Handbook of genome research : genomics, proteomics, metabolomics, bioinformatics, ethics & legal issues

Volume 1 Part I Key Organisms 1 1 Genome Projects on Model Organisms 3 Alfred Pühler, Doris Jording, Jörn Kalinowski, Detlev Buttgereit, Renate Renkawitz-Pohl, Lothar Altschmied, Antoin Danchin, Agnieszka Sekowska, Horst Feldmann, Hans-Peter Klenk, and Manfred Kröger 1.1 Introduction 3 1.2 Genome Projects of Selected Prokaryotic Model Organisms 4 1.2.1 The Gram_ Enterobacterium Escherichia coli 4 1.2.1.1 The Organism 4 1.2.1.2 Characterization of the Genome and Early Sequencing Efforts 7 1.2.1.3 Structure of the Genome Project 7 1.2.1.4 Results from the Genome Project 8 1.2.1.5 Follow-up Research in the Postgenomic Era 9 1.2.2 The Gram+ Spore-forming Bacillus subtilis 10 1.2.2.1 The Organism 10 1.2.2.2 A Lesson from Genome Analysis: The Bacillus subtilis Biotope 11 1.2.2.3 To Lead or to Lag: First Laws of Genomics 12 1.2.2.4 Translation: Codon Usage and the Organization of the Cell’s Cytoplasm 13 1.2.2.5 Post-sequencing Functional Genomics: Essential Genes and Expression-profiling Studies 13 1.2.2.6 Industrial Processes 15 1.2.2.7 Open Questions 15 1.2.3 The Archaeon Archaeoglobus fulgidus 16 1.2.3.1 The Organism 16 1.2.3.2 Structure of the Genome Project 17 1.2.3.3 Results from the Genome Project 18 1.2.3.4 Follow-up Research 20 1.3 Genome Projects of Selected Eukaryotic Model Organisms 20 1.3.1 The Budding Yeast Saccharomyces cerevisiae 20 1.3.1.1 Yeast as a Model Organism 20 Contents Handbook of Genome Research. Genomics, Proteomics, Metabolomics, Bioinformatics, Ethical and Legal Issues. Edited by Christoph W. Sensen Copyright © 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31348-6 VIII Contents 1.3.1.2 The Yeast Genome Sequencing Project 21 1.3.1.3 Life with Some 6000 Genes 23 1.3.1.4 The Yeast Postgenome Era 25 1.3.2 The Plant Arabidopsis thaliana 25 1.3.2.1 The Organism 25 1.3.2.2 Structure of the Genome Project 27 1.3.2.3 Results from the Genome Project 28 1.3.2.4 Follow-up Research in the Postgenome Era 29 1.3.3 The Roundworm Caenorhabditis elegans 30 1.3.3.1 The Organism 30 1.3.3.2 The Structure of the Genome Project 31 1.3.3.3 Results from the Genome Project 32 1.3.3.4 Follow-up Research in the Postgenome Era 33 1.3.4 The Fruitfly Drosophila melanogaster 34 1.3.4.1 The Organism 34 1.3.4.2 Structure of the Genome Project 35 1.3.4.3 Results of the Genome Project 36 1.3.4.4 Follow-up Research in the Postgenome Era 37 1.4 Conclusions 37 References 39 2 Environmental Genomics: A Novel Tool for Study of Uncultivated Microorganisms 45 Alexander H. Treusch and Christa Schleper 2.1 Introduction: Why Novel Approaches to Study Microbial Genomes? 45 2.2 Environmental Genomics: The Methodology 46 2.3 Where it First Started: Marine Environmental Genomics 48 2.4 Environmental Genomics of Defined Communities: Biofilms and Microbial Mats 50 2.5 Environmental Genomics for Studies of Soil Microorganisms 50 2.6 Biotechnological Aspects 53 2.7 Conclusions and Perspectives 54 References 55 3 Applications of Genomics in Plant Biology 59 Richard Bourgault, Katherine G. Zulak, and Peter J. Facchini 3.1 Introduction 59 3.2 Plant Genomes 60 3.2.1 Structure, Size, and Diversity 60 3.2.2 Chromosome Mapping: Genetic and Physical 61 3.2.3 Large-scale Sequencing Projects 62 3.3 Expressed Sequence Tags 64 3.4 Gene Expression Profiling Using DNA Microarrays 66 3.5 Proteomics 68 3.6 Metabolomics 70 Contents IX 3.7 Functional Genomics 72 3.7.1 Forward Genetics 72 3.7.2 Reverse Genetics 73 3.8 Concluding Remarks 76 References 77 4 Human Genetic Diseases 81 Roger C. Green 4.1 Introduction 81 4.1.1 The Human Genome Project: Where Are We Now and Where Are We Going? 