The Human Genome: A User's Guide, 3rd Edition

The Human Genome......Page 2
Copyright......Page 5
Dedication......Page 6
Acknowledgments......Page 7
Prologue: The Answer in a Nutshell......Page 9
The Basics of Heredity: How Traits Are Passed Along in Families......Page 13
Mendel’s Laws......Page 14
What Mendel Did......Page 15
Concept: What Passes from One Generation to the Next Is Information......Page 17
Concept: Dominant Alleles Mask the Detection of Recessive Alleles......Page 18
Concept: One Allele Comes from Each Parent; One Allele Passes to Each Child......Page 19
Selection: Artificial, Natural, and Sexual......Page 22
Natural Selection......Page 23
Sexual Selection......Page 24
Human Genetic Diversity......Page 25
Human Dominant Inheritance......Page 26
Human Recessive Inheritance......Page 29
Albinism Is Recessive......Page 30
Transmission of Albinism in Families......Page 32
There Are Many Recessive Traits......Page 33
Pseudo-dominant Inheritance of a Recessive Trait......Page 35
Complementation......Page 37
Epistasis and Pleiotropy......Page 41
Complex Syndromes......Page 42
One Man’s disease is Another Man’s trait......Page 44
The Double Helix: How Cells Preserve Genetic Information......Page 51
The View Through the Microscope......Page 52
DNA and Transformation – Griffiths......Page 54
DNA and Transformation – Hershey and Chase......Page 56
DNA Bases – The Letters of the Genetic Alphabet......Page 57
The DNA Helix......Page 58
Complementary Information......Page 60
DNA Polymerase Replicates DNA......Page 62
Semi-Conservative Replication of DNA......Page 65
Chromatin......Page 66
The First Views of the Human Genetic Blueprint......Page 67
Visible Landmarks on the Chromosomes......Page 68
How to Tell One Chromosome from Another......Page 70
Chromosomes Come in Pairs – Mostly......Page 71
FISH and Chromosome Painting......Page 72
Euchromatin and Heterochromatin......Page 74
Mitochondrial Mode of Inheritance......Page 75
Tools for the Study of DNA......Page 77
Cloning – Making Copies of DNA......Page 78
PCR – Making Copies of DNA......Page 81
How PCR Works......Page 82
Copying DNA Between Two Primers......Page 84
Of Hot Springs and Vent Worms......Page 85
From Reaction to Chain Reaction......Page 86
The Central Dogma of Molecular Biology: How Cells Orchestrate the Use of Genetic Information......Page 93
Permanent DNA and Temporary RNA Copies......Page 94
What is RNA for?......Page 97
The Process of Transcription......Page 99
Orchestrating Expression......Page 101
The Concept of a Promoter......Page 102
Cis and Trans......Page 103
Northern Blots: One Gene at a Time......Page 105
Microarrays......Page 106
An Example of Two Regulatory Factors That Play a Critical Role in the Eye......Page 108
Enhancers – Another Level of Regulation......Page 110
RNA Turnover......Page 111
Inducible genes......Page 112
Hormones......Page 113
Epigenetic control of gene expression......Page 114
What constitutes normal?......Page 116
The Problem with Diagnosing an Inducible Phenotype......Page 117
Induction and Gene Regulation......Page 118
So What or Who Is Normal Anyway?......Page 119
The Genetic Code: How the Cell Makes Proteins from Genetic Information Encoded in mRNA Molecules......Page 125
The genetic code......Page 126
Codons and the Code......Page 127
Moving things in and out of the nucleus......Page 129
Translation......Page 130
Translation Requires an Adaptor Molecule Called tRNA......Page 131
Messenger rna structure......Page 132
Splicing......Page 134
Genes with Multiple Introns......Page 135
Where Does Splicing Cut?......Page 137
Modular genes......Page 138
The Implications of Modular Genes......Page 139
What are proteins?......Page 140
How We Become Human......Page 145
Developmental Regulatory Events......Page 147
Eye-building Genes in Flies and Humans......Page 149
Where Do All of the Differences in Proteins Come From?......Page 150
We Are All Mutants: How Mutation Alters Function......Page 153
