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Genetic Analysis
AN INTEGRATED APPROACH
Third Edition

Mark F. Sanders
University of California at Davis

John L. Bowman
Monash University,
Melbourne, Australia
University of California at Davis

330 Hudson Street, NY NY 10013

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Library of Congress Cataloging-in-Publication Data

Names: Sanders, Mark Frederick, author. | Bowman, John L., author.

Title: Genetic analysis : an integrated approach / Mark F. Sanders, John L. Bowman.
Description: Third edition. | New York : Pearson Education, Inc., [2019] |
   Includes bibliographical references and index.
Identifiers: LCCN 2017052380 | ISBN 9780134605173 | ISBN 0134605179
Subjects: | MESH: Genetic Phenomena | Genetic Techniques
Classification: LCC QH430 | NLM QU 500 | DDC 616/.042--dc23
LC record available at https://lccn.loc.gov/2017052380

1 17

ISBN-10: 0134605179
ISBN-13: 9780134605173

www.pearsonhighered.com
Table of Contents
1 2
The Molecular Basis of Transmission Genetics 30
Heredity, Variation, and
Evolution 1 2.1 Gregor Mendel Discovered the Basic
­Principles of Genetic Transmission 31
Mendel’s Modern Experimental Approach 31
1.1 Modern Genetics Is in Its Second
Century 2 Five Critical Experimental Innovations 33
The Development of Modern Genetics 2
The Four Phases of Modern Genetics 3
2.2 Monohybrid Crosses Reveal the
­Segregation of Alleles 34
Genetics—Central to Modern Biology 5
Identifying Dominant and Recessive Traits 34
Evidence of Particulate Inheritance and Rejection of the
1.2 The Structure of DNA Suggests Blending Theory 36
a ­Mechanism for Replication 6 Segregation of Alleles 36
The Discovery of DNA Structure 6
Hypothesis Testing by Test-Cross Analysis 37
DNA Nucleotides 7
Hypothesis Testing by F2 Self-Fertilization 38
DNA Replication 9
Genetic Analysis 2.1 39
Genetic Analysis 1.1 10
Experimental Insight 1.1 10 2.3 Dihybrid and Trihybrid Crosses Reveal the
Independent Assortment of Alleles 40
1.3 DNA Transcription and Messenger Dihybrid-Cross Analysis of Two Genes 40
RNA Translation Express Genes 11 Experimental Insight 2.1 41
Transcription 12 Testing Independent Assortment by Test-Cross
Translation 13 Analysis 43
Genetic Analysis 1.2 14 Genetic Analysis 2.2 44
Testing Independent Assortment by Trihybrid-Cross
Analysis 45
1.4 Genetic Variation Can Be Detected
The Rediscovery of Mendel’s Work 46
by Examining DNA, RNA, and Proteins 15
Gel Electrophoresis 15 Experimental Insight 2.2 46
Stains, Blots, and Probes 16
DNA Sequencing and Genomics 18 2.4 Probability Theory Predicts Mendelian
Proteomics and Other “-omic” Analyses 18 Ratios 47
The Product Rule 47

1.5 Evolution Has a Genetic Basis 19 The Sum Rule 47

Darwin’s Theory of Evolution 19 Conditional Probability 47

Four Evolutionary Processes 20 Binomial Probability 48

Tracing Evolutionary Relationships 21

2.5 Chi-Square Analysis Tests the Fit
Genetic Analysis 1.3 24
between Observed Values and Expected
Case Study Ancient DNA: Genetics Looks into
Outcomes 49
the Past 24
Summary 26 • Preparing for Problem Chi-Square Analysis 50
Solving 27 • Problems 27 Chi-Square Analysis of Mendel’s Data 50

    iii
iv    CONTENTS

2.6 Autosomal Inheritance and ­Molecular 3.5 Human Sex-Linked Transmission Follows
Genetics Parallel the Predictions of Distinct Patterns 91
­Mendel’s Hereditary Principles 51 Expression of X-Linked Recessive Traits 92
Autosomal Dominant Inheritance 52 X-Linked Dominant Trait Transmission 93
Autosomal Recessive Inheritance 53 Y-Linked Inheritance 93
Prospective and Retrospective Predictions in Genetic Analysis 3.3 95
Human Genetics 53
Molecular Genetics of Mendel’s Traits 54 3.6 Dosage Compensation Equalizes the
Genetic Analysis 2.3 55 Expression of Sex-Linked Genes 96
Case Study OMIM, Gene Mutations, and Human Case Study The (Degenerative) Evolution
Hereditary Disease 57 of the Mammalian Y Chromosome 97
Summary 59 • Preparing for Problem Summary 99 • Preparing for Problem
Solving 60 • Problems 60 Solving 99 • Problems 100

