目录 Ⅰ 基因如何决定性状 1 遗传的基础：性状如何在家庭中传递 3 1.1 孟德尔定律 4 1.2 选择：人工，自然和性选择 12 1.3 人类遗传多样性 15 1.4 人类显性遗传 16 1.5 人类隐性遗传 19 1.6 遗传互补 27 1.7 上位效应和基因多效性 31 1.8 复杂性症状 32 1.9 一个人的疾病是另一人的性状 34 2 双螺旋：细胞如何保存遗传信息 41 2.1 细胞的内幕 42 2.2 DNA：遗传信息的存储器 44 2.3 DNA和双螺旋 47 2.4 DNA复制 50 2.5 染色质 56 2.6 什么是染色体？ 57 2.7 常染色质和异染色质 64 2.8 线粒体的染色体：人类基因组中的另一个“基因组” 65 2.9 DNA的体外研究 67 Ⅱ 基因如何行使功能 3 分子生物学的中心法则：细胞如何编排使用遗传信息 83 3.1 什么是RNA？ 84 3.2 RNA是做什么的？ 87 3.3 RNA转录 89 3.4 表达的编排 91 3.5 检测基因表达 95 3.6 转录因子的相互作用 98 3.7 可诱导基因 102 3.8 基因表达的表观调控 104 3.9 什么是“正常”？ 106 4 遗传密码：细胞如何从编码在mRNA分子中的遗传信息产生出蛋白质 115 4.1 遗传密码 116 4.2 细胞核内外的物质传递 119 4.3 分子生物学的中心法则 120 4.4 翻译 120 4.5 信使RNA结构 122 4.6 剪切 124 4.7 模块化的基因 128 4.8 什么是蛋白质？ 130 4.9 基因产物与发育 135 5 我们都是突变体：突变如何改变功能 143 5.1 什么是突变？ 144 5.2 突变的产生 147 5.3 如何检测突变 153 5.4 主要突变类型 159 5.5 调节基因表达的DNA序列突变 166 5.6 拷贝数变异：好东西的过多或过少 167 5.7 重复序列扩增 169 5.8 男性的生命时钟 180 5.9 最大的突变目标 180 5.10 突变导致的功能缺失与损害 183 Ⅲ 染色体如何移动 6 有丝分裂和减数分裂：细胞如何变动你的基因 199 6.1 细胞周期 200 6.2 有丝分裂 201 6.3 配子生成：减数分裂都实现了什么？ 207 6.4 减数分裂细节 211 6.5 减数分裂中染色体配对机制 217 6.6 遗传的染色体基础 219 6.7 非整倍体：染色体数目过多或过少 224 6.8 单亲二体性 230 6.9 部分非整倍性 236 6.10 女性的生命时钟 238 附录6.1 减数分裂分离失败(不分离) ：遗传的染色体理论之证据 240 7 特殊的一对：X与Y染色体如何打乱了规则 247 7.1 X和Y染色体在世代间的传递 248 7.2 人类如何应付男女之间性染色体数目的差别 249 7.3 如何实现X染色体失活 250 7.4 倾斜的X染色体失活——大部分细胞失活相同的X染色体 251 7.5 逃过X染色体失活的基因 255 7.6 失活X染色体在女性种系细胞中的激活 255 7.7 X染色体在男性减数分裂期间的失活 255 7.8 X染色体失活与性染色体非整倍性表型 257 7.9 人类Y染色体结构 259 7.10 X连锁的隐性遗传 262 7.11 X连锁的显性遗传 265 Ⅳ 基因如何影响复杂性状 8 性别决定：基因如何做出发育的选择 273 8.1 性别：一个复杂的发育性状 274 8.2 X和Y染色体与性别的关系 278 8.3 Y染色体上的SRY：雄性分化的遗传决定因素 279 8.4 激素在早期发育中的作用 282 8.5 X染色体上的雄性激素受体：性别分化通路中的另一环节 285 8.6 性别鉴定的遗传学 287 8.7 性取向的遗传学 288 9 复杂性：多因子组合如何产生性状 299 9.1 双基因二等位基因遗传 300 9.2 双基因三等位基因遗传 304 9.3 多因子遗传 305 9.4 数量性状 307 9.5 加性效应和阈值 309 9.6 这是遗传的吗？ 310 9.7 基因和环境：可诱导性状 312 9.8 基因和环境：感染性疾病 315 9.9 拟表型 319 9.10 基因型的兼容性：谁的基因组受影响？ 322 9.11 表型异质性：一个基因，多种性状 324 9.12 基因型和表现型的异质性 325 9.13 可变的表型表现性 328 9.14 表型修饰因子 329 9.15 复杂性背后的生化通路 331 9.16 行为遗传学 334 9.17 基因表达：复杂性的另一层次 337 10 多次打击假说：基因如何引起癌症 343 10.1 抗癌之战 344 10.2 癌症：一种细胞周期调控的缺陷 345 10.3 癌症：一种基因病 346 10.4 癌症和环境 348 10.5 肿瘤抑制基因与两次打击假说 348 10.6 肿瘤抑制基因缺陷的细胞特异性 352 10.7 多次打击假说 353 10.8 原癌基因的激活和癌基因在致肿瘤发生中的作用 355 10.9 DNA修复的缺陷 357 10.10 个体化医学 358 10.11 癌症的生物标志物 361 Ⅴ 怎样发现基因 11 基因猎取：如何建立和使用遗传图谱 369 11.1 什么是遗传图谱？ 370 11.2 什么是遗传标记？ 372 11.3 在有图谱之前发现基因 378 11.4 确定定位内容 380 11.5 以重组来衡量遗传距离 382 11.6 物理图谱和物理距离 388 11.7 遗传图谱是如何绘制的？ 393 11.8 图谱之后做什么？ 