Discovering genomics, proteomics, and bioinformatics / 2nd ed.

Foreword p. ix
Preface p. xi
Acknowledgments p. xiv
Genome Sequences p. 1
What's Wrong with My Child? p. 2
First Patients p. 3
Clinical Presentation p. 3
Family Pedigree p. 4
Karyotyping and Linkage Analysis p. 5
DNA Sequence Analysis p. 5
Summary 1.1 p. 7
What Is an E-Value? p. 7
The Next Steps in Understanding the Disease p. 9
The Need for an Animal Model System p. 9
What Was the Other Protein that Gave Lots of BLASTp Hits? p. 9
Does Utrophin Play a Role in Muscular Dystrophy, Too? p. 10
What Does Dystrophin Do? p. 10
What's Special about This Graph? p. 12
Why Do DMD Patients' Muscles Deteriorate after the First Three Years? p. 13
Is It Possible to Have DMD and Be Wild-Type for Dystrophin? p. 13
How Can They Have Muscular Dystrophy if Their Dystrophin Genes Are Normal? p. 14
What Do You Mean by Highly Unlikely? p. 15
Where Is the Muscular Dystrophy Field Now? p. 20
Sixth International Conference on Molecular Causes of Muscular Dystrophies p. 20
The Meeting Begins p. 20
Structural Weaknesses p. 20
Nonfunctional Mutations p. 22
New Paradigms: Nonstructural Causes for Muscular Dystrophies p. 23
Final Presentation p. 27
Is cGMP Production Elevated? p. 28
Summary 1.2 p. 29
Chapter 1 Conclusions p. 29
References p. 29
Genome Sequence Acquisition p. 33
How Are Genomes Sequenced? p. 34
What Is Genomics? p. 34
How Are Whole Genomes Sequenced? p. 34
How Are Organisms Picked for Genome Sequencing? p. 36
What Can You Learn from a Dot Plot? p. 40
How Do You Find Motifs? p. 42
Can We Predict Protein Functions from DNA Sequence? p. 45
What Are "Positives" and What Do They Have to Do with E-values? p. 46
What Shapes Are the Proteins? p. 48
Does Structure Reveal Function? p. 49
Why Do the Databases Contain So Many Partial Sequences? p. 49
Which Sequencing Method Worked Better? p. 51
Annotated Genomes Online p. 54
How Many Proteins Can One Gene Make? p. 54
Can the Genome Alter Gene Expression Without Changing the DNA Sequence? p. 55
What Is the Fifth Base in DNA? Methyl-Cytosine p. 57
Imprinting, Methylation, and Cancer p. 58
Summary 2.1 p. 59
What Have We Learned from Unicellular Genomes? p. 59
Why Do I Get So Many Pimples? p. 59
Which Genes Cause Pimples? p. 60
Are All Bacteria Living in Us Bad for Us? p. 62
Can Microbial Genomes Become Dependent upon Human Genes? p. 64
What Is the Minimum Number of Genes Possible? p. 65
Are All Viral Genomes Smaller than All Bacterial Genomes? p. 66
Is Mimivirus Alive? p. 67
Do Genomes Reflect an Organism's Ecological Niche? p. 68
Can You Estimate the Number of Inversions in a Dot Plot? p. 70
Why Is MED4's Genome So Small? p. 72
How Many Genome Changes Are Required Before a New Species Is Created? p. 73
What Kind of Organism Causes Malaria? p. 74
What Sort of Genome Does Plasmodium Possess? p. 75
Is the Predicted Proteome Equally Bizarre? p. 76
Is There a Model Eukaryote Genome? p. 78
What Did the Investigators Predict for the Future of Genomics? p. 81
Epilog for the Yeast Genome p. 81
Summary 2.2 p. 83
What Have We Learned from Metazoan Genomes? p. 83
Are Animal Genomes Harder to Finish? p. 83
What Are Polythene Chromosomes? p. 83
What Makes a Fly Different from Other Eukaryotes? p. 87
Is the Fly Still a Good Model Organism? p. 88
Fly Genome Epilog p. 89
Do We Need Two Plant Genome Sequences? p. 90
Plants Seem Simpler than Animals, but Are Their Genomes? p. 91
Can We Draw Any Conclusions from Draft Sequences? p. 91
What Lessons Have We Learned? p. 94
Rice Epilog p. 95
What Can We Possibly Learn from a Puffer Fish Genome? p. 96
Did the Genome Reveal Any Surprises? p. 97
Are There More Big Lessons from Tetraodon? p. 98
What Makes Humans Different? p. 99
How Do You Fit a Line to Data? p. 101
