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基因分子生物学(影印版)Molecular Biology of the Gene(6e)
  • 书号:9787030317612
    作者:(美)沃森(Watson,J.D.)等
  • 外文书名:
  • 装帧:平装
    开本:A4
  • 页数:841
    字数:1500000
    语种:en
  • 出版社:科学出版社
    出版时间:2011-07-01
  • 所属分类:Q34 遗传学分支学科 0710 生物学
  • 定价: ¥158.00元
    售价: ¥124.82元
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本书由6位生物学界著名专家合作编著,第一作者沃森(1962年诺贝尔医学或生理学奖获得者)系DNA双螺旋结构发现者、分子生物学科奠基人、人类基因组计划的发起者。本书自1965年第一版出版以来得到生物学界的广泛关注和认可,迄今已成为分子生物学经典教科书。第六版保持前几版的一贯特色:适用于分子生物学科需求;保持与学科进展的同步性,体现最新、最权威的学科知识。
  全书分为5大部分,合计22章,分别是:I.化学与遗传学(5章)——孟德尔世界,核酸遗传信息的传递,弱化学相互作用的重要性,高能键的重要性,弱键与强健决定的大分子结构。II.基因组的维系(6章)——DNA与RNA的结构,基因组结构、染色质与染色体,DNA复制,DNA突变与修复,分子水平的同源重组,位点特异性重组和DNA移位。III.基因组的表达(4章)——转录,RNA剪接,翻译,遗传密码。IV.调控(5章)——原核生物的转录调控,真核生物的转录调控,RNAs的调控,发育与进化中的基因调控,基因组学与系统生物学。V.研究方法(2章)——分子生物学技术,模式生物。
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目录

  • 目录
    PART 1 CHEMISTRY AND GENETICS, 1
    1 The Mendelian View of the World, 5
    2 Nucleic Acids Convey Genetic Information, 19
    3 The Importance of Weak Chemical Interactions, 43
    4 The Importance of High-Energy Bonds, 57
    5 Weak and Strong Bonds Determine Macromolecular Structure, 71
    PART 2 MAINTENANCE OF THE GENOME, 95
    6 The Structures of DNA and RNA, 101
    7 Genome Structure, Chromatin, and the Nucleosome, 135
    8 The Replication of DNA, 195
    9 The Mutability and Repair of DNA, 257
    10 Homologous Recombination at the Molecular Level, 283
    11 Site-Specific Recombination and Transposition of DNA, 319
    PART 3 EXPRESSION OF THE GENOME, 371
    12 Mechanisms of Transcription, 377
    13 RNA Splicing, 415
    14 Translation, 457
    15 The Genetic Code, 521
    PART 4 REGULATION, 541
    16 Transcriptional Regulation in Prokaryotes, 547
    17 Transcriptional Regulation in Eukaryotes, 589
    18 Regulatory RNAs, 633
    19 Gene Regulation in Development and Evolution, 661
    20 Genome Analysis and Systems Biology, 703
    PART 5 METHODS, 733
    20 Techniques of Molecular Biology, 739
    21 Model Organisms, 783
    Index, 819
    Detailed Contents
    PART 1 CHEMISTRY AND GENETICS, 1
    CHAPTER1 · The Mendelian View of the World, 5
    Mendel’s Discoveries, 6
    The Principle of Independent Segregation, 6
    ADVANCED CONCEPTS BOX 1-1 Mendelian Laws, 6
    Some Alleles Are neither Dominant nor Recessive, 8
    Principle of Independent Assortment, 8
    Chromosomal Theory of Heredity, 8
    Gene Linkage and Crossing Over, 9
    KEY EXPERIMENTS BOX 1-2 Genes Are Linked to Chromosomes, 10
    Chromosome Mapping, 12
    The Origin of Genetic Variability through Mutations, 15
    Early Speculations about What Genes Are and How They Act, 16
    Preliminary Attempts to Find a Gene–Protein Relationship, 16
    SUMMARY, 17
    BIBLIOGRAPHY, 18
    CHAPTER2 · Nucleic Acids Convey Genetic Information, 19
    Avery’s Bombshell: DNA Can Carry Genetic Specificity, 20
    Viral Genes Are Also Nucleic Acids, 21
    The Double Helix, 21
    Finding the Polymerases That Make DNA, 23
    KEY EXPERIMENTS BOX 2-1 Chargaff’s Rules, 24
    Experimental Evidence Favors Strand Separation during DNA Replication, 25
    The Genetic Information within DNA Is Conveyed by the Sequence of Its Four Nucleotide Building Blocks, 28
    KEY EXPERIMENTS BOX 2-2, Evidence That Genes Control Amino Acid Sequences in Proteins, 29
    DNA Cannot Be the Template That Directly Orders Amino Acids during Protein Synthesis, 30
    RNA Is Chemically Very Similar to DNA, 30
    The Central Dogma, 32
    The Adaptor Hypothesis of Crick, 32
    Discovery of Transfer RNA, 32
    The Paradox of the Nonspecific-Appearing Ribosomes, 33
    Discovery of Messenger RNA (mRNA), 34
    Enzymatic Synthesis of RNA upon DNA Templates, 35
    Establishing the Genetic Code, 36
    Establishing the Direction of Protein Synthesis, 38
    Start and Stop Signals Are Also Encoded within DNA, 39
    The Era of Genomics, 39
    SUMMARY, 40
    BIBLIOGRAPHY, 41
    CHAPTER3 · The Importance of Weak Chemical Interactions, 43
    Characteristics of Chemical Bonds, 43
    Chemical Bonds Are Explainable in Quantum-Mechanical Terms, 44
    Chemical-Bond Formation Involves a Change in the Form of Energy, 45
    Equilibrium between Bond Making and Breaking, 45
    The Concept of Free Energy, 46
    Keq Is Exponentially Related to ΔG, 46
    Covalent Bonds Are Very Strong, 46
    Weak Bonds in Biological Systems, 47
    Weak Bonds Have Energies between 1 and 7 kcal/mol, 47
    Weak Bonds Are Constantly Made and Broken at Physiological Temperatures, 47
    The Distinction between Polar and Nonpolar Molecules, 47
    van der Waals Forces, 48
    Hydrogen Bonds, 49
    Some Ionic Bonds Are Hydrogen Bonds, 50
    Weak Interactions Demand Complementary Molecular Surfaces, 51
    Water Molecules Form Hydrogen Bonds, 51
    Weak Bonds between Molecules in Aqueous Solutions, 51
    Organic Molecules That Tend to Form Hydrogen Bonds Are Water Soluble, 52
    ADVANCED CONCEPTS BOX 3-1 The Uniqueness of Molecular Shapes and the Concept of Selective Stickiness, 53
    Hydrophobic “Bonds” Stabilize Macromolecules, 54
    The Advantage of ΔG between 2 and 5 kcal/mole, 55
    Weak Bonds Attach Enzymes to Substrates, 55
    Weak Bonds Mediate Most Protein–DNA and Protein–Protein Interactions, 55
    SUMMARY, 56
    BIBLIOGRAPHY, 56
    CHAPTER4 · The Importance of High-Energy Bonds, 57
    Molecules That Donate Energy Are Thermodynamically Unstable, 57
    Enzymes Lower Activation Energies in Biochemical Reactions, 59
    Free Energy in Biomolecules, 60
    High-Energy Bonds Hydrolyze with Large Negative ΔG, 60
    High-Energy Bonds in Biosynthetic Reactions, 62
    Peptide Bonds Hydrolyze Spontaneously, 62
    Coupling of Negative with Positive ΔG, 63
    Activation of Precursors in Group Transfer Reactions, 63
    ATP Versatility in Group Transfer, 64
    Activation of Amino Acids by Attachment of AMP, 65
    Nucleic Acid Precursors Are Activated by the Presence of , 66
    The Value of ~ Release in Nucleic Acid Synthesis, 66
    Splits Characterize Most Biosynthetic Reactions, 67
    SUMMARY, 68
    BIBLIOGRAPHY, 69
    CHAPTER5 · Weak and Strong Bonds Determine Macromolecular Structure, 71
    Higher-Order Structures Are Determined by Intra- and Intermolecular Interactions, 71
    DNA Can Form a Regular Helix, 71
    RNA Forms a Wide Variety of Structures, 73
    Chemical Features of Protein Building Blocks, 73
    The Peptide Bond, 75
    There Are Four Levels of Protein Structure, 75
    α Helices and β Sheets Are the Common Forms of Secondary Structure, 76
    TECHNIQUES BOX 5-1 Determination of Protein Structure, 78
    The Specific Conformation of a Protein Results from Its Pattern of Hydrogen Bonds, 80
    α Helices Come Together to Form Coiled-Coils, 80
    Most Proteins Are Modular, Containing Two or Three Domains, 82
    Proteins Are Composed of a Surprisingly Small Number of Structural Motifs, 82
    ADVANCED CONCEPTS BOX 5-2 Large Proteins Are Often Constructed of Several Smaller Polypeptide Chains, 83
    Different Protein Functions Arise from Various Domain Combinations, 84
    Weak Bonds Correctly Position Proteins along DNA and RNA Molecules, 85