396 12 人类基因组：DNA序列如何启动全基因组的研究 405 12.1 人类基因组计划 406 12.2 人类基因组序列 416 12.3 其他的基因组计划 418 12.4 人类基因组中的基因 420 12.5 人类基因组的变异 428 12.6 全基因组技术 432 12.7 全基因组关联分析 433 12.8 等位基因共享和同胞对分析 439 12.9 拷贝数变异和基因剂量 440 12.10 全基因组测序 443 Ⅵ 基因在检测和治疗中的作用 13 遗传检测和筛查：基因型如何提供重要信息 455 13.1 什么是医学遗传学 457 13.2 筛查相比较于测试 459 13.3 胚胎植入前遗传筛查 461 13.4 妊娠首三个月的产前诊断 463 13.5 妊娠中三个月的产前诊断 465 13.6 羊膜腔穿刺和绒膜绒毛取样 466 13.7 胎儿细胞分析 469 13.8 性别选择 473 13.9 新生儿筛查 474 13.10 成年人遗传筛查和检测 475 13.11 道德、法律和社会问题 480 14 基于基因的治疗如何实现医学个体化 487 14.1 替换丢失的基因或功能——RPE65 的故事 488 14.2 替换丢失的基因ADA——缺陷 492 14.3 以疾病病理的下游为治疗靶标 493 14.4 抑制有害的基因型——siRNAs 和miRNAs 的使用 495 14.5 基因补充治疗——增加相同的东西 497 14.6 癌症治疗策略 498 14.7 基于基因的治疗代替基因疗法 500 14.8 基因疗法的导入 502 14.9 我们需要全身的治疗吗？ 503 14.10 基因治疗的最大问题是什么？ 505 14.11 我们治疗哪些病人？ 506 15 担忧、信任和期望：过去和现状如何决定基因组医学的未来 513 15.1 担忧：一段优生学的荒诞记录 514 15.2 信任：一个关于伦理、法律和社会进步的故事 518 15.3 期望：一个对于我们基因的未来想象 522 思考题答案 527 词汇表 553 索引 575 Contents Acknowledgments xi Prologue: The Answer in a Nutshell xiii I HOW GENES SPECIFY A TRAIT 1 The Basics of Heredity: How Traits Are Passed Along in Families 3 1.1 Mendel’s Laws 4 1.2 Selection: Artifi cial, Natural, and Sexual 12 1.3 Human Genetic Diversity 15 1.4 Human Dominant Inheritance 16 1.5 Human Recessive Inheritance 19 1.6 Complementation 27 1.7 Epistasis and Pleiotropy 31 1.8 Complex Syndromes 32 1.9 One Man’s Disease Is Another Man’s Trait 34 2 The Double Helix: How Cells Preserve Genetic Information 41 2.1 Inside the Cell 42 2.2 DNA: The Repository of Genetic Information 44 2.3 DNA and the Double Helix 47 2.4 DNA Replication 50 2.5 Chromatin 56 2.6 What Are Chromosomes? 57 2.7 Euchromatin and Heterochromatin 64 2.8 The Mitochondrial Chromosome: The “Other Genome” in the Human Genome 65 2.9 DNA in vitro 67 II HOW GENES FUNCTION 3 The Central Dogma of Molecular Biology: How Cells Orchestrate the Use of Genetic Information 83 3.1 What Is RNA? 84 3.2 What Is RNA For? 87 3.3 Transcription of RNA 89 3.4 Orchestrating Expression 91 3.5 Monitoring Gene Expression 95 3.6 Interaction of Transcription Factors 98 3.7 Inducible Genes 102 3.8 Epigenetic Control of Gene Expression 104 3.9 What Constitutes Normal? 106 4 The Genetic Code: How the Cell Makes Proteins from Genetic Information Encoded in mRNA Molecules 115 4.1 The Genetic Code 116 4.2 Moving Things In and Out of the Nucleus 119 4.3 The Central Dogma of Molecular Biology 120 4.4 Translation 120 4.5 Messenger RNA Structure 122 4.6 Splicing 124 4.7 Modular Genes 128 4.8 What Are Proteins? 130 4.9 Gene Products and Development 135 5 We Are All Mutants: How Mutation Alters Function 143 5.1 What Is a Mutation? 144 5.2 The Process of Mutation 147 5.3 How We Detect Mutations 153 5.4 Basic Mutations 159 5.5 Mutations in DNA Sequences that Regulate Gene Expression 166 5.6 Copy Number Variation: Too Much or Too Little of a Good Thing 167 5.7 Expanded Repeat Traits 169 5.8 The Male Biological Clock 180 5.9 Mutation Target Size 180 5.10 Absent Essentials and Monkey Wrenches 183 III HOW CHROMOSOMES MOVE 6 Mitosis and Meiosis: How Cells Move Your Genes Around 199 6.1 The Cell Cycle 200 6.2 Mitosis 201 6.3 Gametogenesis: What Is Meiosis Trying to Accomplish? 