Whose DNA Did We Sequence? p. 102
Can We Describe a Typical Human Gene? p. 103
Human Genome Epilog p. 106
What Is the Next Goal in Human Genomics? p. 108
Summary 2.3 p. 109
Chapter 2 Conclusions p. 109
References p. 109
Comparative Genomics in Evolution and Medicine p. 113
Comparative Genomics p. 114
How Can E. coli Be Lethal and in Our Intestines at the Same Time? p. 114
How Can You Tell if Base Compositions Are Different? p. 115
Two Hundred Genomes: What Can Comparative Genomics Tell Us about Prokaryotes? p. 116
Do All Prokaryotes Have One Circular Chromosome? p. 116
Are the Genomes Still Changing? p. 117
How Many Genomes Are There? p. 118
What Can We Learn by Comparing Many Whole Genomes? p. 121
What Can We See at the Chromosomal Perspective? p. 123
Summary 3.1 p. 145
Evolution of Genomes p. 126
What Organism Is the Root of the Tree of Life? p. 126
What Are the Origins of our Nuclear Genes? p. 129
Are the Hit Numbers Significantly Different p. 132
Is There Evidence of Intermediate Stages in Genomic Evolution? p. 132
Are You Going to Eat That? p. 133
A Missing Link of Biblical Proportions p. 136
Could Nuclei Evolve without Symbiosis? p. 137
Are We Related to Rats? p. 138
What Is the Origin of Our Species? p. 139
Are We All of African Descent? p. 141
How Do You Know if the Tree Is Correct? p. 143
Have We Stopped Evolving? p. 143
Summary 3.2 p. 145
Genomic Identifications p. 145
How Can We Identify Biological Weapons? p. 145
How Long Can DNA Survive? p. 149
How Did Tuberculosis Reach North America? p. 152
How Are Newly Emerging Diseases Identified? p. 155
What Other Outbreaks Are Coming? p. 159
Summary 3.3 p. 161
Biomedical Genome Research p. 162
Can We Use Genomic Sequences to Make New Vaccines? p. 162
Can We Make New Types of Antibiotics? p. 164
Can We Invent a New Class of Medication? p. 166
Is There an Alternative Way to Inhibit RNAs? p. 169
Are There More Stable RNA Genomes We Can Target? p. 170
Summary 3.4 p. 172
Chapter 3 Conclusions p. 172
References p. 172
Genomic Variations p. 177
Environmental Case Study p. 178
Can Genomic Diversity Affect Global Warming? p. 178
How Do You Measure Genetic Diversity? p. 180
How Do You Model Population Diversity? p. 184
Summary 4.1 p. 186
Human Genomic Variation p. 186
How Much Variation Is in the Human Genome? p. 186
What's the Difference Between a Mutation and an Allele? p. 187
Why Should We Care about NSPs? p. 188
Are All SNPs Really SNPs? p. 188
Do Any SNPs Produce Common Phenotypes? p. 192
Are There Vital SNPs That Can Surprise Me? p. 194
Patent Law and Genomics p. 195
Why the SNP Frenzy? Pharmacogenomics! p. 196
Summary 4.2 p. 198
The Ultimate Genomic Phenotype-Death? p. 198
Why Do We Age? p. 199
Are There Hidden Costs for a Prolonged Life? p. 200
Do Bacteria Experience Genomic Tradeoffs Too? p. 201
Summary 4.3 p. 202
Ethical Consequences of Genomic Variations p. 203
Are Genetically Modified Organisms Bad? p. 203
Is Genetic Testing Good? p. 205
What Does a Positive Test Result Really Mean? p. 208
Genomic Diversity Banks and Small Populations p. 209
Who Benefits from Genomic Medicine? p. 210
Are There Simple Applications for Complex Genomes? p. 210
Should I Get a Genetic Test? p. 211
Should Humans Be Cloned? p. 212
Summary 4.4 p. 214
Chapter 4 Conclusions p. 214
References p. 214
Genome Expression p. 217
Why Can't I Just Take a Pill to Lose Weight? p. 218
Hungry for Knowledge p. 219
Saturday, 21 October. 7:30 A.M. p. 219
Library Opens at 8:30 A.M. on Saturdays p. 219
Building a Model for Weight Homeostasis p. 220
Cloning the Leptin Gene p. 220
Functional Tests for Leptin p. 223
Time to Visit Grandma p. 224
Grandma Gives You Homework! p. 224
Chapter 5 Conclusions p. 231
References p. 231
Basic Research with DNA Microarrays p. 233