    Proteins Scan along DNA to Locate a Specific DNA-Binding Site, 87
    Diverse Strategies for Protein Recognition of RNA, 88
    Allostery: Regulation of a Protein’s Function by Changing Its Shape, 90
    The Structural Basis of Allosteric Regulation Is Known for Examples Involving Small Ligands, Protein–Protein Interactions, and Protein Modification, 90
    Not All Regulation of Proteins Is Mediated by Allosteric Events, 93
    SUMMARY, 93
    BIBLIOGRAPHY, 94
    PART2 MAINTENANCE OF THE GENOME, 95
    CHAPTER6 · The Structures of DNA and RNA, 101
    DNA Structure,102
    DNA Is Composed of Polynucleotide Chains, 102
    Each Base Has Its Preferred Tautomeric Form, 104
    The Two Strands of the Double Helix Are Held Together by Base Pairing in an Antiparallel Orientation, 105
    The Two Chains of the Double Helix Have Complementary Sequences, 106
    Hydrogen Bonding Is Important for the Specificity of Base Pairing, 106
    Bases Can Flip Out from the Double Helix, 107
    DNA Is Usually a Right-Handed Double Helix, 107
    The Double Helix Has Minor and Major Grooves, 108
    KEY EXPERIMENTS BOX 6-1 DNA Has 10.5 Base Pairs per Turn of the Helix in Solution: The Mica Experiment, 108
    The Major Groove Is Rich in Chemical Information, 109
    The Double Helix Exists in Multiple Conformations, 110
    KEY EXPERIMENTS BOX 6-2 How Spots on an X-ray Film Reveal the Structure of DNA, 112
    DNA Can Sometimes Form a Left-Handed Helix, 113
    DNA Strands Can Separate (Denature) and Reassociate, 113
    Some DNA Molecules Are Circles, 116
    DNA Topology, 117
    Linking Number Is an Invariant Topological Property of Covalently Closed, Circular DNA, 117
    Linking Number Is Composed of Twist and Writhe, 117
    Lk0 Is the Linking Number of Fully Relaxed cccDNA under Physiological Conditions, 119
    DNA in Cells Is Negatively Supercoiled, 120
    Nucleosomes Introduce Negative Supercoiling in Eukaryotes, 120
    Topoisomerases Can Relax Supercoiled DNA, 121
    Prokaryotes Have a Special Topoisomerase That Introduces Supercoils into DNA, 121
    Topoisomerases Also Unknot and Disentangle DNA Molecules, 121
    Topoisomerases Use a Covalent Protein–DNA Linkage to Cleave and Rejoin DNA Strands, 123
    Topoisomerases Form an Enzyme Bridge and Pass DNA Segments through Each Other, 123
    DNA Topoisomers Can Be Separated by Electrophoresis, 125
    Ethidium Ions Cause DNA to Unwind, 126
    RNA Structure, 127
    RNA Contains Ribose and Uracil and Is Usually Single-Stranded, 127
    RNA Chains Fold Back on Themselves to Form Local Regions of Double Helix Similar to A-Form DNA, 127
    KEY EXPERIMENTS BOX 6-3 Proving that DNA Has a Helical Periodicity of about 10.5 Base Pairs per Turn from the Topological Properties of DNA Rings, 128
    RNA Can Fold Up into Complex Tertiary Structures, 129
    Some RNAs Are Enzymes, 130
    The Hammerhead Ribozyme Cleaves RNA by the Formation of a 2′, 3′ Cyclic Phosphate, 131
    Did Life Evolve from an RNA World?, 132
    SUMMARY, 132
    BIBLIOGRAPHY, 133
    CHAPTER7 · Genome Structure, Chromatin, and the Nucleosome, 135
    Genome Sequence and Chromosome Diversity, 136
    Chromosomes Can Be Circular or Linear, 136
    Every Cell Maintains a Characteristic Number of Chromosomes, 137
    Genome Size Is Related to the Complexity of the Organism, 139
    The E. coli Genome Is Composed Almost Entirely of Genes, 140
    More Complex Organisms Have Decreased Gene Density, 140
    Genes Make Up Only a Small Proportion of the Eukaryotic Chromosomal DNA, 141
    The Majority of Human Intergenic Sequences Are Composed of Repetitive DNA, 143
    Chromosome Duplication and Segregation, 144
    Eukaryotic Chromosomes Require Centromeres, Telomeres, and Origins of Replication to Be Maintained during Cell Division, 144
    Eukaryotic Chromosome Duplication and Segregation Occur in Separate Phases of the Cell Cycle, 147
    Chromosome Structure Changes as Eukaryotic Cells Divide, 149
    Sister-Chromatid Cohesion and Chromosome Condensation Are Mediated by SMC Proteins, 150
    Mitosis Maintains the Parental Chromosome Number, 152
    During Gap Phases, Cells Prepare for the Next Cell Cycle Stage and Check That the Previous Stage Is Completed Correctly, 152
    Meiosis Reduces the Parental Chromosome Number, 154
    Different Levels of Chromosome Structure Can Be Observed by Microscopy, 156
    The Nucleosome, 157
    Nucleosomes Are the Building Blocks of Chromosomes, 157
    KEY EXPERIMENTS BOX 7-1 Micrococcal Nuclease and the DNA Associated with the Nucleosome, 158
    Histones Are Small, Positively Charged Proteins, 159
    The Atomic Structure of the Nucleosome, 160
    Histones Bind Characteristic Regions of DNA within the Nucleosome, 162
    Many DNA Sequence–Independent Contacts Mediate the Interaction between the Core Histones and DNA, 162
    The Histone Amino-Terminal Tails Stabilize DNA Wrapping around the Octamer, 165
    Wrapping of the DNA around the Histone Protein Core Stores Negative Superhelicity, 166
    KEY EXPERIMENTS BOX 7-2 Nucleosomes and Superhelical Density, 166
    Higher-Order Chromatin Structure, 169
    Heterochromatin and Euchromatin, 169
    Histone H1 Binds to the Linker DNA between Nucleosomes, 169
    Nucleosome Arrays Can Form More Complex Structures: The 30-nm Fiber, 170
    The Histone Amino-Terminal Tails Are Required for the Formation of the 30-nm Fiber, 172
    Further Compaction of DNA Involves Large Loops of Nucleosomal DNA, 172
    Histone Variants Alter Nucleosome Function, 174
    Regulation of Chromatin Structure, 174
    The Interaction of DNA with the Histone Octamer Is Dynamic, 174
    Nucleosome-Remodeling Complexes Facilitate Nucleosome Movement, 175
    Some Nucleosomes Are Found in Specific Positions: Nucleosome Positioning, 179
    KEY EXPERIMENTS BOX 7-3 Determining Nucleosome Position in the Cell, 180
    Modification of the Amino-Terminal Tails of the Histones Alters Chromatin Accessibility, 182
    Protein Domains in Nucleosome-Remodeling and -Modifying Complexes Recognize Modified Histones, 184
    Specific Enzymes Are Responsible for Histone Modification, 185
    Nucleosome Modification and Remodeling Work Together to Increase DNA Accessibility, 186
    Nucleosome Assembly, 187
    Nucleosomes Are Assembled Immediately after DNA Replication, 187
    Assembly of Nucleosomes Requires Histone “Chaperones,” 189
    SUMMARY, 192
    BIBLIOGRAPHY, 193
    CHAPTER8 · The Replication of DNA, 195
    The Chemistry of DNA Synthesis, 196
    DNA Synthesis Requires Deoxynucleoside Triphosphates and a Primer:Template Junction, 196
    DNA Is Synthesized by Extending the 3′ End of the Primer, 197
    Hydrolysis of Pyrophosphate Is the Driving Force for DNA Synthesis, 198
    The Mechanism of DNA Polymerase, 198
    DNA Polymerases Use a Single Active Site to Catalyze DNA Synthesis, 198
    TECHNIQUES BOX 8-1 Incorporation Assays Can Be Used to Measure Nucleic Acid and Protein Synthesis, 200
    DNA Polymerases Resemble a Hand That Grips the Primer:Template Junction, 202
    MEDICAL CONNECTIONS BOX 8-2 Anticancer and Antiviral Agents Target DNA Replication, 203
    DNA Polymerases Are Processive Enzymes, 207
