Human Genome (eBook)

Front Cover 1
The Human Genome 4
Copyright Page 5
Contents 8
Acknowledgments 12
Prologue: The Answer in a Nutshell 14
SECTION I: HOW GENES SPECIFY A TRAIT 16
Chapter 1 The Basics of Heredity: How Traits Are Passed Along in Families 18
1.1 Mendel's Laws 19
1.2 Selection: Artificial, Natural, and Sexual 27
1.3 Human Genetic Diversity 30
1.4 Human Dominant Inheritance 31
1.5 Human Recessive Inheritance 34
1.6 Complementation 42
1.7 Epistasis and Pleiotropy 46
1.8 Complex Syndromes 47
1.9 One Man's Disease Is Another Man's Trait 49
Chapter 2 The Double Helix: How Cells Preserve Genetic Information 56
2.1 Inside the Cell 57
2.2 DNA: The Repository of Genetic Information 59
2.3 DNA and the Double Helix 62
2.4 DNA Replication 65
2.5 Chromatin 71
2.6 What Are Chromosomes? 72
2.7 Euchromatin and Heterochromatin 79
2.8 The Mitochondrial Chromosome: The "Other Genome" in the Human Genome 80
2.9 DNA in vitro 82
SECTION II: HOW GENES FUNCTION 96
Chapter 3 The Central Dogma of Molecular Biology: How Cells Orchestrate the Use of Genetic Information 98
3.1 What Is RNA? 99
3.2 What Is RNA For? 102
3.3 Transcription of RNA 104
3.4 Orchestrating Expression 106
3.5 Monitoring Gene Expression 110
3.6 Interaction of Transcription Factors 113
3.7 Inducible Genes 117
3.8 Epigenetic Control of Gene Expression 119
3.9 What Constitutes Normal? 121
Chapter 4 The Genetic Code: How the Cell Makes Proteins from Genetic Information Encoded in mRNA Molecules 130
4.1 The Genetic Code 131
4.2 Moving Things In and Out of the Nucleus 134
4.3 The Central Dogma of Molecular Biology 135
4.4 Translation 135
4.5 Messenger RNA Structure 137
4.6 Splicing 139
4.7 Modular Genes 143
4.8 What Are Proteins? 145
4.9 Gene Products and Development 150
Chapter 5 We Are All Mutants: How Mutation Alters Function 158
5.1 What Is a Mutation? 159
5.2 The Process of Mutation 162
5.3 How We Detect Mutations 168
5.4 Basic Mutations 174
5.5 Mutations in DNA Sequences that Regulate Gene Expression 181
5.6 Copy Number Variation: Too Much or Too Little of a Good Thing 182
5.7 Expanded Repeat Traits 184
5.8 The Male Biological Clock 195
5.9 Mutation Target Size 195
5.10 Absent Essentials and Monkey Wrenches 198
SECTION III: HOW CHROMOSOMES MOVE 212
Chapter 6 Mitosis and Meiosis: How Cells Move Your Genes Around 214
6.1 The Cell Cycle 215
6.2 Mitosis 216
6.3 Gametogenesis: What Is Meiosis Trying to Accomplish? 222
6.4 Meiosis in Detail 226
6.5 Mechanisms of Chromosome Pairing in Meiosis 232
6.6 The Chromosomal Basis of Heredity 234
6.7 Aneuploidy: When Too Much or Too Little Counts 239
6.8 Uniparental Disomy 245
6.9 Partial Aneuploidies 251
6.10 The Female Biological Clock 253
Appendix 6.1 Failed Meiotic Segregation (Nondisjunction) as Proof of the Chromosome Theory of Heredity 255
Chapter 7 The Odd Couple: How the X and Y Chromosomes Break the Rules 262
7.1 Passing the X and Y Chromosomes between Generations 263
7.2 How Humans Cope with the Difference in Number of Sex Chromosomes between Males and Females 264
7.3 How X Inactivation Works 265
7.4 Skewed X Inactivation – When Most Cells Inactivate the Same X 266
7.5 Genes that Escape X-Inactivation 270
7.6 Reactivation of the Inactive X Chromosome in the Female Germline 270
7.7 X Chromosome Inactivation During Male Meiosis 270
7.8 X Inactivation and the Phenotypes of Sex Chromosome Aneuploidy 272
7.9 The Structure of the Human Y Chromosome 274
7.10 X-Linked Recessive Inheritance 277
7.11 X-Linked Dominant Inheritance 280
SECTION IV: HOW GENES CONTRIBUTE TO COMPLEX TRAITS 286
Chapter 8 Sex Determination: How Genes Determine a Developmental Choice 288
8.1 Sex as a Complex Developmental Characteristic 289
8.2 What Do the X and Y Chromosomes Have to Do With Sex? 293
8.3 SRY on the Y: The Genetic Determinant of Male Sexual Differentiation 294
8.4 The Role of Hormones in Early Development 297
8.5 Androgen Receptor on the X: Another Step in the Sexual Differentiation Pathway 300
8.6 Genetics of Gender Identification 302
8.7 Genetics of Sexual Orientation 303
Chapter 9 Complexity: How Traits Can Result from Combinations of Factors 314