81 4.1.1.1 What Have We Learned? 81 4.2 Genetic Influences on Human Health 83 4.3 Genomics and Single-gene Defects 84 4.3.1 The Availability of the Genome Sequence Has Changed the Way in which Disease Genes Are Identified 84 4.3.1.1 Positional Candidate Gene Approach 85 4.3.1.2 Direct Analysis of Candidate Genes 85 4.3.2 Applications in Human Health 86 4.3.2.1 Genetic Testing 86 4.3.3 Gene Therapy 87 4.4 Genomics and Polygenic Diseases 87 4.4.1 Candidate Genes and their Variants 88 4.4.2 Linkage Disequilibrium Mapping 89 4.4.2.1 The Hapmap Project 89 4.4.3 Whole-genome Resequencing 90 4.5 The Genetic Basis of Cancer 90 4.5.1 Breast Cancer 91 4.5.1.1 Cancer Risk in Carriers of BRCA Mutations 92 4.5.2 Colon Cancer 93 4.5.2.1 Familial Adenomatous Polyposis 93 4.5.2.2 Hereditary Non-polyposis Colon Cancer 93 4.5.2.3 Modifier Genes in Colorectal Cancer 94 4.6 Genetics of Cardiovascular Disease 94 4.6.1 Monogenic Disorders 95 4.6.1.1 Hypercholesterolemia 95 4.6.1.2 Hypertension 95 4.6.1.3 Clotting Factors 95 4.6.1.4 Hypertrophic Cardiomyopathy 95 4.6.1.5 Familial Dilated Cardiomyopathy 96 4.6.1.6 Familial Arrhythmias 96 4.6.2 Multifactorial Cardiovascular Disease 96 4.7 Conclusions 97 References 98 X Contents Part II Genomic and Proteomic Technologies 103 5 Genomic Mapping and Positional Cloning, with Emphasis on Plant Science 105 Apichart Vanavichit, Somvong Tragoonrung, and Theerayut Toojinda 5.1 Introduction 105 5.2 Genome Mapping 105 5.2.1 Mapping Populations 105 5.2.2 Molecular Markers: The Key Mapping Reagents 106 5.2.2.1 RFLP 107 5.2.2.2 RAPD 107 5.2.2.3 AFLP 107 5.2.2.4 SSR 108 5.2.2.5 SSCP 108 5.2.3 Construction of a Linkage Map 108 5.3 Positional Cloning 110 5.3.1 Successful Positional Cloning 110 5.3.2 Defining the Critical Region 111 5.3.3 Refining the Critical Region: Genetic Approaches 112 5.3.4 Refining the Critical Region: Physical Approaches 113 5.3.5 Cloning Large Genomic Inserts 114 5.3.6 Radiation Hybrid Map 114 5.3.7 Identification of Genes Within the Refined Critical Region 115 5.3.7.1 Gene Detection by CpG Island 115 5.3.7.2 Exon Trapping 115 5.3.7.3 Direct cDNA Selection 115 5.4 Comparative Mapping and Positional Cloning 115 5.4.1 Synteny, Colinearity, and Positional Cloning 116 5.4.2 Bridging Model Organisms 117 5.4.3 Predicting Candidate Genes in the Critical Region 118 5.4.4 EST: Key to Gene Identification in the Critical Region 118 5.4.5 Linkage Disequilibrium Mapping 120 5.5 Genetic Mapping in the Post-genomics Era 120 5.5.1 eQTL 121 References 123 6 DNA Sequencing Technology 129 Lyle R. Middendorf, Patrick G. Humphrey, Narasimhachari Narayanan, and Stephen C. Roemer 6.1 Introduction 129 6.2 Overview of Sanger Dideoxy Sequencing 130 6.3 Fluorescence Dye Chemistry 131 6.3.1 Fluorophore Characteristics 