4
3 Gene Interaction 105
Cell Division and
­Chromosome Heredity 67 4.1 Interactions between Alleles Produce
­Dominance Relationships 106
3.1 Mitosis Divides Somatic Cells 68 The Molecular Basis of Dominance 106

The Cell Cycle 68 Functional Effects of Mutation 107

Substages of M Phase 69 Notational Systems for Genes and Allele

Relationships 109
Chromosome Movement and Distribution 72
Incomplete Dominance 110
Completion of Cell Division 73
Codominance 110
Cell Cycle Checkpoints 74
Dominance Relationships of ABO Alleles 110
Genetic Analysis 4.1 113
3.2 Meiosis Produces Cells for Sexual
Reproduction 75 Allelic Series 113
Meiosis Features Two Cell Divisions 75 Lethal Alleles 116
Meiosis I 76 Delayed Age of Onset 118
Meiosis II 79
4.2 Some Genes Produce Variable
Meiosis Generates Mendelian Ratios 80
Phenotypes 118
Sex-Limited Traits 119
3.3 The Chromosome Theory of ­Heredity Sex-Influenced Traits 119
Proposes That Genes Are Carried on
Incomplete Penetrance 120
Chromosomes 82
Variable Expressivity 120
Genetic Analysis 3.1 84
Gene–Environment Interactions 121
X-Linked Inheritance 85 Pleiotropic Genes 122
Testing the Chromosome Theory of Heredity 86
4.3 Gene Interaction Modifies Mendelian
3.4 Sex Determination Is Chromosomal Ratios 122
and Genetic 87 Gene Interaction in Pathways 122
Sex Determination in Drosophila 87 The One Gene–One Enzyme Hypothesis 124
Genetic Analysis 3.2 88 Experimental Insight 4.1 125
Mammalian Sex Determination 89 Genetic Dissection to Investigate Gene Action 127
Diversity of Sex Determination 89 Genetic Analysis 4.2 128
Experimental Insight 3.1 90 Epistasis and Its Results 129
 CONTENTS     v

4.4 Complementation Analysis Distinguishes Allelic Phase 168

Mutations in the Same Gene from Lod Score Analysis 169
­Mutations in Different Genes 133 Experimental Insight 5.1 171
Genetic Analysis 4.3 134 Genetic Analysis 5.3 172
Case Study Complementation Groups in a Human Genome-Wide Association Studies 172
Cancer-Prone Disorder 136 Linkage Disequilibrium and Evolutionary Analysis 174
Summary 137 • Preparing for Problem
Solving 138 • Problems 138 Case Study Mapping the Gene for Cystic
Fibrosis 175
Summary 176 • Preparing for Problem

5 Solving 177 • Problems 177

Genetic Linkage and

­Mapping in Eukaryotes 145
6
Genetic Analysis and
5.1 Linked Genes Do Not Assort Mapping in Bacteria and
Independently 146 Bacteriophages 185
Detecting Genetic Linkage 147
The Discovery of Genetic Linkage 149 6.1 Specialized Methods Are Used for Genetic
Detecting Autosomal Genetic Linkage through Test-Cross Analysis of Bacteria 186
Analysis 150 Bacterial Culture and Growth Analysis 186
Cytological Evidence of Recombination 153 Characteristics of Bacterial Genomes 188
Genetic Analysis 5.1 154 Plasmids in Bacterial Cells 189
Research Technique 6.1 189
5.2 Genetic Linkage Mapping Is Based on
­Recombination Frequency between 6.2 Bacteria Transfer Genes by
Genes 155 Conjugation 191
The First Genetic Linkage Map 155 Conjugation Identified 193
Map Units 156 Transfer of the F Factor 194
Chi-Square Analysis of Genetic Linkage Data 156 Formation of an Hfr Chromosome 196
Hfr Gene Transfer 196
5.3 Three-Point Test-Cross Analysis Maps
Interrupted Mating and Time-of-Entry Mapping 198
Genes 156
Time-of-Entry Mapping Experiments 198
Identifying Parental, Single-Crossover, and Double-­
Crossover Gametes in Three-Point Mapping 157 Genetic Analysis 6.1 199
Constructing a Three-Point Recombination Map 158 Consolidation of Hfr Maps 200
Determining Gamete Frequencies from Genetic Maps 161 Conjugation with F′ Strains Produces Partial Diploids 201
Correction of Genetic Map Distances 162 Plasmids and Conjugation in Archaea 203
Genetic Analysis 5.2 163 6.3 Bacterial Transformation Produces Genetic
Recombination 203
5.4 Multiple Factors Cause Recombination
to Vary 164 Genetic Analysis 6.2 204
Sex Affects Recombination 164 Steps in Transformation 205
Recombination Is Dominated by Hotspots 165 Mapping by Transformation 205
Genome Sequence Analysis Reveals Recombination 6.4 Bacterial Transduction Is Mediated
Hotspot Distribution 166 by Bacteriophages 205
5.5 Human Genes Are Mapped Using Bacteriophage Life Cycles 205
­Specialized Methods 166 Generalized Transduction 208
Mapping with Genetic Markers 166 Cotransduction 209
The Inheritance of Disease-Causing Genes Linked to Cotransduction Mapping 209
Genetic Markers 167 Specialized Transduction 211
vi    CONTENTS

