTPP primer design 195
5.3.4 Genotyping experiment 211
5.4 An updated and integrated PCR-RFLP tool for SNP genotyping (SNP-RFLPing 2) 213
5.4.1 Original functions in SNP-RFLPing (ver. 1) and their improvements 213
5.4.2 New improvements in SNP-RFLPing 2 215
5.4.3 Common output examples for SNP-RFLPing 2 218
5.5 SNP ID-centric retrieval for flanking sequences (SNP-Flankplus) 223
5.5.1 Input 223
5.5.2 Output 225
5.5.3 A tool for integrated to SNP related primer design 226
5.6 A primer designer for cost-effective SNP genotyping (Prim-SNPing) 227
5.6.1 Input 227
5.6.2 Output 230
5.6.3 Advantages of Prim-SNPing 233
5.7 An improved and visualized COBRA software for epigenomic studies (Methyl-Typing) 235
5.7.1 Input 235
5.7.2 Analysis 237
5.7.3 Output 237
5.7.4 Experimental results 242
5.7.5 Advantages of Methyl-Typing 243
5.8 Drug-, protein interaction- and tagSNP-integrated SNP retrieval and genotyping tool (Drug-SNPing) 246
5.8.1 Input 246
5.8.2 Output 248
5.8.3 The importance of Drug-SNPing 254
VI. CONCLUSION 256
VII. FUTURE WORKS 260
REFERENCES 262
APPENDIX I. List of abbreviations 283
APPENDIX II. Related links 285
APPENDIX III. The available bioinformatics related systems and resources in the dissertation 287
APPENDIX IV. User manuals 290
APPENDIX V. Publication list 291
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