5.1 What is a Mutation?......Page 154
An Example of a Chemical (EMS) that Causes Mutations......Page 157
Radiation Can Cause Mutation......Page 159
Mutations Can Happen without Environmental Exposure......Page 161
How Often Do Mutations Happen?......Page 162
5.3 How We Detect Mutations......Page 163
5.4 Basic Mutations......Page 164
Sequence Tagged Sites and the Bioinformatics Revolution......Page 168
Missense Mutations Change the Protein Sequence......Page 169
Nonsense Mutations Truncate the Protein......Page 170
Mutations Don’t Always Change the Protein......Page 172
Insertions and Deletions......Page 173
Splice Site Mutations......Page 175
5.5 Mutations in DNA Sequences that Regulate Gene Expression......Page 176
5.6 Copy Number Variation: Too Much or Too Little of a Good Thing......Page 177
5.7 Expanded Repeat Traits......Page 179
Expanding and Contracting Repeats......Page 180
The Effect of Repeat Length Differences......Page 184
Genetic Testing and HD......Page 185
Long Repeats Beget Longer Repeats......Page 187
Anticipation......Page 188
5.9 Mutation Target Size......Page 190
Does Large Size Affect the Genetic Behavior of These Genes?......Page 191
5.10 Absent Essentials and Monkey Wrenches......Page 193
The Expected Case: A Loss-of-function Mutation Produces a Recessive Trait......Page 195
The Surprising Case: A Loss-of-function Mutation Produces a Dominant Trait......Page 197
The Expected Case: The Proverbial Monkey Wrench Results in a Dominant Trait......Page 198
The Surprising Case: A Gain of Function Results in a Recessive Trait......Page 200
In Summary......Page 202
Mitosis and Meiosis: How Cells Move Your Genes Around......Page 209
The Cell Cycle......Page 210
Mitosis Ensures that Two Daughter Cells Have the Same Genotype......Page 211
Gametogenesis: What Is Meiosis Trying to Accomplish?......Page 217
Meiosis Is Executed Quite Differently in Human Males and Females......Page 220
Meiosis Made Simple......Page 221
Recombination Commits Paired Chromosomes to Segregate from Their Homologs......Page 222
Centromeres Mediate Chromosome Movement......Page 226
Mechanisms of Chromosome Pairing in Meiosis......Page 227
Doing Meiosis with Two Pairs of Chromosomes......Page 229
Gene Pairs Located on Different Chromosomes Segregate at Random......Page 230
Recombination Between Pairs of Genes Located on the Same Chromosome......Page 231
Aneuploidy: When Too Much or Too Little Counts......Page 234
Down Syndrome, or Trisomy for Chromosome 21......Page 236
Most Cases of Down Syndrome Are Due to Nondisjunction in the Mother......Page 238
Uniparental Isodisomy “Uncovers” Mutations......Page 240
Zygote Rescue......Page 242
Uniparental Disomy in the Absence of Mutations......Page 243
The Effects of Paternal vs. Maternal Imprinting......Page 244
Mechanism of Parent of Origin Effects......Page 245
Translocations and Down Syndrome......Page 246
The Female Biological Clock......Page 248
The Odd Couple: How the X and Y Chromosomes Break the Rules......Page 257
Passing the X and Y Chromosomes Between Generations......Page 258
How Humans Cope with the Difference in Number of Sex Chromosomes Between Males and Females......Page 259
How X Inactivation Works......Page 260
Skewed X Inactivation – When Most Cells Inactivate the Same X......Page 261
Skewed Inactivation in Monozygotic Twins......Page 262
Skewed X Inactivation in Females Heterozygous for Chromosome Rearrangements......Page 263
X Chromosome Inactivation During Male Meiosis......Page 265
Variability of Turner Syndrome......Page 267
Other Sex Chromosome Aneuploidies......Page 268
Structure of the Y Chromosome......Page 269
Recombination among Palindromic Repeats and Male Infertility......Page 270
X-Linked Recessive Inheritance......Page 272
X-Linked Dominant Inheritance......Page 275
Sex Determination: How Genes Determine a Developmental Choice......Page 283
Sex as a Complex Developmental Characteristic......Page 284