6.5 Bacteriophage Chromosomes Are Mapped 7.3 DNA Replication Is Semiconservative

by Fine-Structure Analysis 211 and Bidirectional 244
Genetic Analysis 6.3 212 Three Competing Models of Replication 245
Genetic Complementation Analysis 213 The Meselson–Stahl Experiment 245
Intragenic Recombination Analysis 213 Origin and Directionality of Replication in
Bacterial DNA 247
Deletion-Mapping Analysis 214
Multiple Replication Origins in Eukaryotes 248
6.6 Lateral Gene Transfer Alters Genomes 214 7.4 DNA Replication Precisely Duplicates the
Lateral Gene Transfer and Genome Evolution 215 Genetic Material 249
Identifying Lateral Gene Transfer in Genomes 216 DNA Sequences at Replication Origins 249
Case Study The Evolution of Antibiotic Resistance Molecular Biology of Replication Initiation 253
and Its Impact on Medical Practice 217 Continuous and Discontinuous Strand Replication 253
Summary 218 • Preparing for Problem
Solving 219 • Problems 219 RNA Primer Removal and Okazaki Fragment
Ligation 254
Synthesis of Leading and Lagging Strands at the

APPLICATION A ­Replication Fork 255

DNA Proofreading 256
Human Hereditary ­Disease Supercoiling and Topoisomerases 257
and Genetic Counseling Replication at the Ends of Linear Chromosomes 257
Genetic Analysis 7.2 258
A.1 Hereditary Disease and Disease Genes 225 7.5 Methods of Molecular Genetic
Types of Hereditary Disease 225 ­Analysis Make Use of DNA Replication
Genetic Testing and Diagnosis 226 Processes 260
The Polymerase Chain Reaction 261
A.2 Genetic Counseling 227
Separation of PCR Products 262
Indicators and Goals of Genetic Counseling 227
Dideoxynucleotide DNA Sequencing 263
Assessing and Communicating Risks and Options 228
New Generations of DNA Sequencing Technology 266
Ethical Issues in Genetic Medicine 231
Genetic Analysis 7.3 267
Genetic Counseling and Ethical Issues 232
In Closing 233 Case Study DNA Helicase Gene Mutations and
Problems 234 Human Progeroid Syndrome 269
Summary 270 • Preparing for Problem
Solving 271 • Problems 271

7
DNA Structure and 8
Replication 235 Molecular Biology of
Transcription and RNA
7.1 DNA Is the Hereditary Molecule of Life 236
Processing 275
Chromosomes Contain DNA 236
A Transformation Factor Responsible for Heredity 236
8.1 RNA Transcripts Carry the Messages of
DNA Is the Transformation Factor 238
Genes 276
DNA Is the Hereditary Molecule 238
RNA Nucleotides and Structure 276
7.2 The DNA Double Helix Consists of Experimental Discovery of Messenger RNA 277
Two Complementary and Antiparallel Categories of RNA 278
Strands 240
8.2 Bacterial Transcription Is a Four-Stage
DNA Nucleotides 240
Process 279
The DNA Duplex 241
Bacterial RNA Polymerase 280
Genetic Analysis 7.1 244 Bacterial Promoters 280
 CONTENTS     vii