207 6.4 Meiosis in Detail 211 6.5 Mechanisms of Chromosome Pairing in Meiosis 217 6.6 The Chromosomal Basis of Heredity 219 6.7 Aneuploidy: When Too Much or Too Little Counts 224 6.8 Uniparental Disomy 230 6.9 Partial Aneuploidies 236 6.10 The Female Biological Clock 238 Appendix 6.1 Failed Meiotic Segregation (Nondisjunction) as Proof of the Chromosome Theory of Heredity 240 7 The Odd Couple: How the X and Y Chromosomes Break the Rules 247 7.1 Passing the X and Y Chromosomes between Generations 248 7.2 How Humans Cope with the Difference in Number of Sex Chromosomes between Males and Females 249 7.3 How X Inactivation Works 250 7.4 Skewed X Inactivation – When Most Cells Inactivate the Same X 251 7.5 Genes that Escape X-Inactivation 255 7.6 Reactivation of the Inactive X Chromosome in the Female Germline 255 7.7 X Chromosome Inactivation During Male Meiosis 255 7.8 X Inactivation and the Phenotypes of Sex Chromosome Aneuploidy 257 7.9 The Structure of the Human Y Chromosome 259 7.10 X-Linked Recessive Inheritance 262 7.11 X-Linked Dominant Inheritance 265 IV HOW GENES CONTRIBUTE TO COMPLEX TRAITS 8 Sex Determination: How Genes Determine a Developmental Choice 273 8.1 Sex as a Complex Developmental Characteristic 274 8.2 What Do the X and Y Chromosomes Have to Do With Sex? 278 8.3 SRY on the Y: The Genetic Determinant of Male Sexual Differentiation 279 8.4 The Role of Hormones in Early Development 282 8.5 Androgen Receptor on the X: Another Step in the Sexual Differentiation Pathway 285 8.6 Genetics of Gender Identifi cation 287 8.7 Genetics of Sexual Orientation 288 9 Complexity: How Traits Can Result from Combinations of Factors 299 9.1 Digenic Diallelic Inheritance 300 9.2 Digenic Triallelic Inheritance 304 9.3 Multifactorial Inheritance 305 9.4 Quantitative Traits 307 9.5 Additive Effects and Thresholds 309 9.6 Is It Genetic? 310 9.7 Genes and Environment: Inducible Traits 312 9.8 Genes and Environment: Infectious Disease 315 9.9 Phenocopies 319 9.10 Genotypic Compatibility: Whose Genome Matters? 322 9.11 Phenotypic Heterogeneity: One Gene, Many Traits 324 9.12 Genotypic and Phenotypic Heterogeneity 325 9.13 Variable Expressivity 328 9.14 Phenotypic Modifi ers 329 9.15 Biochemical Pathways Underlying Complexity 331 9.16 Behavioral Genetics 334 9.17 Genes Expression: Another Level of Complexity 337 10 The Multiple-Hit Hypothesis: How Genes Play a Role in Cancer 343 10.1 The War on Cancer 344 10.2 Cancer as a Defect in Regulation of the Cell Cycle 345 10.3 Cancer as a Genetic Disease 346 10.4 Cancer and the Environment 348 10.5 Tumor Suppressor Genes and