Defining Features of a Complex Developmental Phenotype......Page 285
Secondary Sexual Characteristics......Page 287
What Do the X and Y Chromosomes Have to Do With Sex?......Page 288
SRY Initiates Male Sexual Differentiation......Page 289
The SRY Gene Causes the Indifferent Gonads to Develop as Testes......Page 291
Gonads Dictate the Next Step in Development of Somatic Sexual Characteristics......Page 292
Congenital Adrenal Hyperplasia and Ambiguous Genitalia......Page 293
Hormones Carry Signals to Other Cells in the Body......Page 294
Mutations in the Gene that Encodes the Androgen Receptor......Page 295
Mechanisms of Gender Identification......Page 297
Genetics of Sexual Orientation......Page 298
The Genetics of Sexual Orientation: Population Studies......Page 299
The Genetics of Sexual Orientation: Family Studies......Page 300
What If the Results Mean Something Else?......Page 304
Reprise......Page 305
Complexity: How Traits Can Result from Combinations of Factors......Page 309
Digenic diallelic Inheritance......Page 310
digenic Triallelic Inheritance......Page 314
Multifactorial Inheritance......Page 315
Rules for Multifactorial Inheritance......Page 316
Quantitative Traits......Page 317
Many Traits Are Specified by Additive Effects of More than One Gene......Page 318
Additive Effects and Thresholds......Page 319
Is it Genetic?......Page 320
Genetic Classification Assists Risk Estimation......Page 321
Genes and Environment: Inducible Traits......Page 322
Mad Cows and Cannibals......Page 323
Genes and Environment: Infectious Disease......Page 325
Infectious Organisms......Page 327
Host Defenses......Page 328
Phenocopies......Page 329
Identity by State......Page 330
What If We Don’t Realize It Is Genetic? What If It Looks Genetic but It Isn’t?......Page 331
Genotypic Compatability: Whose Genome Matters?......Page 332
Phenotypic Heterogeneity: One Gene, Many Traits......Page 334
Genotypic and Phenotypic Heterogeneity......Page 335
Different Mutations Associated with Variation in Expressivity......Page 338
Phenotypic Modifiers......Page 339
The Biochemical Assembly Line......Page 341
Gene Families......Page 343
Behavioral Genetics......Page 344
Genetics of Violent Aggression in a Dutch Family......Page 345
GENE EXpression: ANoTHER LEVEL OF Complexity......Page 347
Genes Are Not Always Destiny......Page 349
The Multiple-Hit Hypothesis: How Genes Play a Role in Cancer......Page 353
The War on Cancer......Page 354
Cancer as a Defect in Regulation of the Cell Cycle......Page 355
Accumulation of Mutations in Somatic Cells Can Cause Tumors......Page 356
Hereditary Retinoblastoma: A Model for Understanding the Genetics of Tumor Formation......Page 358
The Two-Hit Hypothesis......Page 359
Loss of Heterozygosity......Page 360
Cell-Type Specificity of tumor suppressoR Gene Defects......Page 362
Adenomatous Polyposis Coli......Page 363
How Do the Products of Tumor Suppressor Genes Act to Prevent Tumor Formation?......Page 364
The End Run: Dominant Tumor-Promoting Mutations Push the Cell into the Division Cycle......Page 365
Defects in DNA Repair......Page 367
Personalized Medicine......Page 368
Building Magic Bullets – The Imatinib Story......Page 369
Acute Myeloid Leukemia: Wielding a Molecular Lance......Page 370
Fluorescent In Situ Hybridization (FISH)......Page 371
A Concluding Thought......Page 373
The Gene Hunt: How Genetic Maps Are Built and Used......Page 379
What is a Genetic Map?......Page 380
What is a Genetic Marker?......Page 382
The Development of the Human Genetic Map......Page 383
Informativeness......Page 386
Differences between the Male and Female Maps......Page 387
Finding Genes before there were Maps......Page 388
Ideal Gene Mapping Situation......Page 390
Correct Classification of the Phenotype......Page 391
Linkage......Page 392
The LOD Score and the Recombination Fraction......Page 394
How Many People Do We Have to Include in a Linkage Study?......Page 396
Multipoint Information......Page 397