Transcription Initiation 281 Ribosome Structures 317

Genetic Analysis 8.1 283 A Three-Dimensional View of the Ribosome 319
Transcription Elongation and Termination 284 Research Technique 9.1 319
Transcription Termination Mechanisms 284
9.2 Translation Occurs in Three Phases 320
8.3 Eukaryotic Transcription Is More Translation Initiation 320
­Diversified and Complex than Bacterial
Polypeptide Elongation 324
Transcription 286
Genetic Analysis 9.1 326
Polymerase II Transcription of mRNA in Eukaryotes 287
Translation Termination 327
Research Technique 8.1 288
Pol II Promoter Recognition 289
Detecting Promoter Consensus Elements 290
9.3 Translation Is Fast and Efficient 327
The Translational Complex 327
Other Regulatory Sequences and Chromatin-Based
Regulation of RNA Pol II Transcription 291 Translation of Polycistronic mRNA 329
RNA Polymerase I Promoters 292
RNA Polymerase III Promoters 292 9.4 The Genetic Code Translates Messenger
Archaeal Promoters and Transcription 292 RNA into Polypeptide 329
The Evolutionary Implications of Comparative The Genetic Code Displays Third-Base Wobble 330
Transcription 293 The (Almost) Universal Genetic Code 331
Genetic Analysis 9.2 332
8.4 Posttranscriptional Processing Modifies
RNA Molecules 294 Charging tRNA Molecules 333
Capping 5′ Pre-mRNA 294 Protein Folding and Posttranslational Polypeptide
Processing 333
Polyadenylation of 3′ Pre-mRNA 295
The Signal Hypothesis 334
The Torpedo Model of Transcription Termination 296
Introns 296
9.5 Experiments Deciphered the Genetic
Pre-mRNA Splicing 297
Code 334
Splicing Signal Sequences 298
No Overlap in the Genetic Code 335
A Gene Expression Machine Couples Transcription and
Pre-mRNA Processing 298 A Triplet Genetic Code 336

Alternative Patterns of RNA Transcription and Alternative No Gaps in the Genetic Code 336
RNA Splicing 301 Deciphering the Genetic Code 337
Self-Splicing Introns 302 Genetic Analysis 9.3 339
Genetic Analysis 8.2 303 Case Study Antibiotics and Translation
Ribosomal RNA Processing 304 Interference 340
Transfer RNA Processing 304 Summary 340 • Preparing for Problem
Solving 341 • Problems 342
RNA Editing 307
Case Study Sexy Splicing: Alternative mRNA Splicing
and Sex Determination in Drosophila 307
Summary 308 • Preparing for Problem
Solving 309 • Problems 309
APPLICATION B
Human Genetic Screening

9 B.1 Presymptomatic Diagnosis of Huntington’s

Disease 348
The Molecular Biology Trinucleotide Repeat Expansion 348
of Translation 314 Detecting the Number of Repeats 348

9.1 Polypeptides Are Amino Acid Chains That B.2 Newborn Genetic Screening 349
Are Assembled at Ribosomes 315 Phenylketonuria and the First Newborn Genetic Test 349
Amino Acid Structure 315 Living with PKU 350
Polypeptide and Transcript Structure 315 The Recommended Uniform Screening Panel 351
viii    CONTENTS

B.3 Genetic Testing to Identify Carriers 353 10.4 Chromosome Breakage Causes ­Mutation
Testing Blood Proteins 353 by Loss, Gain, and Rearrangement of
DNA-Based Carrier Screening and Diagnostic Chromosomes 375
Verification 353 Partial Chromosome Deletion 375
Carrier Screening Criteria 353 Unequal Crossover 376
Pharmacogenetic Screening 354 Detecting Duplication and Deletion 377
Deletion Mapping 377
B.4 Prenatal Genetic Testing 354
Invasive Screening Using Amniocentesis or Chorionic 10.5 Chromosome Breakage Leads
­Villus Sampling 354
to Inversion and Translocation
Noninvasive Prenatal Testing 356 of Chromosomes 378
Maternal Serum Screening 356 Chromosome Inversion 378
Preimplantation Genetic Screening 356
Genetic Analysis 10.3 379
Experimental Insight 10.1 382
B.5 Direct-to-Consumer Genetic Testing 357
Chromosome Translocation 383
B.6 Opportunities and Choices 359
Problems 359 10.6 Eukaryotic Chromosomes Are Organized
into Chromatin 385

10 Chromatin Compaction 386

Histone Proteins and Nucleosomes 386
Eukaryotic C
­ hromosome Higher Order Chromatin Organization and Chromosome
Structure 389
Abnormalities and Nucleosome Disassembly, Synthesis, and Reassembly
­Molecular Organization 361 during Replication 389
Position Effect Variegation: Effect of Chromatin State on
Transcription 390
10.1 Chromosome Number and Shape Vary
among Organisms 362 Case Study Human Chromosome Evolution 392
Chromosomes in Nuclei 362 Summary 393 • Preparing for Problem
Solving 394 • Problems 394
Chromosome Visualization 363
Chromosome Banding 364
Heterochromatin and Euchromatin 365