132 6.3.2 Commercial Dye Fluorophores 132 6.3.3 Energy Transfer 136 6.3.4 Fluorescence Lifetime 137 Contents XI 6.4 Biochemistry of DNA Sequencing 138 6.4.1 Sequencing Applications and Strategies 138 6.4.1.1 New Sequence Determination 139 6.4.1.2 Confirmatory Sequencing 140 6.4.2 DNA Template Preparation 140 6.4.2.1 Single-stranded DNA Template 140 6.4.2.2 Double-stranded DNA Template 140 6.4.2.3 Vectors for Large-insert DNA 141 6.4.2.4 PCR Products 141 6.4.3 Enzymatic Reactions 141 6.4.3.1 DNA Polymerases 141 6.4.3.2 Labeling Strategy 142 6.4.3.3 The Template–Primer–Polymerase Complex 143 6.4.3.4 Simultaneous Bi-directional Sequencing 144 6.5 Fluorescence DNA Sequencing Instrumentation 144 6.5.1 Introduction 144 6.5.1.1 Excitation Energy Sources 144 6.5.1.2 Fluorescence Samples 145 6.5.1.3 Fluorescence Detection 145 6.5.1.4 Overview of Fluorescence Instrumentation Related to DNA Sequencing 145 6.5.2 Information Throughput 147 6.5.2.1 Sample Channels (n) 147 6.5.2.2 Information per Channel (d) 147 6.5.2.3 Information Independence (I) 148 6.5.2.4 Time per Sample (t) 148 6.5.3 Instrument Design Issues 148 6.5.4 Forms of Commercial Electrophoresis used for Fluorescence DNA Sequencing 149 6.5.4.1 Slab Gels 149 6.5.4.2 Capillary Gels 151 6.5.4.3 Micro-Grooved Channel Gel Electrophoresis 151 6.5.5 Non-electrophoresis Methods for Fluorescence DNA Sequencing 152 6.5.6 Non-fluorescence Methods for DNA Sequencing 152 6.6 DNA Sequence Analysis 153 6.6.1 Introduction 153 6.6.2 Lane Detection and Tracking 153 6.6.3 Trace Generation and Base Calling 155 6.6.4 Quality/Confidence Values 157 6.7 DNA Sequencing Approaches to Achieving the $1000 Genome 159 6.7.1 Introduction 159 6.7.2 DNA Degradation Strategy 161 6.7.3 DNA Synthesis Strategy 162 6.7.4 DNA Hybridization Strategy 163 6.7.5 Nanopore Filtering Strategy 164 References 165 XII Contents 7 Proteomics and Mass Spectrometry for the Biological Researcher 181 Sheena Lambert and David C. Schriemer 7.1 Introduction 181 7.2 Defining the Sample for Proteomics 184 7.2.1 Minimize Cellular Heterogeneity, Avoid Mixed Cell Populations 184 7.2.2 Use Isolated Cell Types and/or Cell Cultures 185 7.2.3 Minimize Intracellular Heterogeneity 186 7.2.4 Minimize Dynamic Range 186 7.2.5 Maximize Concentration/Minimize Handling 187 7.3 New Developments – Clinical Proteomics 187 7.4 Mass Spectrometry – The Essential Proteomic Technology 188 7.4.1 Sample Processing 190 7.4.2 Instrumentation 191 7.4.3 MS Bioinformatics/Sequence Databases 193 7.5 Sample-driven Proteomics Processes 195 7.5.1 Direct MS Analysis of a Protein Digest 196 7.5.2 Direct MS–MS Analysis of a Digest 198 7.5.3 LC–MS–MS of a Protein Digest 199 7.5.4 Multidimensional LC–MS–MS of a Digest (Top-down vs. Bottom-up Proteomics) 201 7.6 Conclusions 204 References 205 8 Proteome Analysis by Capillary Electrophoresis 211 Md Abul Fazal, David Michels, James Kraly, and Norman J. Dovichi 8.1 Introduction 211 8.2 Capillary Electrophoresis 212 8.2.1 Instrumentation 212 8.2.2 Injection 212 8.2.3 Electroosmosis 212 8.2.4 Separation 213 8.2.5 Detection 214 8.3 Capillary Electrophoresis for Protein Analysis 215 8.3.1 Capillary Isoelectric Focusing 215 8.3.2 SDS/Capillary Sieving Electrophoresis 215 8.3.3 Free