    Exonucleases Proofread Newly Synthesized DNA, 208
    The Replication Fork, 209
    Both Strands of DNA Are Synthesized Together at the Replication Fork, 209
    The Initiation of a New Strand of DNA Requires an RNA Primer, 210
    RNA Primers Must Be Removed to Complete DNA Replication, 211
    DNA Helicases Unwind the Double Helix in Advance of the Replication Fork, 211
    TECHNIQUES BOX 8-3 Determining the Polarity of a DNA Helicase, 212
    DNA Helicase Pulls Single-Stranded DNA through a Central Protein Pore, 214
    Single-Stranded DNA-Binding Proteins Stabilize ssDNA prior to Replication, 215
    Topoisomerases Remove Supercoils Produced by DNA Unwinding at the Replication Fork, 216
    Replication Fork Enzymes Extend the Range of DNA Polymerase Substrates, 217
    The Specialization of DNA Polymerases, 218
    DNA Polymerases Are Specialized for Different Roles in the Cell, 218
    Sliding Clamps Dramatically Increase DNA Polymerase Processivity, 219
    Sliding Clamps Are Opened and Placed on DNA by Clamp Loaders, 222
    ADVANCED CONCEPTS BOX 8-4 ATP Control of Protein Function: Loading a Sliding Clamp, 223
    DNA Synthesis at the Replication Fork, 225
    Interactions between Replication Fork Proteins Form the E. coli Replisome, 228
    Initiation of DNA Replication, 230
    Specific Genomic DNA Sequences Direct the Initiation of DNA Replication, 230
    The Replicon Model of Replication Initiation, 230
    Replicator Sequences Include Initiator Binding Sites and Easily Unwound DNA, 231
    KEY EXPERIMENTS BOX 8-5 The Identification of Origins of Replication and Replicators, 232
    Binding and Unwinding: Origin Selection and Activation by the Initiator Protein, 235
    Protein–Protein and Protein–DNA Interactions Direct the Initiation Process, 235
    ADVANCED CONCEPTS BOX 8-6 The Replication Factory Hypothesis, 237
    Eukaryotic Chromosomes Are Replicated Exactly Once per Cell Cycle, 239
    Prereplicative Complex Formation Is the First Step in the Initiation of Replication in Eukaryotes, 240
    Pre-RC Formation and Activation Are Regulated to Allow Only a Single Round of Replication during Each Cell Cycle, 241
    Similarities between Eukaryotic and Prokaryotic DNA Replication Initiation, 244
    ADVANCED CONCEPTS BOX 8-7 E. coli DNA Replication Is Regulated by DnaA·ATP Levels and SeqA, 244
    Finishing Replication, 246
    Type II Topoisomerases Are Required to Separate Daughter DNA Molecules, 246
    Lagging-Strand Synthesis Is Unable to Copy the Extreme Ends of Linear Chromosomes, 247
    Telomerase Is a Novel DNA Polymerase That Does Not Require an Exogenous Template, 248
    Telomerase Solves the End Replication Problem by Extending the 3′ End of the Chromosome, 250
    MEDICAL CONNECTIONS BOX 8-8 Aging, Cancer, and the Telomere Hypothesis, 251
    Telomere-Binding Proteins Regulate Telomerase Activity and Telomere Length, 252
    Telomere-Binding Proteins Protect Chromosome Ends, 253
    SUMMARY, 255
    BIBLIOGRAPHY, 256
    CHAPTER9 · The Mutability and Repair of DNA, 257
    Replication Errors and Their Repair, 258
    The Nature of Mutations, 258
    Some Replication Errors Escape Proofreading, 259
    MEDICAL CONNECTIONS BOX 9-1 Expansion of Triple Repeats Causes Disease, 259
    Mismatch Repair Removes Errors That Escape Proofreading, 260
    DNA Damage, 265
    DNA Undergoes Damage Spontaneously from Hydrolysis and Deamination, 265
    DNA Is Damaged by Alkylation, Oxidation, and Radiation, 265
    MEDICAL CONNECTIONS BOX 9-2 The Ames Test, 266
    Mutations Are Also Caused by Base Analogs and Intercalating Agents, 268
    Repair of DNA Damage, 269
    Direct Reversal of DNA Damage, 270
    Base Excision Repair Enzymes Remove Damaged Bases by a Base-Flipping Mechanism, 270
    Nucleotide Excision Repair Enzymes Cleave Damaged DNA on Either Side of the Lesion, 273
    Recombination Repairs DNA Breaks by Retrieving Sequence Information from Undamaged DNA, 275
    DSBs in DNA Are Also Repaired by Direct Joining of Broken Ends, 275
    MEDICAL CONNECTIONS BOX 9-3 Nonhomologous End Joining, 276
    Translesion DNA Synthesis Enables Replication to Proceed across DNA Damage, 278
    ADVANCED CONCEPTS BOX 9-4 The Y Family of DNA Polymerases, 280
    SUMMARY, 281
    BIBLIOGRAPHY, 282
    CHAPTER10 · Homologous Recombination at the Molecular Level, 283
    DNA Breaks Are Common and Initiate Recombination, 284
    Models for Homologous Recombination, 284
    Strand Invasion Is a Key Early Step in Homologous Recombination, 286
    Resolving Holliday Junctions Is a Key Step to Finishing Genetic Exchange, 288
    The Double-Strand Break–Repair Model Describes Many Recombination Events, 288
    Homologous Recombination Protein Machines, 291
    ADVANCED CONCEPTS BOX 10-1 How to Resolve a Recombination Intermediate with Two Holliday Junctions, 292
    The RecBCD Helicase/Nuclease Processes Broken DNA Molecules for Recombination, 293
    Chi Sites Control RecBCD, 296
    RecA Protein Assembles on Single-Stranded DNA and Promotes Strand Invasion, 297
    Newly Base-Paired Partners Are Established within the RecA Filament, 299
    RecA Homologs Are Present in All Organisms, 301
    The RuvAB Complex Specifically Recognizes Holliday Junctions and Promotes Branch Migration, 301
    RuvC Cleaves Specific DNA Strands at the Holliday Junction to Finish Recombination, 302
    Homologous Recombination in Eukaryotes, 303
    Homologous Recombination Has Additional Functions in Eukaryotes, 303
    Homologous Recombination Is Required for Chromosome Segregation during Meiosis, 304
    Programmed Generation of Double-Stranded DNA Breaks Occurs during Meiosis, 305
    MRX Protein Processes the Cleaved DNA Ends for Assembly of the RecA-like Strand-Exchange Proteins, 307
    Dmc1 Is a RecA-like Protein That Specifically Functions in Meiotic Recombination, 308
    Many Proteins Function Together to Promote Meiotic Recombination, 308
    MEDICAL CONNECTIONS BOX 10-2 The Product of the Tumor Suppressor Gene BRCA2 Interacts with Rad51 Protein and Controls Genome Stability, 309
    Mating-Type Switching, 310
    Mating-Type Switching Is Initiated by a Site-Specific Double- Strand Break, 311
    Mating-Type Switching Is a Gene Conversion Event and Not Associated with Crossing Over, 312
    Genetic Consequences of the Mechanism of Homologous Recombination, 314
    One Cause of Gene Conversion Is DNA Repair during Recombination, 315
    SUMMARY, 316
    BIBLIOGRAPHY, 317
    CHAPTER11 · Site-Specific Recombination and Transposition of DNA, 319
    Conservative Site-Specific Recombination, 320
    Site-Specific Recombination Occurs at Specific DNA
    Sequences in the Target DNA, 320
    Site-Specific Recombinases Cleave and Rejoin DNA Using a Covalent Protein–DNA Intermediate, 322
    Serine Recombinases Introduce Double-Strand Breaks in DNA and Then Swap Strands to Promote Recombination, 324
    Structure of the Serine Recombinase–DNA Complex Indicates That Subunits Rotate to Achieve Strand Exchange, 325
    Tyrosine Recombinases Break and Rejoin One Pair of DNA Strands at a Time, 326
    Structures of Tyrosine Recombinases Bound to DNA Reveal the Mechanism of DNA Exchange, 327