10.2 Nondisjunction Leads to Changes in

11
­Chromosome Number 366 Gene Mutation, DNA
Chromosome Nondisjunction 366 Repair, and Homologous
Gene Dosage Alteration 366 Recombination 399
Genetic Analysis 10.1 368
Aneuploidy in Humans 368 11.1 Mutations Are Rare and Random and Alter
Mosaicism 370 DNA Sequence 400
Uniparental Disomy 371 Proof of the Random Mutation Hypothesis 400
Germ-Line and Somatic Mutations 401
10.3 Changes in Euploid Content Lead Point Mutations 401
to Polyploidy 371 Base-Pair Substitution Mutations 401
Causes of Autopolyploidy and Allopolyploidy 371 Frameshift Mutations 402
Genetic Analysis 10.2 372 Regulatory Mutations 402
Consequences of Polyploidy 373 Experimental Insight 11.1 404
Polyploidy and Evolution 374 Forward Mutation and Reversion 405
 CONTENTS     ix

11.2 Gene Mutations May Arise from

­Spontaneous Events 405 12
Spontaneous DNA Replication Errors 405 Regulation of Gene
Genetic Analysis 11.1 407 Expression in Bacteria and
Spontaneous Nucleotide Base Changes 409
Bacteriophage 439
11.3 Mutations May Be Caused by Chemicals 12.1 Transcriptional Control of Gene
or Ionizing Radiation 410 ­Expression Requires DNA–Protein
Chemical Mutagens 410 Interaction 440
Radiation-Induced DNA Damage 412 Negative and Positive Control of Transcription 441
The Ames Test 413 Regulatory DNA-Binding Proteins 441

12.2 The lac Operon Is an Inducible Operon

11.4 Repair Systems Correct Some DNA
System under Negative and Positive
Damage 415
Control 443
Direct Repair of DNA Damage 415
Lactose Metabolism 443
Genetic Analysis 11.2 416
lac Operon Structure 444
DNA Damage-Signaling Systems 419 lac Operon Function 444

11.5 Proteins Control Translesion DNA 12.3 Mutational Analysis Deciphers Genetic
­Synthesis and the Repair of Double-Strand ­Regulation of the lac Operon 447
Breaks 420 Analysis of Structural Gene Mutations 447
Translesion DNA Synthesis 420 lac Operon Regulatory Mutations 448
Double-Strand Break Repair 420 Molecular Analysis of the lac Operon 451
Genetic Analysis 12.1 452

11.6 DNA Double-Strand Breaks Experimental Insight 12.1 453

­Initiate ­Homologous Recombination 422
The Holliday Model 422 12.4 Transcription from the Tryptophan Operon
The Bacterial RecBCD Pathway 422 Is Repressible and Attenuated 454
The Double-Stranded Break Model of Homologous Feedback Inhibition of Tryptophan Synthesis 455
Recombination 422 Attenuation of the trp Operon 456
Attenuation Mutations 459
Attenuation in Other Amino Acid Operon Systems 459
11.7 Transposable Genetic Elements Move
throughout the Genome 425
12.5 Bacteria Regulate the Transcription
The Characteristics and Classification of Transposable
Elements 425 of Stress Response Genes and Also
The Mutagenic Effect of Transposition 426
Translation 459
Alternative Sigma Factors and Stress Response 459
Transposable Elements in Bacterial Genomes 426
Transposable Elements in Eukaryotic Genomes 427 Genetic Analysis 12.2 460
The Discovery of Ds and Ac Elements in Maize 427 Translational Regulation in Bacteria 461
Genetic Analysis 11.3 428
Drosophila P Elements 429
12.6 Riboswitches Regulate Bacterial
­Transcription, Translation, and mRNA
Retrotransposons 430
Stability 462
Case Study Mendel’s Peas Are Shaped by Riboswitch Regulation of Transcription 462
Transposition 431
Summary 432 • Preparing for Problem Riboswitch Regulation of Translation 463
Solving 434 • Problems 434 Riboswitch Control of mRNA Stability 464
x    CONTENTS

12.7 Antiterminators and Repressors Control 13.3 RNA-Mediated Mechanisms Control Gene
Lambda Phage Infection of E. coli 464 Expression 498
The Lambda Phage Genome 465 Gene Silencing by Double-Stranded RNA 499
Early Gene Transcription 465 Constitutive Heterochromatin Maintenance 501
Cro Protein and the Lytic Cycle 466 The Evolution and Applications of RNAi 502
The l Repressor Protein and Lysogeny 468 Case Study Environmental Epigenetics 502
Resumption of the Lytic Cycle following Lysogeny Summary 503 • Preparing for Problem
Induction 468 Solving 504 • Problems 504
Case Study Vibrio cholerae—Stress Response Leads
to Serious Infection Through Positive Control of
Transcription 469
Summary 470 • Preparing for Problem
Solving 471 • Problems 471
14
Analysis of Gene Function
by Forward Genetics and
13 Reverse Genetics 507
Regulation of 14.1 Forward Genetic Screens Identify Genes
Gene ­Expression in by Their Mutant Phenotypes 509
Eukaryotes 476 General Design of Forward Genetic Screens 509
Specific Strategies of Forward Genetic Screens 509
13.1 Cis-Acting Regulatory Sequences Bind Analysis of Mutageneses 513
Trans-Acting Regulatory Proteins to Control Identifying Interacting and Redundant Genes Using
Eukaryotic Transcription 478 Modifier Screens 514