Solution Electrophoresis 217 8.4 Single-cell Analysis 218 8.5 Two-dimensional Separations 219 8.6 Conclusions 221 References 222 9 A DNA Microarray Fabrication Strategy for Research Laboratories 223 Daniel C. Tessier, Mélanie Arbour, François Benoit, Hervé Hogues, and Tracey Rigby 9.1 Introduction 223 Contents XIII 9.2 The Database 228 9.3 High-throughput DNA Synthesis 230 9.3.1 Scale and Cost of Synthesis 230 9.3.2 Operational Constraints 231 9.3.3 Quality-control Issues 232 9.4 Amplicon Generation 232 9.5 Microarraying 234 9.6 Probing and Scanning Microarrays 234 9.7 Conclusion 235 References 237 10 Principles of Application of DNA Microarrays 239 Mayi Arcellana-Panlilio 10.1 Introduction 239 10.2 Definitions 240 10.3 Types of Array 240 10.4 Production of Arrays 241 10.4.1 Sources of Arrays 241 10.4.2 Array Content 242 10.4.3 Slide Substrates 242 10.4.4 Arrayers and Spotting Pins 243 10.5 Interrogation of Arrays 243 10.5.1 Experimental Design 244 10.5.2 Sample Preparation 246 10.5.3 Labeling 247 10.5.4 Hybridization and Post-hybridization Washes 249 10.5.5 Data Acquisition and Quantification 250 10.6 Data Analysis 251 10.7 Documentation of Microarrays 254 10.8 Applications of Microarrays in Cancer Research 255 10.9 Conclusion 256 References 257 11 Yeast Two-hybrid Technologies 261 Gregor Jansen, David Y. Thomas, and Stephanie Pollock 11.1 Introduction 261 11.2 The Classical Yeast Two-hybrid System 262 11.3 Variations of the Two-hybrid System 263 11.3.1 The Reverse Two-hybrid System 263 11.3.2 The One-hybrid System 264 11.3.3 The Repressed Transactivator System 264 11.3.4 Three-hybrid Systems 264 11.4 Membrane Yeast Two-hybrid Systems 265 11.4.1 SOS Recruitment System 266 11.4.2 Split-ubiquitin System 266 XIV Contents 11.4.3 G-Protein Fusion System 266 11.4.4 The Ire1 Signaling System 268 11.4.5 Non-yeast Hybrid Systems 269 11.5 Interpretation of Two-hybrid Results 269 11.6 Conclusion 270 References 271 12 Structural Genomics 273 Aalim M. Weljie, Hans J. Vogel, and Ernst M. Bergmann 12.1 Introduction 273 12.2 Protein Crystallography and Structural Genomics 274 12.2.1 High-throughput Protein Crystallography 274 12.2.2 Protein Production 276 12.2.3 Protein Crystallization 278 12.2.4 Data Collection 279 12.2.5 Structure Solution and Refinement 281 12.2.6 Analysis 282 12.3 NMR and Structural Genomics 282 12.3.1 High-throughput Structure Determination by NMR 282 12.3.1.1 Target Selection 282 12.3.1.2 High-throughput Data Acquisition 284 12.3.1.3 High-throughput Data Analysis 286 12.3.2 Other Non-structural Applications of NMR 287 12.3.2.1 Suitability Screening for Structure Determination 288 12.3.2.2 Determination of Protein Fold 289 12.3.2.3 Rational Drug Target Discovery and Functional Genomics 290 12.4 Epilogue 290 References 292 Volume 2 Part III Bioinformatics 297 13 Bioinformatics Tools for DNA Technology 299 Peter Rice 13.1 Introduction 299 13.2 Alignment Methods 299 13.2.1 Pairwise Alignment 300 13.2.2 Local Alignment 302 13.2.3 Variations on Pairwise Alignment 303 13.2.4 Beyond Simple Alignment 304 13.2.5 Other Alignment Methods 305 13.3 Sequence Comparison Methods 305 13.3.1 Multiple Pairwise Comparisons 307 Contents XV 13.4 Consensus Methods 309 13.5 Simple Sequence Masking 