    MEDICAL CONNECTIONS BOX 11-1 Application of Site-Specific Recombination to Genetic Engineering, 327
    Biological Roles of Site-Specific Recombination, 328
    λ Integrase Promotes the Integration and Excision of a Viral Genome into the Host-Cell Chromosome, 329
    Bacteriophage λ Excision Requires a New DNA-Bending Protein, 331
    The Hin Recombinase Inverts a Segment of DNA Allowing Expression of Alternative Genes, 331
    Hin Recombination Requires a DNA Enhancer, 332
    Recombinases Convert Multimeric Circular DNA Molecules into Monomers, 333
    There Are Other Mechanisms to Direct Recombination to Specific Segments of DNA, 334
    Transposition, 334
    Some Genetic Elements Move to New Chromosomal Locations by Transposition, 334
    ADVANCED CONCEPTS BOX 11-2 The Xer Recombinase Catalyzes the Monomerization of Bacterial Chromosomes and of Many Bacterial Plasmids, 335
    There Are Three Principal Classes of Transposable Elements, 338
    DNA Transposons Carry a Transposase Gene, Flanked by Recombination Sites, 339
    Transposons Exist as Both Autonomous and Nonautonomous Elements, 339
    Virus-like Retrotransposons and Retroviruses Carry Terminal Repeat Sequences and Two Genes
    Important for Recombination, 340
    Poly-A Retrotransposons Look Like Genes, 340
    DNA Transposition by a Cut-and-Paste Mechanism, 340
    The Intermediate in Cut-and-Paste Transposition Is Finished by Gap Repair, 342
    There Are Multiple Mechanisms for Cleaving the Nontransferred Strand during DNA Transposition, 343
    DNA Transposition by a Replicative Mechanism, 345
    Virus-like Retrotransposons and Retroviruses Move Using an RNA Intermediate, 347
    ADVANCED CONCEPTS BOX 11-3 The Pathway of Retroviral cDNA Formation, 349
    DNA Transposases and Retroviral Integrases Are Members of a Protein Superfamily, 351
    Poly-A Retrotransposons Move by a “Reverse Splicing” Mechanism, 352
    Examples of Transposable Elements and Their Regulation, 354
    IS4-Family Transposons Are Compact Elements with Multiple Mechanisms for Copy Number Control, 355
    KEY EXPERIMENTS BOX 11-4 Maize Elements and the Discovery of Transposons, 356
    Tn10 Transposition Is Coupled to Cellular DNA Replication, 358
    Phage Mu Is an Extremely Robust Transposon, 359
    Mu Uses Target Immunity to Avoid Transposing into Its Own DNA, 359
    ADVANCED CONCEPTS BOX 11-5 Mechanism of Transposition Target Immunity, 361
    Tc1/mariner Elements Are Extremely Successful DNA Elements in Eukaryotes, 362
    Yeast Ty Elements Transpose into Safe Havens in the Genome, 362
    LINEs Promote Their Own Transposition and Even Transpose Cellular RNAs, 363
    V(D)J Recombination, 365
    The Early Events in V(D)J Recombination Occur by a Mechanism Similar to Transposon Excision, 367
    SUMMARY, 369
    BIBLIOGRAPHY, 369
    EXPRESSION OF THE GENOME, 371
    CHAPTER12 · Mechanisms of Transcription, 377
    RNA Polymerases and the Transcription Cycle, 378
    RNA Polymerases Come in Different Forms but Share Many Features, 378
    Transcription by RNA Polymerase Proceeds in a Series of Steps, 380
    Transcription Initiation Involves Three Defined Steps, 382
    The Transcription Cycle in Bacteria, 383
    Bacterial Promoters Vary in Strength and Sequence but Have Certain Defining Features, 383
    The σ Factor Mediates Binding of Polymerase to the Promoter, 384
    Transition to the Open Complex Involves Structural Changes in RNA Polymerase and in the Promoter DNA, 386
    TECHNIQUES BOX 12-1 Consensus Sequences, 388
    Transcription Is Initiated by RNA Polymerase without the Need for a Primer, 388
    During Initial Transcription, RNA Polymerase Remains Stationary and Pulls Downstream DNA into Itself, 389
    Promoter Escape Involves Breaking Polymerase–Promoter Interactions and Polymerase Core–σ Interactions, 390
    The Elongating Polymerase Is a Processive Machine That Synthesizes and Proofreads RNA, 391
    ADVANCED CONCEPTS BOX 12-2 The Single-Subunit RNA Polymerases, 393
    RNA Polymerase Can Become Arrested and Need Removing, 394
    Transcription Is Terminated by Signals within the RNA Sequence, 394
    Transcription in Eukaryotes, 396
    RNA Polymerase II Core Promoters Are Made Up of Combinations of Four Different Sequence Elements, 397
    RNA Polymerase II Forms a Preinitiation Complex with General Transcription Factors at the Promoter, 398
    Promoter Escape Requires Phosphorylation of the Polymerase “Tail,” 398
    TBP Binds to and Distorts DNA Using a β Sheet Inserted into the Minor Groove, 400
    The Other General Transcription Factors Also Have Specific Roles in Initiation, 401
    In Vivo, Transcription Initiation Requires Additional Proteins, Including the Mediator Complex, 402
    Mediator Consists of Many Subunits, Some Conserved from Yeast to Human, 403
    A New Set of Factors Stimulate Pol II Elongation and RNA Proofreading, 404
    Elongating RNA Polymerase Must Deal with Histones in Its Path, 405
    Elongating Polymerase Is Associated with a New Set of Protein Factors Required for Various Types of RNA Processing, 406
    Transcription Termination Is Linked to RNA Destruction by a Highly Processive RNase, 410
    Transcription by RNA Polymerases I and III, 410
    RNA Pol I and Pol III Recognize Distinct Promoters, Using Distinct Sets of Transcription Factors, but Still Require TBP, 410
    Pol III Promoters Are Found Downstream of Transcription Start Site, 412
    SUMMARY, 413
    BIBLIOGRAPHY, 414
    CHAPTER13 · RNA Splicing, 415
    The Chemistry of RNA Splicing, 417
    Sequences within the RNA Determine Where Splicing Occurs, 417
    The Intron Is Removed in a Form Called a Lariat as the Flanking Exons Are Joined, 418
    KEY EXPERIMENTS BOX 13-1 Adenovirus and the Discovery of Splicing, 419
    Exons from Different RNA Molecules Can Be Fused by trans-Splicing, 421
    The Spliceosome Machinery, 422
    RNA Splicing Is Carried Out by a Large Complex Called the Spliceosome, 422
    Splicing Pathways, 424
    Assembly, Rearrangements, and Catalysis within the Spliceosome: The Splicing Pathway, 424
    Self-Splicing Introns Reveal That RNA Can Catalyze RNA Splicing, 426
    Group I Introns Release a Linear Intron Rather Than a Lariat, 426
    KEY EXPERIMENTS BOX 13-2 Converting Group I Introns into Ribozymes, 428
    How Does the Spliceosome Find the Splice Sites Reliably?, 430
    A Small Group of Introns Are Spliced by an Alternative Spliceosome Composed of a Different Set of snRNPs, 432
    Alternative Splicing, 432
    Single Genes Can Produce Multiple Products by Alternative Splicing, 432
    Several Mechanisms Exist to Ensure Mutually Exclusive Splicing, 435
    The Curious Case of the Drosophila Dscam Gene: Mutually Exclusive Splicing on a Grand Scale, 436
    Mutually Exclusive Splicing of Dscam Exon 6 Cannot Be Accounted for by Any Standard Mechanism and Instead Uses a Novel Strategy, 437
    Alternative Splicing Is Regulated by Activators and Repressors, 439
    Regulation of Alternative Splicing Determines the Sex of Flies, 441
    KEY EXPERIMENTS BOX 13-3 Identification of Docking Site and Selector Sequences, 442
    MEDICAL CONNECTIONS BOX 13-4 Defects in Pre-mRNA Splicing Cause Human Disease, 445