the Two-Hit Hypothesis 348 10.6 Cell-Type Specifi city of Tumor Suppressor Gene Defects 352 10.7 The Multi-Hit Hypothesis 353 10.8 The Activation of Proto-Oncogenes and the Role of Oncogenes in Promoting Cancer 355 10.9 Defects in DNA Repair 357 10.10 Personalized Medicine 358 10.11 Cancer Biomarkers 361 V HOW GENES ARE FOUND 11 The Gene Hunt: How Genetic Maps Are Built and Used 369 11.1 What Is a Genetic Map? 370 11.2 What Is a Genetic Marker? 372 11.3 Finding Genes before There Were Maps 378 11.4 Defi ning the Thing to Be Mapped 380 11.5 Recombination as a Measure of Genetic Distance 382 11.6 Physical Maps and Physical Distances 388 11.7 How Did They Build Genetic Maps? 393 11.8 After the Map: What Came Next? 396 12 The Human Genome: How the Sequence Enables Genome-wide Studies 405 12.1 The Human Genome Project 406 12.2 The Human Genome Sequence 416 12.3 The Other Genome Projects 418 12.4 The Genes in the Human Genome 420 12.5 Human Genome Variation 428 12.6 Genome-wide Technologies 432 12.7 Genome-wide Association 433 12.8 Allele Sharing and Sib Pair Analysis 439 12.9 Copy Number Variation and Gene Dosage 440 12.10 Whole Genome Sequencing 443 VI HOW GENES PLAY A ROLE IN TESTING AND TREATMENT 13 Genetic Testing and Screening:How Genotyping Can Offer Important Insights 455 13.1 What Is Medical Genetics? 457 13.2 Screening vs. Testing 459 13.3 Preimplantation Genetic Screening 461 13.4 Prenatal Diagnosis During the First Trimester 463 13.5 Prenatal Diagnosis During the Second Trimester 465 13.6 Amniocentesis and Chorionic Villus Sampling 466 13.7 Analysis of Fetal Cells 469 13.8 Sex Selection 473 13.9 Newborn Screening 474 13.10 Adult Genetic Screening and Testing 475 13.11 Ethical, Legal, and Social Issues 480 14 Magic Bullets: How Gene-based Therapies Personalize Medicine 487 14.1 Replacing a Lost Gene or Funtion – The RPE65 Story 488 14.2 Replacing a Lost Gene – ADA Defi ciency 492 14.3 Targeting Downstream Disease Pathology 493 14.4 Suppressing the Unwanted Genotype – Use of siRNAs and miRNAs 495 14.5 Gene Supplement Therapy – More of the Same 497 14.6 Strategies for Cancer Therapy 498 14.7 Gene-based Therapy Instead of Gene Therapy 500 14.8 Delivering Gene Therapy 502 14.9 Do We Have to Treat the Whole Body? 503 14.10 What Are the Biggest Problems with Gene Therapy? 505 14.11 So, Whom Do We Treat? 506 15 Fears, Faith, and Fantasies: How the Past and Present Shape the Future of Genomic Medicine 513 15.1 Fears – A Tale of Eugenics 514 15.2 Faith – A Tale of Ethical, Legal, and Social Advances 518 15.3 Fantasies – A Tale of Our Genetic Future 522 Answers to Study Questions 527 Glossary 553 Index 575
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