309 13.6 Unusual Sequence Composition 309 13.7 Repeat Identification 310 13.8 Detection of Patterns in Sequences 311 13.8.1 Physical Characteristics 312 13.8.2 Detecting CpG Islands 313 13.8.3 Known Sequence Patterns 314 13.8.4 Data Mining with Sequence Patterns 315 13.9 Restriction Sites and Promoter Consensus Sequences 315 13.9.1 Restriction Mapping 315 13.9.2 Codon Usage Analysis 315 13.9.3 Plotting Open Reading Frames 317 13.9.4 Codon Preference Statistics 318 13.9.5 Reading Frame Statistics 320 13.10 The Future for EMBOSS 321 References 322 14 Software Tools for Proteomics Technologies 323 David S. Wishart 14.1 Introduction 323 14.2 Protein Identification 324 14.2.1 Protein Identification from 2D Gels 324 14.2.2 Protein Identification from Mass Spectrometry 328 14.2.3 Protein Identification from Sequence Data 332 14.3 Protein Property Prediction 334 14.3.1 Predicting Bulk Properties (pI, UV absorptivity, MW) 334 14.3.2 Predicting Active Sites and Protein Functions 334 14.3.3 Predicting Modification Sites 338 14.3.4 Finding Protein Interaction Partners and Pathways 338 14.3.5 Predicting Sub-cellular Location or Localization 339 14.3.6 Predicting Stability, Globularity, and Shape 340 14.3.7 Predicting Protein Domains 341 14.3.8 Predicting Secondary Structure 342 14.3.9 Predicting 3D Folds (Threading) 343 14.3.10 Comprehensive Commercial Packages 344 References 347 15 Applied Bioinformatics for Drug Discovery and Development 353 Jian Chen, ShuJian Wu, and Daniel B. Davison 15.1 Introduction 353 15.2 Databases 353 15.2.1 Sequence Databases 354 15.2.1.1 Genomic Sequence Databases 354 15.2.1.2 EST Sequence Databases 355 XVI Contents 15.2.1.3 Sequence Variations and Polymorphism Databases 356 15.2.2 Expression Databases 357 15.2.2.1 Microarray and Gene Chip 357 15.2.2.2 Others (SAGE, Differential Display) 358 15.2.2.3 Quantitative PCR 358 15.2.3 Pathway Databases 358 15.2.4 Cheminformatics 359 15.2.5 Metabonomics and Proteomics 360 15.2.6 Database Integration and Systems Biology 360 15.3 Bioinformatics in Drug-target Discovery 362 15.3.1 Target-class Approach to Drug-target Discovery 362 15.3.2 Disease-oriented Target Identification 364 15.3.3 Genetic Screening and Comparative Genomics in Model Organisms for Target Discovery 365 15.4 Support of Compound Screening and Toxicogenomics 366 15.4.1 Improving Compound Selectivity 367 15.4.1.1 Phylogeny Analysis 367 15.4.1.2 Tissue Expression and Biological Function Implication 368 15.4.2 Prediction of Compound Toxicity 369 15.4.2.1 Toxicogenomics and Toxicity Signature 369 15.4.2.2 Long QT Syndrome Assessment 370 15.4.2.3 Drug Metabolism and Transport 371 15.5 Bioinformatics in Drug Development 372 15.5.1 Biomarker Discovery 372 15.5.2 Genetic Variation and Drug Efficacy 373 15.5.3 Genetic Variation and Clinical Adverse Reactions 374 15.5.4 Bioinformatics in Drug Life-cycle Management (Personalized Drug and Drug Competitiveness) 376 15.6 Conclusions 376 References 377 16 Genome Data Representation Through Images: The MAGPIE/Bluejay System 383 Andrei Turinsky, Paul M. K. Gordon, Emily Xu, Julie Stromer, and Christoph W. Sensen 16.1 Introduction 383 16.2 The MAGPIE Graphical System 384 16.3 The Hierarchical MAGPIE Display System 386 16.4 Overview