    Exon Shuffling, 446
    Exons Are Shuffled by Recombination to Produce Genes Encoding New Proteins, 446
    RNA Editing, 448
    RNA Editing Is Another Way of Altering the Sequence of an mRNA, 448
    Guide RNAs Direct the Insertion and Deletion of Uridines, 450
    MEDICAL CONNECTIONS BOX 13-5 Deaminases and HIV, 450
    mRNA Transport, 452
    Once Processed, mRNA Is Packaged and Exported from the Nucleus into the Cytoplasm for Translation, 452
    SUMMARY, 454
    BIBLIOGRAPHY, 455
    CHAPTER14 · Translation, 457
    Messenger RNA, 458
    Polypeptide Chains Are Specified by Open Reading Frames, 458
    Prokaryotic mRNAs Have a Ribosome-Binding Site That Recruits the Translational Machinery, 459
    Eukaryotic mRNAs Are Modified at Their 5′ and 3′ Ends to Facilitate Translation, 460
    Transfer RNA, 461
    tRNAs Are Adaptors between Codons and Amino Acids, 461
    ADVANCED CONCEPTS BOX 14-1 CCA-Adding Enzymes: Synthesizing RNA without a Template, 462
    tRNAs Share a Common Secondary Structure That Resembles a Cloverleaf, 462
    tRNAs Have an L-shaped Three-Dimensional Structure, 463
    Attachment of Amino Acids to tRNA, 464
    tRNAs Are Charged by the Attachment of an Amino Acid to the 3′-Terminal Adenosine Nucleotide via a High-Energy Acyl Linkage, 464
    Aminoacyl-tRNA Synthetases Charge tRNAs in Two Steps, 464
    Each Aminoacyl-tRNA Synthetase Attaches a Single Amino Acid to One or More tRNAs, 466
    tRNA Synthetases Recognize Unique Structural Features of Cognate tRNAs, 466
    Aminoacyl-tRNA Formation Is Very Accurate, 468
    Some Aminoacyl-tRNA Synthetases Use an Editing Pocket to Charge tRNAs with High Accuracy, 468
    The Ribosome Is Unable to Discriminate between Correctly and Incorrectly Charged tRNAs, 469
    The Ribosome, 469
    ADVANCED CONCEPTS BOX 14-2 Selenocysteine, 470
    The Ribosome Is Composed of a Large and a Small Subunit, 471
    The Large and Small Subunits Undergo Association and Dissociation during Each Cycle of
    Translation, 472
    New Amino Acids Are Attached to the Carboxyl Terminus of the Growing Polypeptide Chain, 474
    Peptide Bonds Are Formed by Transfer of the Growing Polypeptide Chain from One tRNA to Another, 474
    Ribosomal RNAs Are Both Structural and Catalytic Determinants of the Ribosome, 475
    The Ribosome Has Three Binding Sites for tRNA, 475
    Channels through the Ribosome Allow the mRNA and Growing Polypeptide to Enter and/or Exit the Ribosome, 476
    Initiation of Translation, 479
    Prokaryotic mRNAs Are Initially Recruited to the Small Subunit by Base Pairing to rRNA, 480
    A Specialized tRNA Charged with a Modified Methionine Binds Directly to the Prokaryotic Small Subunit, 480
    Three Initiation Factors Direct the Assembly of an Initiation Complex That Contains mRNA and the Initiator tRNA, 481
    Eukaryotic Ribosomes Are Recruited to the mRNA by the 5′ Cap, 482
    The Start Codon Is Found by Scanning Downstream from the 5′ End of the mRNA, 483
    ADVANCED CONCEPTS BOX 14-3 uORFs and IRESs: Exceptions That Prove the Rule, 485
    Translation Initiation Factors Hold Eukaryotic mRNAs in Circles, 487
    Translation Elongation, 487
    Aminoacyl-tRNAs Are Delivered to the A Site by Elongation Factor EF-Tu, 488
    The Ribosome Uses Multiple Mechanisms to Select against Incorrect Aminoacyl-tRNAs, 488
    The Ribosome Is a Ribozyme, 491
    Peptide Bond Formation and the Elongation Factor EF-G Drive Translocation of the tRNAs and the mRNA, 492
    EF-G Drives Translocation by Displacing the tRNA Bound to the A Site, 494
    EF-Tu–GDP and EF-G–GDP Must Exchange GDP for GTP prior to Participating in a New Round of Elongation, 495
    A Cycle of Peptide Bond Formation Consumes Two Molecules of GTP and One Molecule of ATP, 495
    Termination of Translation, 496
    Release Factors Terminate Translation in Response to Stop Codons, 496
    Short Regions of Class I Release Factors Recognize Stop Codons and Trigger Release of the Peptidyl Chain, 496
    ADVANCED CONCEPTS BOX 14-4 GTP-Binding Proteins, Conformational Switching, and the Fidelity and Ordering of the Events of Translation, 498
    GDP/GTP Exchange and GTP Hydrolysis Control the Function of the Class II Release Factor, 499
    The Ribosome Recycling Factor Mimics a tRNA, 500
    MEDICAL CONNECTIONS BOX 14-5 Antibiotics Arrest Cell Division by Blocking Specific Steps in Translation, 502
    Regulation of Translation, 503
    Protein or RNA Binding Near the Ribosome-Binding Site Negatively Regulates Bacterial Translation Initiation, 504
    Regulation of Prokaryotic Translation: Ribosomal Proteins Are Translational Repressors of Their Own Synthesis, 505
    Global Regulators of Eukaryotic Translation Target Key Factors Required for mRNA Recognition and Initator tRNA Ribosome Binding, 508
    Spatial Control of Translation by mRNA-Specific 4E-BPs, 510
    An Iron-Regulated, RNA-Binding Protein Controls Translation of Ferritin, 511
    Translation of thet Yeast Transcriptional Activator Gcn4 Is Controlled by Short Upstream ORFs and Ternary Complex Abundance, 512
    Translation-Dependent Regulation of mRNA and Protein Stability, 514
    The SsrA RNA Rescues Ribosomes That Translate Broken mRNAs, 514
    Eukaryotic Cells Degrade mRNAs That Are Incomplete or Have Premature Stop Codons, 516
    SUMMARY, 518
    BIBLIOGRAPHY, 519
    CHAPTER15 · The Genetic Code, 521
    The Code Is Degenerate, 521
    Perceiving Order in the Makeup of the Code, 522
    Wobble in the Anticodon, 523
    Three Codons Direct Chain Termination, 525
    How the Code Was Cracked, 525
    Stimulation of Amino Acid Incorporation by Synthetic mRNAs, 526
    Poly-U Codes for Polyphenylalanine, 527
    Mixed Copolymers Allowed Additional Codon Assignments, 527
    Transfer RNA Binding to Defined Trinucleotide Codons, 528
    Codon Assignments from Repeating Copolymers, 529
    Three Rules Govern the Genetic Code, 530
    Three Kinds of Point Mutations Alter the Genetic Code, 531
    Genetic Proof That the Code Is Read in Units of Three, 532
    Suppressor Mutations Can Reside in the Same or a Different Gene, 532
    Intergenic Suppression Involves Mutant tRNAs, 533
    Nonsense Suppressors Also Read Normal Termination Signals, 535
    Proving the Validity of the Genetic Code, 535
    The Code Is Nearly Universal, 536
    SUMMARY, 538
    BIBLIOGRAPHY, 538
    REGULATION, 541
    PART4 REGULATION, 541
    CHAPTER16 · Transcriptional Regulation in Prokaryotes, 547
    Principles of Transcriptional Regulation, 547
    Gene Expression Is Controlled by Regulatory Proteins, 547
    Most Activators and Repressors Act at the Level of Transcription Initiation, 548
    Many Promoters Are Regulated by Activators That Help RNA Polymerase Bind DNA and by Repressors That Block That Binding, 548
    Some Activators and Repressors Work by Allostery and Regulate Steps in Transcriptional Initiation after RNA Polymerase Binding, 550
    Action at a Distance and DNA Looping, 551
    Cooperative Binding and Allostery Have Many Roles in Gene Regulation, 552
    Antitermination and Beyond: Not All of Gene Regulation Targets Transcription Initiation, 552