Introduction to Microarrays p. 234
What Happened to My Home Brew? p. 234
Where's the Probe? p. 235
Microarray Data Look Good, but Are They Real? p. 237
How Do You Analyze These Data? p. 238
Why Should You Log-Transform Microarray Data? p. 239
How Do You Measure Similarity between Expression Patterns? p. 240
How Do You Cluster Genes? p. 241
Can Chips Reveal Regulatory Sequences? p. 245
Can We Formulate Testable Predictions with These Data? p. 245
Microarrays Seem Too Good to Be True-Are They? p. 248
Why Did the Beer Blow? p. 249
What Can We Learn from Stressed-Out Yeast? p. 250
Do Fungi Feel Stress? p. 251
What Goes Up? p. 251
Why Are There So Many Copies of Some Genes but Not Others? p. 252
How Well Do Promoters Control Gene Expression? p. 253
Do Promoters Work in Reverse? p. 254
Summary 6.1 p. 254
Alternative Uses of DNA Microarrays p. 254
Why Do So Many Unrelated Genes Share the Same Expression Profile? p. 255
Is It Useful to Compare the Columns of a Gene Expression Matrix? p. 256
Can Cells Verify Their Own Genes? p. 258
Which Predicted Genes Are Real and Which Ones Aren't? p. 259
Can Microarrays Improve Annotations? p. 259
Could a Microarray Validate Annotation of an Entire Genome? p. 259
Summary 6.2 p. 261
Chapter 6 Conclusions p. 261
References p. 261
Applied Research with DNA Microarrays p. 263
Cancer and Genomic Microarrays p. 264
Are There Better Ways to Diagnose Cancer? p. 264
What Are Signature Genes, and How Do You Use Them? p. 266
Can Breast Cancer Be Categorized with Microarrays? p. 268
What Genomic Changes Occur in Cancer Cells? p. 270
Summary 7.1 p. 272
Improving Health Care with DNA Microarrays p. 273
Why Is the Tuberculosis Vaccine Less Effective Now? p. 273
Can We Choose the Most Effective Medication for Each Cancer? p. 276
Can We Predict Effectiveness of Chemotherapy? p. 276
What Happens When You Accumulate Fat? p. 277
What Effect Does Leptin Have on wt Adipose Tissue? p. 281
Summary 7.2 p. 282
Chapter 7 Conclusions p. 282
References p. 282
Proteomics p. 285
Introduction p. 285
What Do All These Proteins Do? p. 286
Where Are These Proteins Located? p. 289
Which Proteins Are Needed in Different Conditions? p. 290
How Do You Know if You Have Sampled Enough Cells? p. 292
Summary 8.1 p. 294
Protein 3D Structures p. 295
Does a Protein's Shape Reveal Its Function? p. 295
Can We Use Structures to Develop Better Drugs? p. 297
Can One Protein Kill You? p. 297
Summary 8.2 p. 299
Protein Interaction Networks p. 299
Which Proteins Interact with Each Other? p. 299
Can Sequence Analysis Uncover Interactions? p. 300
Can We Detect Protein Interactions? p. 300
Is Sup35 a Central Protein in the Network? p. 303
Is It Possible to Understand Proteome-Wide Interactions? p. 304
Summary 8.3 p. 306
Measuring Proteins p. 307
Which Proteins Are Present? p. 307
What Are 2D Gels? p. 307
What Proteins Do Our White Blood Cells Need to Kill a Pathogen? p. 310
How Do You Identify Proteins on 2D Gels? p. 311
How Much of Each Protein Is Present? p. 314
Can We Quantify Proteomes in Cultured Cells? p. 314
Can We Quantify Proteins in Any Cell? p. 316
Nice Idea, But Does ICAT Work? p. 316
Is the Last Unexplored Ecosystem on Earth Inside the Cell? p. 319
Can We Make Protein Microarrays? p. 320
Can Microarrays Detect Proteome Interactions? p. 320
Can Protein Microarrays Measure Kinase Activity? p. 321
Are All Cells Equal? p. 323
What Does a Proteome Produce? p. 325
Summary 8.4 p. 327
Chapter 8 Conclusions p. 327
References p. 327
Whole Genome Perspective p. 329
Why Can't We Cure More Diseases? p. 330
How Are New Medications Developed? p. 331
Location, Location, Location p. 331
Delivery Vehicles p. 331
Specificity p. 333
What's the Right Dose? p. 335
How Many Drugs Does It Take to Cure a Disease? p. 336