Images 387 16.4.1 Whole Project View 387 16.5 Coding Region Displays 391 16.5.1 Contiguous Sequence with ORF Evidence 391 16.5.2 Contiguous Sequence with Evidence 394 16.5.3 Expressed Sequence Tags 394 16.5.4 ORF Close-up 395 Contents XVII 16.6 Coding Sequence Function Evidence 396 16.6.1 Analysis Tools Summary 396 16.6.2 Expanded Tool Summary 397 16.7 Secondary Genome Context Images 399 16.7.1 Base Composition 399 16.7.2 Sequence Repeats 400 16.7.3 Sequence Ambiguities 401 16.7.4 Sequence Strand Assembly Coverage 402 16.7.5 Restriction Enzyme Fragmentation 402 16.7.6 Agarose Gel Simulation 403 16.8 The Bluejay Data Visualization System 404 16.9 Bluejay Architecture 405 16.10 Bluejay Display and Data Exploration 407 16.10.1 The Main Bluejay Interface 407 16.10.2 Semantic Zoom and Levels of Details 408 16.10.3 Operations on the Sequence 408 16.10.4 Interaction with Individual Elements 410 16.10.5 Eukaryotic Genomes 411 16.11 Bluejay Usability Features 411 16.12 Conclusions and Open Issues 413 References 414 17 Bioinformatics Tools for Gene-expression Studies 415 Greg Finak, Michael Hallett, Morag Park, and François Pepin 17.1 Introduction 415 17.1.1 Microarray Technologies 416 17.1.1.1 cDNA Microarrays 416 17.1.1.2 Oligonucleotide Microarrays 417 17.1.2 Objectives and Experimental Design 417 17.2 Background Knowledge and Tools 419 17.2.1 Standards 419 17.2.2 Microarray Data Management Systems 420 17.2.3 Statistical and General Analysis Software 420 17.3 Preprocessing 421 17.3.1 Image, Spot, and Array Quality 421 17.3.2 Gene Level Summaries 422 17.3.3 Normalization 422 17.4 Class Comparison – Differential Expression 423 17.5 Class Prediction 425 17.6 Class Discovery 426 17.6.1 Clustering Algorithms 426 17.6.2 Validation of Clusters 427 17.7 Searching for Meaning 428 References 430 XVIII Contents 18 Protein Interaction Databases 433 Gary D. Bader and Christopher W. V. Hogue 18.1 Introduction 433 18.2 Scientific Foundations of Biomolecular Interaction Information 434 18.3 The Graph Abstraction for Interaction Databases 434 18.4 Why Contemplate Integration of Interaction Data? 435 18.5 A Requirement for More Detailed Abstractions 435 18.6 An Interaction Database as a Framework for a Cellular CAD System 437 18.7 BIND – The Biomolecular Interaction Network Database 437 18.8 Other Molecular-interaction Databases 439 18.9 Database Standards 439 18.10 Answering Scientific Questions Using Interaction Databases 440 18.11 Examples of Interaction Databases 440 References 455 19 Bioinformatics Approaches for Metabolic Pathways 461 Ming Chen, Andreas Freier, and Ralf Hofestädt 19.1 Introduction 461 19.2 Formal Representation of Metabolic Pathways 463 19.3 Database Systems and Integration 463 19.3.1 Database Systems 463 19.3.2 Database Integration 465 19.3.3 Model-driven Reconstruction of Molecular Networks 466 19.3.3.1 Modeling Data Integration 467 19.3.3.2 Object-oriented Modeling 469 19.3.3.3 Systems Reconstruction 471 19.4 Different Models and Aspects 472 19.4.1 Petri Net Model 473 19.4.1.1 Basics 473 19.4.1.2 Hybrid Petri Nets 474 19.4.1.3 Applications 476 19.4.1.4 Petri Net Model Construction 478 19.5 Simulation Tools 479 19.5.1 Metabolic Data Integration 481 19.5.2 Metabolic Pathway Layout 