A Map Based on the Sequence......Page 398
Physical Markers Detectable Under the Microscope......Page 399
Synteny: Correlating the Human and Animal Model Maps at the Physical Level......Page 400
The Sequence as the Final Physical Map......Page 402
How Did they Build Genetic Maps?......Page 403
Putting a Gene Onto a Map......Page 404
Getting from the Map to the Gene......Page 406
From Animal Models to Human Disease Genes......Page 408
Using the Sequence to Find Human Disease Genes......Page 410
The Human Genome: How the Sequence Enables Genome-wide Studies......Page 415
The Human Genome Project......Page 416
What Is the Human Genome Project?......Page 417
The Human Genome Timeline......Page 418
Who Carried Out the Human Genome Project?......Page 423
Who Owns Your Genome Sequence?......Page 424
How Big Are the Chromosomes?......Page 426
The X and Y Chromosomes......Page 427
The Other Genome Projects......Page 428
How Do Animal Genome Projects Inform Human Studies?......Page 429
How Many Genes Are There?......Page 430
Identifying the Genes......Page 432
Gene Deserts......Page 433
How Are the Genes Distributed?......Page 434
Gene Families and Paralogy......Page 435
What Is Out There Besides the Genes?......Page 437
We Are All Amazingly Similar......Page 438
Variation Between Populations......Page 439
Genome-wide Technologies......Page 442
Association......Page 443
Multi-testing......Page 444
Two-stage GWAS......Page 445
Linkage Disequilibrium......Page 446
Genes and Environment......Page 447
“Fourth Quadrant” Strategies......Page 448
Allele Sharing and Sib Pair Analysis......Page 449
Copy Number Variation and Gene Dosage......Page 450
Whole Genome Sequencing......Page 453
Finding a Causative Mutation......Page 454
Finding a New Disease Gene......Page 455
Whole Genome Diagnostics......Page 456
Cancer Diagnostics......Page 457
Pharmacogenomics......Page 458
What’s Next?......Page 459
Genetic Testing and Screening: How Genotyping Can Offer Important Insights......Page 465
What Is Medical Genetics?......Page 467
Biochemical vs. Genetic Assays......Page 469
Screening Populations vs. Testing Individuals......Page 470
Preimplantation Genetic Screening......Page 471
Minimally Invasive Screening......Page 473
Ultrasound......Page 474
prenatal diagnosis during the Second Trimester......Page 475
Amniocentesis and Chorionic Villus Sampling......Page 476
Chorionic Villus Sampling......Page 477
Karyotyping......Page 479
DNA Analysis......Page 480
Be Sure Your Information Is Correct......Page 481
Where to Turn for Genetic Testing......Page 482
Sex Selection......Page 483
Newborn Screening......Page 484
Adult Genetic Screening and Testing......Page 485
Direct-to-Consumer Testing......Page 487
Research-based Testing......Page 488
Genetic Matchmaking and Other Strategies......Page 490
The “Maybe” Result......Page 492
The Line that Can’t Be Crossed......Page 493
Magic Bullets: How Gene-based Therapies Personalize Medicine......Page 497
14.1 REPLACING A LOST GENE OR FUNCTION – THE RPE65 STORY......Page 498
14.2 REPLACING A LOSTGENE – ADA DEFICIENCY......Page 502
14.3 TARGETING DOWNSTREAM DISEASE PATHOLOGY......Page 503
14.4 SUPPRESSING THE UNWANTED GENOTYPE – USE OF siRNAs AND miRNAs......Page 505
14.5 GENE SUPPLEMENTTHERAPY – MORE OF THE SAME......Page 507
14.6 STRATEGIES FOR CANCER THERAPY......Page 508
14.7 GENE-BASED THERAPY INSTEAD OF GENE THERAPY......Page 510
14.8 DELIVERING GENE THERAPY......Page 512
14.9 DO WE HAVE TO TREAT THE WHOLE BODY?......Page 513
14.10 WHAT ARE THE BIGGEST PROBLEMS WITH GENE THERAPY?......Page 515
14.11 SO, WHOM DO WE TREAT?......Page 516
Fears, Faith, and Fantasies: How the Past and Present Shape the Future of Genomic Medicine......Page 523
Fears – A Tale of Eugenics......Page 524
Faith – A Tale of Ethical, Legal, and Social Advances......Page 528
Fantasies – A Tale of Our Genetic Future......Page 532
Answers to Study Questions......Page 537
Glossary......Page 563
Index......Page 585