    Regulation of Transcription Initiation: Examples from Prokaryotes, 553
    An Activator and a Repressor Together Control the lac Genes, 553
    CAP and Lac Repressor Have Opposing Effects on RNA Polymerase Binding to the lac Promoter, 554
    CAP Has Separate Activating and DNA-Binding Surfaces, 555
    CAP and Lac Repressor Bind DNA Using a Common Structural Motif, 556
    KEY EXPERIMENTS BOX 16-1 Activator Bypass Experiments, 557
    The Activities of Lac Repressor and CAP Are Controlled Allosterically by Their Signals, 559
    Combinatorial Control: CAP Controls Other Genes As Well, 560
    KEY EXPERIMENTS BOX 16-2 Jacob, Monod, and the Ideas Behind Gene Regulation, 561
    Alternative σ Factors Direct RNA Polymerase to Alternative Sets of Promoters, 563
    NtrC and MerR: Transcriptional Activators That Work by Allostery Rather than by Recruitment, 564
    NtrC Has ATPase Activity and Works from DNA Sites Far from the Gene, 564
    MerR Activates Transcription by Twisting Promoter DNA, 565
    Some Repressors Hold RNA Polymerase at the Promoter Rather than Excluding It, 566
    AraC and Control of the araBAD Operon by Antiactivation, 567
    The Case of Bacteriophage λ: Layers of Regulation, 568
    Alternative Patterns of Gene Expression Control Lytic and Lysogenic Growth, 569
    Regulatory Proteins and Their Binding Sites, 570
    λ Repressor Binds to Operator Sites Cooperatively, 571
    ADVANCED CONCEPTS BOX 16-3 Concentration, Affinity, and Cooperative Binding, 572
    Repressor and Cro Bind in Different Patterns to Control Lytic and Lysogenic Growth, 573
    Lysogenic Induction Requires Proteolytic Cleavage of λ Repressor, 574
    Negative Autoregulation of Repressor Requires Long- Distance Interactions and a Large DNA Loop, 575
    Another Activator, λ CII, Controls the Decision between Lytic and Lysogenic Growth upon Infection of a New Host, 577
    The Number of Phage Particles Infecting a Given Cell Affects Whether the Infection Proceeds Lytically or Lysogenically, 578
    Growth Conditions of E. coli Control the Stability of CII Protein and thus the Lytic/Lysogenic Choice, 578
    KEY EXPERIMENTS BOX 16-4 Evolution of the λ Switch, 579
    KEY EXPERIMENTS BOX 16-5 Genetic Approaches That Identified Genes Involved in the Lytic/Lysogenic Choice, 581
    Transcriptional Antitermination in λ Development, 582
    Retroregulation: An Interplay of Controls on RNA Synthesis and Stability Determines int Gene Expression, 584
    SUMMARY, 585
    BIBLIOGRAPHY, 586
    CHAPTER17 · Transcriptional Regulation in Eukaryotes, 589
    Conserved Mechanisms of Transcriptional Regulation from Yeast to Mammals, 591
    Activators Have Separate DNA-Binding and Activating Functions, 591
    Eukaryotic Regulators Use a Range of DNA-Binding Domains, but DNA Recognition Involves the Same Principles as Found in Bacteria, 593
    TECHNIQUES BOX 17-1 The Two-Hybrid Assay, 594
    Activating Regions Are Not Well-Defined Structures, 596
    Recruitment of Protein Complexes to Genes by Eukaryotic Activators, 597
    Activators Recruit the Transcriptional Machinery to the Gene, 597
    Activators Also Recruit Nucleosome Modifiers That Help the Transcriptional Machinery Bind at the Promoter or Initiate Transcription, 598
    Activators Recruit an Additional Factor Needed for Efficient Initiation or Elongation at Some Promoters, 600
    Action at a Distance: Loops and Insulators, 601
    Appropriate Regulation of Some Groups of Genes Requires Locus Control Regions, 603
    KEY EXPERIMENTS BOX 17-2 Long-Distance Interactions on the Same and Different Chromosomes, 604
    Signal Integration and Combinatorial Control, 605
    Activators Work Synergistically to Integrate Signals, 605
    Signal Integration: The HO Gene Is Controlled by Two Regulators—One Recruits Nucleosome Modifiers and the Other Recruits Mediator, 607
    Signal Integration: Cooperative Binding of Activators at the Human β-Interferon Gene, 608
    Combinatorial Control Lies at the Heart of the Complexity and Diversity of Eukaryotes, 610
    Combinatorial Control of the Mating-Type Genes from S. cerevisiae, 611
    KEY EXPERIMENTS BOX 17-3 Evolvability of a Regulatory Circuit, 612
    Transcriptional Repressors, 613
    Signal Transduction and the Control of Transcriptional Regulators, 615
    Signals Are Often Communicated to Transcriptional Regulators through Signal Transduction Pathways, 615
    Signals Control the Activities of Eukaryotic Transcriptional Regulators in a Variety of Ways, 617
    Activators and Repressors Sometimes Come in Pieces, 619
    Gene “Silencing” by Modification of Histones and DNA, 620
    Silencing in Yeast Is Mediated by Deacetylation and Methylation of Histones, 621
    In Drosophila, HP1 Recognizes Methylated Histones and Condenses Chromatin, 622
    ADVANCED CONCEPTS BOX 17-4 Is There a Histone Code?, 623
    DNA Methylation Is Associated with Silenced Genes in Mammalian Cells, 624
    MEDICAL CONNECTIONS BOX 17-5 Transcriptional Repression and Human Disease, 626
    Epigenetic Gene Regulation, 626
    Some States of Gene Expression Are Inherited through Cell Division Even When the Initiating Signal Is No Longer Present, 627
    MEDICAL CONNECTIONS BOX 17-6 Using Transcription Factors to Reprogram Somatic Cells into Embryonic Stem Cells, 629
    SUMMARY, 630
    BIBLIOGRAPHY, 631
    CHAPTER18 · Regulatory RNAs, 633
    Regulation by RNAs in Bacteria, 633
    Riboswitches Reside within the Transcripts of Genes Whose Expression They Control through Changes in Secondary Structure, 635
    ADVANCED CONCEPTS BOX 18-1 Amino Acid Biosynthetic Operons Are Controlled by Attenuation, 639
    RNA Interference Is a Major Regulatory Mechanism in Eukaryotes, 641
    Short RNAs That Silence Genes Are Produced from a Variety of Sources and Direct the Silencing of Genes in Three Different Ways, 641
    Synthesis and Function of miRNA Molecules, 643
    miRNAs Have a Characteristic Structure That Assists in Identifying Them and Their Target Genes, 643
    An Active miRNA Is Generated through a Two-Step Nucleolytic Processing, 645
    Dicer Is the Second RNA-Cleaving Enzyme Involved in miRNA Production, 646
    Incorporation of a Guide Strand RNA into RISC Makes the Mature Complex That Is Ready to Silence Gene Expression, 647
    siRNAs Are Regulatory RNAs Generated from Long Double-Stranded RNAs, 649
    Small RNAs Can Transcriptionally Silence Genes by Directing Chromatin Modification, 649
    KEY EXPERIMENTS BOX 18-2 History of miRNAs and RNAi, 650
    The Evolution and Exploitation of RNAi, 652
    Did RNAi Evolve As an Immune System?, 652
    RNAi Has Become a Powerful Tool for Manipulating Gene Expression, 654
    MEDICAL CONNECTIONS BOX 18-3 RNAi and Human Disease, 656
    Regulatory RNAs and X-inactivation, 657
    X-inactivation Creates Mosaic Individuals, 657
    Xist Is an RNA Regulator That Inactivates a Single X Chromosome in Female Mammals, 657
    SUMMARY, 659
    BIBLIOGRAPHY, 660
    CHAPTER19 · Gene Regulation in Development and Evolution, 661
    TECHNIQUES BOX 19-1 Microarray Assays: Theory and Practice, 662
    Three Strategies by Which Cells Are Instructed to Express Specific Sets of Genes during Development, 663