481 19.5.3 Dynamics Representation 482 19.5.4 Hierarchical Concept 482 19.5.5 Prediction Capability 482 19.5.6 Parallel Treatment and Development 482 19.6 Examples and Discussion 483 References 487 20 Systems Biology 491 Nathan Goodman 20.1 Introduction 491 Contents XIX 20.2 Data 492 20.2.1 Available Data Types 492 20.2.2 Data Quality and Data Fusion 493 20.3 Basic Concepts 494 20.3.1 Systems and Models 494 20.3.2 States 494 20.3.3 Informal and Formal Models 495 20.3.4 Modularity 495 20.4 Static Models 496 20.4.1 Graphs 496 20.4.2 Analysis of Static Models 498 20.5 Dynamic Models 499 20.5.1 Types of Model 499 20.5.2 Modeling Formalisms 500 20.6 Summary 500 20.7 Guide to the Literature 501 20.7.1 Highly Recommended Reviews 501 20.7.2 Recommended Detailed Reviews 502 20.7.3 Recommended High-level Reviews 502 References 504 Part IV Ethical, Legal and Social Issues 507 21 Ethical Aspects of Genome Research and Banking 509 Bartha Maria Knoppers and Clémentine Sallée 21.1 Introduction 509 21.2 Types of Genetic Research 509 21.3 Research Ethics 510 21.4 “Genethics” 513 21.5 DNA Banking 516 21.5.1 International 517 21.1.2 Regional 520 21.5.3 National 521 21.6 Ownership 526 21.7 Conclusion 530 References 532 22 Biobanks and the Challenges of Commercialization 537 Edna Einsiedel and Lorraine Sheremeta 22.1 Introduction 537 22.2 Background 538 22.3 Population Genetic Research and Public Opinion 540 22.4 The Commercialization of Biobank Resources 541 22.4.1 An Emerging Market for Biobank Resources 542 XX Contents 22.4.2 Public Opinion and the Commercialization of Genetic Resources 543 22.5 Genetic Resources and Intellectual Property: What Benefits? For Whom? 544 22.5.1 Patents as The Common Currency of the Biotech Industry 544 22.5.2 The Debate over Genetic Patents 545 22.5.3 Myriad Genetics 546 22.5.4 Proposed Patent Reforms 547 22.5.5 Patenting and Public Opinion 548 22.6 Human Genetic Resources and Benefit-Sharing 549 22.7 Commercialization and Responsible Governance of Biobanks 551 22.7.1 The Public Interest and the Exploitation of Biobank Resources 552 22.7.2 The Role of the Public and Biobank Governance 553 22.8 Conclusion 554 References 555 23 The (Im)perfect Human – His Own Creator? Bioethics and Genetics at the Beginning of Life 561 Gebhard Fürst 23.1 Life Sciences and the Untouchable Human Being 563 23.2 Consequences from the Untouchability of Humans and Human Dignity for the Bioethical Discussion 564 23.3 Conclusion 567 References 570 Part V Outlook 571 24 The Future of Large-Scale Life Science Research 573 Christoph W. Sensen 24.1 Introduction 573 24.2 Evolution of the Hardware 574 24.2.1 DNA Sequencing as an Example 574 24.2.2 General Trends 574 24.2.3 Existing Hardware Will be Enhanced for more Throughput 575 24.2.4 The PC-style Computers that Run most Current Hardware will be Replaced with Web-based Computing 575 24.2.5 Integration of Machinery will Become Tighter 576 24.2.6 More and more Biological and Medical Machinery will be “Genomized” 576 24.3 Genomic Data and Data Handling 577 24.4 Next-generation Genome Research Laboratories 579 24.4.1 The Toolset of the Future 579 24.4.2 Laboratory Organization 581 24.5 Genome Projects of the Future 582 24.6 Epilog 583 Subject Index 585