9.1 Digenic Diallelic Inheritance 315
9.2 Digenic Triallelic Inheritance 319
9.3 Multifactorial Inheritance 320
9.4 Quantitative Traits 322
9.5 Additive Effects and Thresholds 324
9.6 Is It Genetic? 325
9.7 Genes and Environment: Inducible Traits 327
9.8 Genes and Environment: Infectious Disease 330
9.9 Phenocopies 334
9.10 Genotypic Compatibility: Whose Genome Matters? 337
9.11 Phenotypic Heterogeneity: One Gene, Many Traits 339
9.12 Genotypic and Phenotypic Heterogeneity 340
9.13 Variable Expressivity 343
9.14 Phenotypic Modifiers 344
9.15 Biochemical Pathways Underlying Complexity 346
9.16 Behavioral Genetics 349
9.17 Genes Expression: Another Level of Complexity 352
Chapter 10 The Multiple-Hit Hypothesis: How Genes Play a Role in Cancer 358
10.1 The War on Cancer 359
10.2 Cancer as a Defect in Regulation of the Cell Cycle 360
10.3 Cancer as a Genetic Disease 361
10.4 Cancer and the Environment 363
10.5 Tumor Suppressor Genes and the Two-Hit Hypothesis 363
10.6 Cell-Type Specificity of Tumor Suppressor Gene Defects 367
10.7 The Multi-Hit Hypothesis 368
10.8 The Activation of Proto-Oncogenes and the Role of Oncogenes in Promoting Cancer 370
10.9 Defects in DNA Repair 372
10.10 Personalized Medicine 373
10.11 Cancer Biomarkers 376
SECTION V: HOW GENES ARE FOUND 382
Chapter 11 The Gene Hunt: How Genetic Maps Are Built and Used 384
11.1 What Is a Genetic Map? 385
11.2 What Is a Genetic Marker? 387
11.3 Finding Genes before There Were Maps 393
11.4 Defining the Thing to Be Mapped 395
11.5 Recombination as a Measure of Genetic Distance 397
11.6 Physical Maps and Physical Distances 403
11.7 How Did They Build Genetic Maps? 408
11.8 After the Map: What Came Next? 411
Chapter 12 The Human Genome: How the Sequence Enables Genome-wide Studies 420
12.1 The Human Genome Project 421
12.2 The Human Genome Sequence 431
12.3 The Other Genome Projects 433
12.4 The Genes in the Human Genome 435
12.5 Human Genome Variation 443
12.6 Genome-wide Technologies 447
12.7 Genome-wide Association 448
12.8 Allele Sharing and Sib Pair Analysis 454
12.9 Copy Number Variation and Gene Dosage 455
12.10 Whole Genome Sequencing 458
SECTION VI: HOW GENES PLAY A ROLE IN TESTING AND TREATMENT 468
Chapter 13 Genetic Testing and Screening: How Genotyping Can Offer Important Insights 470
13.1 What Is Medical Genetics? 472
13.2 Screening vs. Testing 474
13.3 Preimplantation Genetic Screening 476
13.4 Prenatal Diagnosis During the First Trimester 478
13.5 Prenatal Diagnosis During the Second Trimester 480
13.6 Amniocentesis and Chorionic Villus Sampling 481
13.7 Analysis of Fetal Cells 484
13.8 Sex Selection 488
13.9 Newborn Screening 489
13.10 Adult Genetic Screening and Testing 490
13.11 Ethical, Legal, and Social Issues 495
Chapter 14 Magic Bullets: How Gene-based Therapies Personalize Medicine 502
14.1 Replacing a Lost Gene or Funtion – The RPE Story 503
14.2 Replacing a Lost Gene – ADA Deficiency 507
14.3 Targeting Downstream Disease Pathology 508
14.4 Suppressing the Unwanted Genotype – Use of siRNAs and miRNAs 510
14.5 Gene Supplement Therapy – More of the Same 512
14.6 Strategies for Cancer Therapy 513
14.7 Gene-based Therapy Instead of Gene Therapy 515
14.8 Delivering Gene Therapy 517
14.9 Do We Have to Treat the Whole Body? 518
14.10 What Are the Biggest Problems with Gene Therapy? 520
14.11 So, Whom Do We Treat? 521
Chapter 15 Fears, Faith, and Fantasies: How the Past and Present Shape the Future of Genomic Medicine 528
15.1 Fears – A Tale of Eugenics 529
15.2 Faith – A Tale of Ethical, Legal, and Social Advances 533
15.3 Fantasies – A Tale of Our Genetic Future 537
Answers to Study Questions 542
Glossary 568
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B 569
C 570
D 573
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M 580
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Index 590
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H 594
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K 595
L 595
M 595
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Q 597
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S 598
T 598
U 599
V 599
W 599
X 599
Y 600
Z 600