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UNIT ONE Genome Sequences1

CHAPTER 1 Genome Sequence Acquisition and Analysis2

1.1 Defining Genomes3

What Is Genomics？3

How Are Whole Genomes Sequenced？3

Math Minute 1.1 What Is an E-Value？5

Why Do the Databases Contain So Many Partial Sequences？6

How Do We Make Sense of All These Bases？9

Box 1.1 Which Draft Sequence Is Better？9

Can We Predict Protein Functions？10

How Well Are Genes Conserved in Diverse Species？12

How Do You Know Which Bases Form a Gene？14

How Many Proteins Can One Gene Make？15

Summary 1.116

1.2 What Have We Learned from the Human Genome Draft Sequences？17

Overview of Human Genome First Draft17

Summary Statements17

Box 1.2 Whose DNA Did We Sequence？17

Math Minute 1.2 How Do Yoou Fit a Line to Data？18

Can We Describe a Typical Human Gene？20

When Are the Data Sufficient？24

Can the Genome Alter Gene Expression Without Changing the DNA Sequence？25

Summary 1.228

Chapter 1 Conclusions28

References28

CHAPTER 2 Genome Sequences Answer Interesting Questions30

2.1 Evolution of Genomes31

How Did Eukaryotes Evolve？31

Math Minute 2.1 Are the Hit Numbers Significantly Different？33

What Is the Origin of Our Species？41

Math Minute 2.2 How Do Yoou Know if the Tree Is Right？45

Summary 2.146

2.2 Genomic Identifications46

How Can We Identify Biological Weapons？47

How Long Can DNA Survive？49

How Did Tuberculosis Reach North America？50

How Are Newly Emerging Diseases Identified？53

Summary 2.257

2.3 Biomedical Genome Research57

Can We Use Genomic Sequences to Make New Vaccines？57

Can We Make New Types of Antibiotics？59

Can We Invent New Types of Medication？62

How Can E.coli Be Lethal and in Our Intestines at the Same Time？64

Math Minute 2.3 How Can Yoou Tell if Base Compositions Are Different？65

Summary 2.366

Chapter 2 Conclusions66

References66

CHAPTER 3 Genomic Variations69

3.1 Environmental Case Study70

Can Genomic Diversity Affect Global Warming？70

Math Minute 3.1 How Do Yoou Measure Genetic Variation？72

Math Minute 3.2 How Are Populations Modeled？74

Summary 3.176

3.2 Human Genomic Variation76

How Much Variation Is in the Human Genome？76

Math Minute 3.3 Are All SNPs Really SNPs？78

Why Should We Care About SNPs？79

Box 3.1 What’s the Difference Between a Mutation and an Allele？80

Are There Any Known Examples of SNPs That Cause Diseases？82

Are There Any Known Changes in Nondisease QTL Due to SNPs？84

Box 3.2 Patent Law and Genomics85

Why the SNP Frenzy？ Pharmacogenomics！86

Summary 3.288

3.3 The Ultimate Genomic Phenotype-Death？89

Why Do We Age？89

Are There Hidden Costs for a Prolonged Life？90

Do Bacteria Experience Genomic Trade-offs Too？91

Summary 3.393

3.4 Ethical Consequences of Genomic Variations93

Are Genetically Modified Organisms Bad？93

Is Genetic Testing Good？95

Are There Simple Applications for Complex Genomes？99

Box 3.3 Should I Get a Genetic Test？99

Summary 3.4101

Chapter 3 Conclusions102

References102

UNIT TWO Genome Expression105

CHAPTER 4 Basic Research with DNA Microarrays106

4.1 Introduction to Microarrays107

What Happened to My Home Brew？107

Math Minute 4.1 How Do Yoou Transform the Data to Avoid Fractions？112

Math Minute 4.2 How Do Yoou Measure Similarity Between Expression Patterns？113

Math Minute 4.3 How Do Yoou Cluster Genes？114

What Can We Learn from Stressed-out Yeast？124

Why Are There So Many Copies of Some Genes but Not Others？125

How Well Do Promoters Control Gene Expression？126

Are Promoters Able to Work in Reverse？127

Summary 4.1128

4.2 Alternative Uses of DNA Microarrays128

Why Do So Many Unrelated Genes Share the Same Expression Profile？128

Math Minute 4.4 Is It Useful to Compare the Columns of a Gene Expression Matrix？129