Overview of Transcriptional Regulatory Interactions in Genetic Analysis 14.1 515

Eukaryotes 479
Integration and Modularity of Eukaryotic Regulatory 14.2 Genes Identified by Mutant Phenotype
Sequences 480 Are Cloned Using Recombinant DNA
Locus Control Regions 481 Technology 516
Enhancer-Sequence Conservation 482 Cloning Genes by Complementation 516
Yeast as a Simple Model for Eukaryotic Genome Sequencing to Determine Gene
Transcription 482 Identification 517
Insulator Sequences 484
14.3 Reverse Genetics Investigates Gene Action
13.2 Chromatin Remodeling and Modification by Progressing from Gene Identification to
Regulates Eukaryotic Transcription 484 Phenotype 519
PEV Mutations 485 Genome Editing 519
Overview of Chromatin Remodeling and Chromatin Use of Homologous Recombination in Reverse Genetics 522
Modification 486 Use of Insertion Mutants in Reverse Genetics 524
Open and Covered Promoters 486 RNA Interference in Gene Activity 525
Mechanisms of Chromatin Remodeling 487 Reverse Genetics by TILLING 525
Chemical Modifications of Chromatin 488 Genetic Analysis 14.2 527
Genetic Analysis 13.1 490
An Example of Inducible Transcriptional Regulation in 14.4 Transgenes Provide a Means of Dissecting
S. cerevisiae 493 Gene Function 527
Facultative Heterochromatin and Developmental Monitoring Gene Expression with Reporter Genes 528
Genes 494 Enhancer Trapping 531
Epigenetic Heritability 494 Investigating Gene Function with Chimeric Genes 532
lncRNAs and Inactivation of Eutherian Mammalian
Case Study Reverse Genetics and Genetic Redundancy
Female X Chromosomes 496
in Flower Development 533
Genomic Imprinting 497 Summary 535 • Preparing for Problem
Nucleotide Methylation 498 Solving 535 • Problems 535
 CONTENTS     xi

APPLICATION C 15.3 Gene Therapy Uses Recombinant DNA

Technology 579
The Genetics Two Forms of Gene Therapy 579

of Cancer Somatic Gene Therapy Using ES Cells 579

Genetic Analysis 15.2 580

C.1 Cancer Is a Somatic Genetic Disease that Is 15.4 Cloning of Plants and Animals Produces
Only Occasionally Inherited 540 Genetically Identical Individuals 583
C.2 What Is Cancer and What Are the Case Study Gene Drive Alleles Can Rapidly Spread
­Characteristics of Cancer? 540 Through Populations 585
Summary 587 • Preparing for Problem
Progression of Abnormalities 540
Solving 588 • Problems 588
The Hallmarks of Cancer Cells and Malignant Tumors 541

16
C.3 The Genetic Basis of Cancer 543
Single Gene Mutations and Cancer Development 543
The Genetic Progression of Cancer Development and
­Cancer Predisposition 546
Genomics: Genetics
Breast and Ovarian Cancer and the Inheritance of Cancer from a Whole-Genome
Susceptibility 548 Perspective 593
C.4 Cancer Cell Genome Sequencing and
Improvements in Therapy 549 16.1 Structural Genomics Provides a Catalog of
The Cancer Genome Atlas 549 Genes in a Genome 594
Epigenetic Irregularities 549 Whole-Genome Shotgun Sequencing 596
Targeted Cancer Therapy 550 Reference Genomes and Resequencing 599
Problems 550 Metagenomics 600
Experimental Insight 16.1 601