What Type of Drug Works Best? p. 336
Can Medication Do More than Simply Mask Symptoms? p. 337
Do We Know the Answers? p. 338
Chapter 9 Conclusions p. 339
References p. 340
Genomic Circuits in Single Genes p. 341
Dissecting a Gene's Circuitry p. 342
How Are Genes Regulated? p. 342
Molecular Dissection of Development p. 343
Expression of Endo16 p. 343
How Does a Gene Control Location, Timing, and Quantity of Transcription? p. 344
Which Modules Control Location? p. 344
Why Do Modules F, E, and DC Promote Expression in the Wrong Cells? p. 345
How Does Lithium Affect Transcription? p. 348
What Controls the Timing of Endo16 Transcription? p. 350
Does Module G Have a Function? p. 351
Can We Draw a Transcription Circuit for Endo16? p. 352
What Makes Module A So Special? p. 355
How Do Module A-Binding Proteins Work? p. 355
Which Module A Sites Respond to Repression by Modules DC, E, and F? p. 359
How Does Module A Interact with the Basic Promoter? p. 360
Are Genes Hard-Wired? p. 361
Do Genes Contain Miniature Computer Programs? p. 363
How Do You Make a Computer Understand Gene Regulation? p. 364
Summary 10.1 p. 366
Integrating Single-Gene Circuits p. 366
How Can We Describe to Others What We Know About a Genome Circuit? p. 366
Does Interactivity Enhance Understanding? p. 366
Technical Hints p. 366
Summary 10.2 p. 367
Chapter 10 Conclusions p. 367
References p. 368
Integrated Genomic Circuits p. 369
Natural Gene Circuits p. 370
Can Genes Form Toggle Switches and Make Choices? p. 370
How Do Toggle Switches Work? p. 370
What Effect Do Noise and Stochastic Behavior Have on a Cell? p. 371
How Are Stochastic Models Applied to Cellular Processes? p. 371
Theory Is Nice, but Do Toggle Switches Really Exist? p. 374
How Can Multicellular Organisms Develop with Noisy Circuits? p. 376
Redundancy: Does Gene Duplication Really Increase Genome Reliability? p. 377
Does Memory Formation Require Toggle Switches? p. 378
Are Simple Models of Complex Circuits Worthwhile? p. 380
How Much Math Is Required to Model Memory? p. 380
How Do You Build Complex Models? p. 381
Can a Transient Stimulus Produce Persistent Kinase Activation? p. 381
Why Does 100 Minutes of 5 nM EGF Achieve Long-Term Activation? p. 382
Is It Possible to Predict Steady-State Behavior? p. 384
Can the Modeled Circuit Accommodate Learning and Forgetting? p. 385
What Roles Do Other Integrated Circuits Play in LTP? p. 386
Do They Need a More Complex Model to Match Reality? p. 387
Are LTP and Long-Term Memory Related? p. 390
What Have We Learned (How Much LTP Have We Generated)? p. 391
Can We Understand Cancer Better by Visualizing Its Circuitry? p. 391
Summary 11.1 p. 393
Synthetic Biology p. 394
Can Humans Engineer a Genetic Toggle Switch? p. 394
How to Build a Toggle Switch p. 394
Can We Build a Synthetic Oscillating Clock? p. 396
How Can You Visualize Gene Regulation Logic? p. 397
Can Synthetic Devices Alter Gene Expression? p. 400
If Circuits Are Interconnected, Does Gene Order Matter? p. 402
Observational Approach p. 402
Computational Approach p. 403
Does Gene1 Have to Be First? p. 404
Summary 11.2 p. 407
Chapter 11 Conclusions p. 407
References p. 407
Modeling Whole-Genome Circuits p. 409
Is Genomics a New Perspective? p. 410
The People Involved: Who Is Doing Systems Biology? p. 410
The Quality of the Message: What Questions Do Systems Biologists Ask? p. 411
Can We Model Entire Eukaryotes with a Systems Approach? p. 411
Does the Proteome Respond Like the Transcriptome? p. 415
Can We Build a Systems Model? p. 416
Context of the Message: What Is the Impact of this Research? p. 417
Will Systems Biology Go Systemic? p. 418
Chapter 12 Conclusions p. 419
References p. 419
Glossary p. 421
Credits p. 435
Index p. 439