Can Cells Verify Their Own Genes？131

Summary 4.2133

Chapter 4 Conclusions135

References135

CHAPTER 5 Applied Research with DNA Microarrays137

5.1 Cancer and Genomic Microarrays138

Are There Better Ways to Diagnose Cancer？138

Math Minute 5.1 What Are Signature Genes，and How Do Yoou Use Them？139

Can Breast Cancer Be Categorized with Microarrays， too？141

What Genomic Changes Occur in Cancer Cells？143

Summary 5.1146

5.2 Improving Health Care with DNA Microarrays146

Why Is the Tuberculosis Vaccine Less Effective Now？146

How Does This Drug Work？149

Can We Predict Which Drugs Will Be Effective in Different Cancers？152

What Happens When You Accumulate Fat？154

Summary 5.2158

Chapter 5 Conclusions158

References158

CHAPTER 6 Proteomics161

6.1 Introduction162

What Do All These Proteins Do？162

Which Proteins Are Needed in Different Conditions？166

Math Minute 6.1 How Do Yoou Know if Yoou Have Sampled Enough Cells？168

Can You Live Without Some Proteins？170

Summary 6.1171

6.2 Protein 3D Structures171

Does a Protein’s Shape Reveal Its Function？172

Can We Use Structures to Develop Better Drugs？173

Can One Protein Kill You？174

6.2 Summary176

6.3 Protein Interaction Networks176

Which Proteins Interact with Each Other？176

How Can We Measure Protein Interactions？177

Math Minute 6.2 Is Sup35 a Central Protein in the Network？179

Is It Possible to Understand Proteome-wide Interactions？181

Summary 6.3183

6.4 Measuring Proteins183

How Do We Know Which Proteins Are Present？184

What Proteins Do Our White Blood Cells Need to Kill a Pathogen？187

How Much of Each Protein Is Present？189

Can We Make Protein Chips？195

Are All Cells Equal？198

What Does a Proteome Produce？200

Summary 6.4202

Chapter 6 Conclusions202

References202

UNIT THREE Whole Genome Perspective205

CHAPTER 7 Genomic Circuits in Single Genes206

7.1 Dissecting a Gene’s Circuitry207

How Do Genomes Control Individual Genes？207

How does a Gene Control Location， Timing，and Quantity of Transcription？210

What Does Module G Do？216

Can We Apply Engineering and Computer Science Concepts to Genes？226

Summary 7.1229

7.2 Integrating Single-Gene Circuits229

How Can We Describe to Others What We Know About a Genome Circuit？229

Technical Hints230

Can We Visualize Circuits for Protein Interaction and DNA Binding？230

Summary 7.2230

Chapter 7 Conclusions230

References231

CHAPTER 8 Integrated Genomic Circuits232

8.1 Simple Integrated Circuits233

Can Genes Form Toggle Switches and Make Choices？233

Math Minute 8.1 How Are Stochastic Models Applied to Cellular Processes？234

Can Humans Engineer a Genetic Toggle Switch？238

Can Humans Build a Synthetic Circadian Clock from a Toggle Switch Design？240

If Toggle Switches Are So Noisy， How Can Multicellular Organisms Develop？241

Redundancy： Is It Really Beneficial to Have More Than One Copy of a Gene？242

Summary 8.1244

8.2 Complex Integrated Circuits244

Are Circuits the Key to Learning？244

Math Minute 8.2 Is It Possible to Predict Steady-state Behavior？250

Can We Understand Cancer Better by Understanding Its Circuitry？257

If Circuits Are Interconnected， Does Gene Order Matter？259

Summary 8.2263

Chapter 8 Conclusions263

References263

CHAPTER 9 Modeling Whole-Genome Circuits265

9.1 Is Genomics a New Perspective？266

The People Involved： Who Is Doing Systems Biology？266

The Quality of the Message： What Questions Do Systems Biologists Ask？267

9.2 Can We Model Entire Eukaryotes with a Systems Approach？267

Genomics versus Proteomics271

Building a Systems Model272

Context of the Message273

9.3 Will Systems Biology Go Systemic？274

Chapter 9 Conclusions274

References275

UNIT FOUR Transition from Genetics to Genomics： Medical Case Studies277

CHAPTER 10 What’s Wrong with My Child？278

10.1 First Patients279

Phase I： Clinical Presentation279

Phase II： Family Pedigree280

Phase III： Karyotyping and Linkage Analysis280

Phase IV： DNA Sequence Analysis281

Summary 10.1283

10.2 The Next Steps in Understanding the Disease284

We Need an Animal Model System284

What Was That Other Protein I Got Lots of Hits For？284

Does Utrophin Play a Role in Muscular Dystrophy， Too？284

What Does Dystrophin Do Anyway？285

Math Minute 10.1 What’s Special about This Graph？286

Why Do DMD Patients’ Muscles Deteriorate After the First Three Years？287

Is It Possible to Have DMD and Be Wild-Type for Dystrophin？288

How Can They Have Muscular Dystrophy if Their Dystrophin Genes Are Normal？288

Math Minute 10.2 What Do Yoou Mean by Highly unlikely？289

Where Is the Muscular Dystrophy Field Now？293

Math Minute 10.3 Is cGMP Production Elevated？301

Summary 10.2： Yoour Final Thoughts303

Chapter 10 Conclusions303

References304

CHAPTER 11 Why Can’t I Just Take a Pill to Lose Weight？306

Hungry for Knowledge307

Saturday， 21 October.7：30 A.M.307

Building a Model for Weight Homeostasis308

Cloning the Leptin Gene308

Functional Tests for Leptin310

Time to Visit Grandma311

Grandma Gives You Homework！311

Chapter 11 Conclusions319

References319

CHAPTER 12 Why Can’t We Cure More Diseases？320

How to Develop a New Medication321

Define the Problem and Devise a Solution321

Focus 1： Location， Location， Location321

Focus 2： Delivery Vehicles321

Focus 3： Specificity—“If It Ain’t Broke， Don’t Fix It”323

Math Minute 12.1 What’s the Right Dose？324

Eye of Newt&？326

Don’t Treat the Symptom， Treat the Cause327

Chapter 12 Conclusions329

References329

GLOSSARY331

CREDITS341

INDEX345