15 16.2 Annotation Ascribes Biological Function to

Recombinant DNA DNA Sequences 602
Experimental Approaches to Structural Annotation 602
­Technology and Its
Computational Approaches to Structural
Applications 552 Annotation 602
Functional Gene Annotation 603
15.1 Specific DNA Sequences Are Identified Research Technique 16.1 604
and Manipulated Using Recombinant DNA Related Genes and Protein Motifs 605
Technology 553 Variation in Genome Organization among Species 605
Restriction Enzymes 553 Three Insights from Genome Sequences 606
Experimental Insight 15.1 554
Genetic Analysis 15.1 556 16.3 Evolutionary Genomics Traces the History of
Genomes 607
Molecular Cloning 557
The Tree of Life 608
DNA Libraries 562
Interspecific Genome Comparisons: Gene Content 608
Advances in Altering and Synthesizing DNA Molecules 564
Research Technique 16.2 610
15.2 Introducing Foreign Genes into Genomes Genetic Analysis 16.1 614
Creates Transgenic Organisms 565
Interspecific Genome Comparisons: Genome
Expression of Heterologous Genes in Bacterial and Fungal Annotation 615
Hosts 565
Interspecific Genome Comparisons: Gene Order 616
Experimental Insight 15.2 569
Transformation of Plant Genomes by Agrobacterium 570 16.4 Functional Genomics Aims to Elucidate
Transgenic Animals 574 Gene Function 618
Manipulation of DNA Sequences in Vivo 578 Transcriptomics 619
xii    CONTENTS

Other “-omes” and “-omics” 621 Continual DNA Transfer from Organelles 654
Use of Yeast Mutants to Categorize Genes 624 Encoding of Organellar Proteins 655
Genetic Networks 625 The Origin of the Eukaryotic Lineage 656
Case Study Genomic Analysis of Insect Guts Secondary and Tertiary Endosymbioses 656
May Fuel the World 627 Case Study Ototoxic Deafness: A ­Mitochondrial
Summary 628 • Preparing for Problem Gene–Environment Interaction 658
Solving 628 • Problems 629 Summary 659 • Preparing for Problem
Solving 660 • Problems 660

17
Organellar Inheritance and
the Evolution of Organellar
18
Developmental
Genomes 632 Genetics 663
17.1 Organellar Inheritance Transmits Genes 18.1 Development Is the Building of a
­Carried on Organellar Chromosomes 633 ­Multicellular Organism 664
The Discovery of Organellar Inheritance 633 Cell Differentiation 665
Homoplasmy and Heteroplasmy 634 Pattern Formation 665
Genome Replication in Organelles 635
Replicative Segregation of Organelle Genomes 635 18.2 Drosophila Development Is a Paradigm
for Animal Development 666
17.2 Modes of Organellar Inheritance Depend The Developmental Toolkit of Drosophila 667
on the Organism 636 Maternal Effects on Pattern Formation 669
Mitochondrial Inheritance in Mammals 637 Coordinate Gene Patterning of the Anterior–Posterior
Genetic Analysis 17.1 639 Axis 669
Mating Type and Chloroplast Segregation in Domains of Gap Gene Expression 670
Chlamydomonas 640 Regulation of Pair-Rule Genes 671
Biparental Inheritance in Saccharomyces cerevisiae 641 Specification of Parasegments by Hox Genes 673
Genetic Analysis 17.2 643 Downstream Targets of Hox Genes 675
Summary of Organellar Inheritance 644 Hox Genes throughout Metazoans 676
Genetic Analysis 18.1 677
17.3 Mitochondria Are the Energy Factories of Stabilization of Cellular Memory by Chromatin
Eukaryotic Cells 644 Architecture 678
Mitochondrial Genome Structure and Gene Content 645
Mitochondrial Transcription and Translation 646 18.3 Cellular Interactions Specify Cell Fate 679
Inductive Signaling between Cells 679
17.4 Chloroplasts Are the Sites of Lateral Inhibition 682
Photosynthesis 648 Cell Death During Development 682
Chloroplast Genome Structure and Gene Content 648
Chloroplast Transcription and Translation 649 18.4 “Evolution Behaves Like a Tinkerer” 683
Editing of Chloroplast mRNA 650 Evolution through Co-option 683
Constraints on Co-option 685
17.5 The Endosymbiosis Theory Explains
­Mitochondrial and Chloroplast 18.5 Plants Represent an Independent
Evolution 651 ­Experiment in Multicellular Evolution 685
Separate Evolution of Mitochondria and Development at Meristems 685
Chloroplasts 651
Combinatorial Homeotic Activity in Floral-Organ
Experimental Insight 17.1 652 Identity 686
 CONTENTS     xiii

20
Genetic Analysis 18.2 689

Case Study Cyclopia and ­Polydactyly—

D­ifferent Shh Mutations with Distinctive Population Genetics and
Phenotypes 690
Summary 691 • Preparing for Problem Evolution at the Population,
Solving 692 • Problems 692 Species, and Molecular
Levels 725

