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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	Index	590
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