    Some mRNAs Become Localized within Eggs and Embryos because of an Intrinsic Polarity in the Cytoskeleton, 663
    Cell-to-Cell Contact and Secreted Cell-Signaling Molecules Both Elicit Changes in Gene Expression in Neighboring Cells, 664
    Gradients of Secreted Signaling Molecules Can Instruct Cells to Follow Different Pathways of Development Based on Their Location, 665
    Examples of the Three Strategies for Establishing Differential Gene Expression, 666
    The Localized Ash1 Repressor Controls Mating Type in Yeast by Silencing the HO Gene, 666
    ADVANCED CONCEPTS BOX 19-2 Review of Cytoskeleton: Asymmetry and Growth, 669
    A Localized mRNA Initiates Muscle Differentiation in the Sea Squirt Embryo, 670
    ADVANCED CONCEPTS BOX 19-3 Overview of Ciona Development, 671
    Cell-to-Cell Contact Elicits Differential Gene Expression in the Sporulating Bacterium, Bacillus subtilis, 672
    A Skin–Nerve Regulatory Switch Is Controlled by Notch Signaling in the Insect Central Nervous System, 673
    A Gradient of the Sonic Hedgehog Morphogen Controls the Formation of Different Neurons in the Vertebrate Neural Tube, 674
    The Molecular Biology of Drosophila Embryogenesis, 676
    An Overview of Drosophila Embryogenesis, 676
    ADVANCED CONCEPTS BOX 19-4 Overview of Drosophila Development, 677
    A Morphogen Gradient Controls Dorsoventral Patterning of the Drosophila Embryo, 679
    Segmentation Is Initiated by Localized RNAs at the Anterior and Posterior Poles of the Unfertilized Egg, 682
    Bicoid and Nanos Regulate hunchback, 683
    KEY EXPERIMENTS BOX 19-5 The Role of Activator Synergy in Development, 684
    MEDICAL CONNECTIONS BOX 19-6 Stem Cells, 686
    The Gradient of Hunchback Repressor Establishes Different Limits of Gap Gene Expression, 687
    Hunchback and Gap Proteins Produce Segmentation Stripes of Gene Expression, 688
    Gap Repressor Gradients Produce Many Stripes of Gene Expression, 689
    KEY EXPERIMENTS BOX 19-7 cis-Regulatory Sequences in Animal Development and Evolution, 690
    Short-Range Transcriptional Repressors Permit Different Enhancers to Work Independently of One Another within the Complex eve Regulatory Region, 692
    Homeotic Genes: An Important Class of Developmental Regulators, 693
    Changes in Homeotic Gene Expression Are Responsible for Arthropod Diversity, 695
    Arthropods Are Remarkably Diverse, 695
    Changes in Ubx Expression Explain Modification of Limbs among the Crustaceans, 695
    ADVANCED CONCEPTS BOX 19-8 Homeotic Genes of Drosophila Are Organized in Special Chromosome Clusters, 696
    Why Insects Lack Abdominal Limbs, 698
    Modification of Flight Limbs Might Arise from the Evolution of Regulatory DNA Sequences, 699
    SUMMARY, 701
    BIBLIOGRAPHY, 702
    CHAPTER20 · Genome Analysis and Systems Biology, 703
    Genomics Overview, 703
    Bioinformatics Tools Facilitate the Genome-wide Identification of Protein-Coding Genes, 703
    Whole-Genome Tiling Arrays Are Used to Visualize the Transcriptome, 704
    Regulatory DNA Sequences Can Be Identified by Using Specialized Alignment Tools, 706
    The ChIP-Chip Assay Is the Best Method for Identifying Enhancers, 708
    TECHNIQUES BOX 20-1 Bioinformatics Methods for the Identification of Complex Enhancers, 708
    Diverse Animals Contain Remarkably Similar Sets of Genes, 711
    Many Animals Contain Anomalous Genes, 712
    Synteny Is Evolutionarily Ancient, 713
    Deep Sequencing Is Being Used to Explore Human Origins, 715
    Systems Biology, 715
    Transcription Circuits Consist of Nodes and Edges, 716
    Negative Autoregulation Dampens Noise and Allows a Rapid Response Time, 717
    Gene Expression Is Noisy, 718
    Positive Autoregulation Delays Gene Expression, 720
    Some Regulatory Circuits Lock in Alternative Stable States, 720
    Feed-Forward Loops Are Three-Node Networks with Beneficial Properties, 722
    KEY EXPERIMENTS BOX 20-2 Bistability and Hysteresis, 722
    Feed-Forward Loops Are Used in Development, 725
    Some Circuits Generate Oscillating Patterns of Gene Expression, 727
    Synthetic Circuits Mimic Some of the Features of Natural Regulatory Networks, 729
    Prospects, 730
    SUMMARY, 730
    BIBLIOGRAPHY, 731
    P METHODS, 733
    PART5 METHODS, 733
    CHAPTER21 · Techniques of Molecular Biology, 739
    Nucleic Acids, 740
    Electrophoresis through a Gel Separates DNA and RNA Molecules according to Size, 740
    Restriction Endonucleases Cleave DNA Molecules at Particular Sites, 742
    DNA Hybridization Can Be Used to Identify Specific DNA Molecules, 743
    Hybridization Probes Can Identify Electrophoretically Separated DNAs and RNAs, 744
    Isolation of Specific Segments of DNA, 746
    DNA Cloning, 746
    Cloning DNA in Plasmid Vectors, 746
    Vector DNA Can Be Introduced into Host Organisms by Transformation, 748
    Libraries of DNA Molecules Can Be Created by Cloning, 748
    Hybridization Can Be Used to Identify a Specific Clone in a DNA Library, 749
    Chemically Synthesized Oligonucleotides, 750
    The Polymerase Chain Reaction Amplifies DNAs by Repeated Rounds of DNA Replication in Vitro, 751
    TECHNIQUES BOX 21-1 Forensics and the Polymerase Chain Reaction, 753
    Nested Sets of DNA Fragments Reveal Nucleotide Sequences, 753
    KEY EXPERIMENTS BOX 21-2 Sequenators Are Used for High- Throughput Sequencing, 757
    Shotgun Sequencing a Bacterial Genome, 757
    The Shotgun Strategy Permits a Partial Assembly of Large Genome Sequences, 758
    The Paired-End Strategy Permits the Assembly of Large- Genome Scaffolds, 760
    The $1000 Human Genome Is within Reach, 762
    Proteins, 764
    Specific Proteins Can Be Purified from Cell Extracts, 764
    Purification of a Protein Requires a Specific Assay, 764
    Preparation of Cell Extracts Containing Active Proteins, 765
    Proteins Can Be Separated from One Another Using Column Chromatography, 765
    Affinity Chromatography Can Facilitate More Rapid Protein Purification, 767
    Separation of Proteins on Polyacrylamide Gels, 768
    Antibodies Are Used to Visualize Electrophoretically Separated Proteins, 769
    Protein Molecules Can Be Directly Sequenced, 769
    Proteomics, 771
    Combining Liquid Chromatography with Mass Spectrometry Identifies Individual Proteins within a Complex Extract, 771
    Proteome Comparisons Identify Important Differences beween Cells, 773
    Mass Spectrometry Can Also Monitor Protein Modification States, 773
    Protein–Protein Interactions Can Yield Information about Protein Function, 774
    Nucleic Acid–Protein Interactions, 775
    The Electrophoretic Mobility of DNA Is Altered by Protein Binding, 776
    DNA-Bound Protein Protects the DNA from Nucleases and Chemical Modification, 777
    Chromatin Immunoprecipitation Can Detect Protein Association with DNA in the Cell, 778
    In Vitro Selection Can Be Used to Identify a Protein’s DNAor RNA-Binding Site, 780
    BIBLIOGRAPHY, 782
    CHAPTER22 · Model Organisms, 783
    Bacteriophage, 784
    Assays of Phage Growth, 786
    The Single-Step Growth Curve, 787
    Phage Crosses and Complementation Tests, 787
    Transduction and Recombinant DNA, 788
    Bacteria, 789
    Assays of Bacterial Growth, 789
    Bacteria Exchange DNA by Sexual Conjugation, Phage-Mediated Transduction, and DNA-Mediated Transformation, 790
    Bacterial Plasmids Can Be Used as Cloning Vectors, 791
    Transposons Can Be Used to Generate Insertional Mutations and Gene and Operon Fusions, 791
    Studies on the Molecular Biology of Bacteria Have Been Enhanced by Recombinant DNA Technology, Whole- Genome Sequencing, and Transcriptional Profiling, 793
    Biochemical Analysis Is Especially Powerful in Simple Cells with Well-Developed Tools of Traditional and Molecular Genetics, 793
    Bacteria Are Accessible to Cytological Analysis, 793
    Phage and Bacteria Told Us Most of the Fundamental Things about the Gene, 794
    Baker’s Yeast, Saccharomyces cerevisiae, 795
    The Existence of Haploid and Diploid Cells Facilitate Genetic Analysis of S. cerevisiae, 795
    Generating Precise Mutations in Yeast Is Easy, 796
    S. cerevisiae Has a Small, Well-Characterized Genome, 796
    S. cerevisiae Cells Change Shape as They Grow, 797
    Arabidopsis, 798
    Arabidopsis Has a Fast Life Cycle with Haploid and Diploid Phases, 798
    Arabidopsis Is Easily Transformed for Reverse Genetics, 799
    Arabidopsis Has a Small Genome That Is Readily Manipulated, 800
    Epigenetics, 801
    Plants Respond to the Environment, 801
    Development and Pattern Formation, 802
    The Nematode Worm, Caenorhabditis elegans, 802
    C.elegans Has a Very Rapid Life Cycle, 803
    C.elegans Is Composed of Relatively Few, Well-Studied Cell Lineages, 804
    The Cell Death Pathway Was Discovered in C. elegans, 805
    RNAi Was Discovered in C. elegans, 805
    The Fruit Fly, Drosophila melanogaster, 806
    Drosophila Has a Rapid Life Cycle, 806
    The First Genome Maps Were Produced in Drosophila, 807
    Genetic Mosaics Permit the Analysis of Lethal Genes in Adult Flies, 809
    The Yeast FLP Recombinase Permits the Efficient Production of Genetic Mosaics, 809
    It Is Easy to Create Transgenic Fruit Flies that Carry Foreign DNA, 810
    The House Mouse, Mus musculus, 812
    Mouse Embryonic Development Depends on Stem Cells, 813
    It Is Easy to Introduce Foreign DNA into the Mouse Embryo, 813
    Homologous Recombination Permits the Selective Ablation of Individual Genes, 814
    Mice Exhibit Epigenetic Inheritance, 816
    BIBLIOGRAPHY, 818
    Index, 819
    Box Contents
    Advanced Concepts
    BOX 1-1 Mendelian Laws, 6
    BOX 3-1 The Uniqueness of Molecular Shapes and the Concept of Selective Stickiness, 53
    BOX 5-2 Large Proteins Are Often Constructed of Several Smaller Polypeptide Chains, 83
    BOX 8-4 ATP Control of Protein Function: Loading a Sliding Clamp, 223
    BOX 8-6 The Replication Factory Hypothesis, 237
    BOX 8-7 E. coli DNA Replication Is Regulated by DnaA·ATP Levels and SeqA, 244
    BOX 9-4 The Y Family of DNA Polymerases, 280
    BOX 10-1 How to Resolve a Recombination Intermediate with Two Holliday Junctions, 292
    BOX 11-2 The Xer Recombinase Catalyzes the Monomerization of Bacterial Chromosomes and of Many Bacterial Plasmids, 335
    BOX 11-3 The Pathway of Retroviral cDNA Formation, 349
    BOX 11-5 Mechanism of Transposition Target Immunity, 361
    BOX 12-2 The Single-Subunit RNA Polymerases, 393
    BOX 14-1 CCA-Adding Enzymes: Synthesizing RNA without a Template, 462
    BOX 14-2 Selenocysteine, 470
    BOX 14-3 uORFs and IRESs: Exceptions That Prove the Rule, 485
    BOX 14-4 GTP-Binding Proteins, Conformational Switching, and the Fidelity and Ordering of the Events of Translation, 498
    BOX 16-3 Concentration, Affinity, and Cooperative Binding, 572
    BOX 17-4 Is There a Histone Code?, 623
    BOX 18-1 Amino Acid Biosynthetic Operons Are Controlled by Attenuation, 639
    BOX 19-2 Review of Cytoskeleton: Asymmetry and Growth, 669
    BOX 19-3 Overview of Ciona Development, 671
    BOX 19-4 Overview of Drosophila Development, 677
    BOX 19-8 Homeotic Genes of Drosophila Are Organized in Special Chromosome Clusters, 696
    Key Experiments
    BOX 1-2 Genes Are Linked to Chromosomes, 10
    BOX 2-1 Chargaff’s Rules, 24
    BOX 2-2 Evidence That Genes Control Amino Acid Sequences in Proteins, 29
    BOX 6-1 DNA Has 10.5 Base Pairs per Turn of the Helix in Solution: The Mica Experiment, 108
    BOX 6-2 How Spots on an X-ray Film Reveal the Structure of DNA, 112
    BOX 6-3 Proving that DNA Has a Helical Periodicity of about 10.5 Base Pairs per Turn from the Topological Properties of DNA Rings, 128
    BOX 7-1 Micrococcal Nuclease and the DNA Associated with the Nucleosome, 158
    BOX 7-2 Nucleosomes and Superhelical Density, 166
    BOX 7-3 Determining Nucleosome Position in the Cell, 180
    BOX 8-5 The Identification of Origins of Replication and Replicators, 232
    BOX 11-4 Maize Elements and the Discovery of Transposons, 356
    BOX 13-1 Adenovirus and the Discovery of Splicing, 419
    BOX 13-2 Converting Group I Introns into Ribozymes, 428
    BOX 13-3 Identification of Docking Site and Selector Sequences, 442
    BOX 16-1 Activator Bypass Experiments, 557
    BOX 16-2 Jacob, Monod, and the Ideas Behind Gene Regulation, 561
    BOX 16-4 Evolution of the λ Switch, 579
    BOX 16-5 Genetic Approaches That Identified Genes Involved in the Lytic/Lysogenic Choice, 581
    BOX 17-2 Long-Distance Interactions on the Same and Different Chromosomes, 604
    BOX 17-3 Evolvability of a Regulatory Circuit, 612
    BOX 18-2 History of miRNAs and RNAi, 650
    BOX 19-5 The Role of Activator Synergy in Development, 684
    BOX 19-7 cis-Regulatory Sequences in Animal Development and Evolution, 690
    BOX 20-2 Bistability and Hysteresis, 722
    BOX 21-2 Sequenators Are Used for High-Throughput Sequencing, 757
    Medical Connections
    BOX 8-2 Anticancer and Antiviral Agents Target DNA Replication, 203
    BOX 8-8 Aging, Cancer, and the Telomere Hypothesis, 251
    BOX 9-1 Expansion of Triple Repeats Causes Disease, 259
    BOX 9-2 The Ames Test, 266
    BOX 9-3 Nonhomologous End Joining, 276
    BOX 10-2 The Product of the Tumor Suppressor Gene BRCA2 Interacts with Rad51 Protein and Controls Genome Stability, 309
    BOX 11-1 Application of Site-Specific Recombination to Genetic Engineering, 327
    BOX 13-4 Defects in Pre-mRNA Splicing Cause Human Disease, 445
    BOX 13-5 Deaminases and HIV, 450
    BOX 14-5 Antibiotics Arrest Cell Division by Blocking Specific Steps in Translation, 502
    BOX 17-5 Transcriptional Repression and Human Disease, 626
    BOX 17-6 Using Transcription Factors to Reprogram Somatic Cells into Embryonic Stem Cells, 629
    BOX 18-3 RNAi and Human Disease, 656
    BOX 19-6 Stem Cells, 686
    Techniques
    BOX 5-1 Determination of Protein Structure, 78
    BOX 8-1 Incorporation Assays Can Be Used to Measure Nucleic Acid and Protein Synthesis, 200
    BOX 8-3 Determining the Polarity of a DNA Helicase, 212
    BOX 12-1 Consensus Sequences, 388
    BOX 17-1 The Two-Hybrid Assay, 594
    BOX 19-1 Microarray Assays: Theory and Practice, 662
    BOX 20-1 Bioinformatics Methods for the Identification of Complex Enhancers, 708
    BOX 21-1 Forensics and the Polymerase Chain Reaction, 753
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