19 20.1 The Hardy–Weinberg Equilibrium Describes

the Relationship of Allele and Genotype
Genetic Analysis of
Frequencies in Populations 726
­Quantitative Traits 696 Populations and Gene Pools 727
The Hardy–Weinberg Equilibrium 727
19.1 Quantitative Traits Display Continuous Determining Autosomal Allele Frequencies in
­Phenotype Variation 697 Populations 729
Genetic Potential 697 The Hardy–Weinberg Equilibrium for More than Two
Major Gene Effects 698 Alleles 731
Additive Gene Effects 698 The Chi-Square Test of Hardy–Weinberg
Continuous Phenotypic Variation from Multiple Additive Predictions 731
Genes 699 Genetic Analysis 20.1 732
Allele Segregation in Quantitative Trait
Production 701 20.2 Natural Selection Operates through
Effects of Environmental Factors on Phenotypic ­Differential Reproductive Fitness within
Variation 702 a Population 732
Genetic Analysis 19.1 703 Differential Reproductive Fitness and Relative
Threshold Traits 704 Fitness 733
Directional Natural Selection 733

19.2 Quantitative Trait Analysis Is Statistical 706 Natural Selection Favoring Heterozygotes 735

Statistical Description of Phenotypic Variation 706 Genetic Analysis 20.2 736

Partitioning Phenotypic Variance 707
Partitioning Genetic Variance 708
20.3 Mutation Diversifies Gene Pools 736
Quantifying the Effects of Mutation on Allele
Frequencies 737
19.3 Heritability Measures the Genetic
Mutation–Selection Balance 737
­Component of Phenotypic Variation 708
Genetic Analysis 19.2 709 20.4 Gene Flow Occurs by the Movement
Broad Sense Heritability 710 of Organisms and Genes between
Twin Studies 710 Populations 737
Narrow Sense Heritability and Artificial Selection 712 Effects of Gene Flow 738
Allele Frequency Equilibrium and Equalization 739
19.4 Quantitative Trait Loci Are the
Genes That Contribute to Quantitative 20.5 Genetic Drift Causes Allele Frequency
Traits 713 Change by Sampling Error 739
QTL Mapping Strategies 714 The Founder Effect 740
Identification of QTL Genes 716 Genetic Bottlenecks 740
Genome-Wide Association Studies 717
20.6 Inbreeding Alters Genotype Frequencies
Case Study The Genetics of Autism Spectrum
but Not Allele Frequencies 741
Disorders 718
Summary 719 • Preparing for Problem The Coefficient of Inbreeding 741
Solving 720 • Problems 720 Inbreeding Depression 743
xiv    CONTENTS

20.7 New Species Evolve by Reproductive D.5 Human Migrations around the Globe 770
Isolation 743 Europe 770
Genetic Analysis 20.3 744 Australia 771
Processes of Speciation 744
D.6 Genetic Evidence for Adaptation to New
Reproductive Isolation and Speciation 746
Environments 772
The Molecular Genetics of Evolution in Darwin’s
Lactose Tolerance 772
Finches 748
Skin Pigmentation 774
High Altitude 774
20.8 Molecular Evolution Changes Genes and
Genomes through Time 748 D.7 Domestication of Plants and Animals:
Vertebrate Steroid Receptor Evolution 749 Maize 775
Case Study Sickle Cell Disease Evolution and Natural
Selection in Humans 750 D.8 The Future 776
Summary 751 • Preparing for Problem Problems 777
Solving 752 • Problems 753

APPLICATION E
APPLICATION D Forensic Genetics
Human Evolutionary
Genetics E.1 CODIS and Forensic Genetic Analysis 780
CODIS History and Markers 780
Electrophoretic Analysis 781
D.1 Genome Sequences Reveal Extent of
Forensic Analysis Using CODIS 782
Human Genetic Diversity 759
Paternity Testing 784
SNP Variation in Humans 760
Individual Identification 785
Variation in CNVs 761
Remains Identified following the 9-11 Attack 785
Identification of the Disappeared in Argentina 786
D.2 Diversity of Extant Humans Suggests an
African Origin 761 E.2 DNA Analysis for Genealogy, Genetic
Mitochondrial Eve 762 Ancestry, and Genetic Health Risk
Y Chromosome Phylogeny 762 Assessment 786
Autosomal Loci 763 Assessing Genealogical Relationships 786
Assessing Genetic Ancestry 787
D.3 Comparisons between Great Apes Identify Genetic Health Risk Assessment 788
Human-Specific Traits 763 Late-Onset Alzheimer Disease 788
Revelations of Great Ape Genomes 763 Celiac Disease 789
Comparing the Human and Chimpanzee One Side of the Equation 789
Genomes 765
Problems 789
References and Additional Reading R-1
D.4 Ancient DNA Reveals the Recent History of
Our Species 766 Appendix: Answers A-1
Neandertals 768 Glossary G-1
Denisovans 769
Credits C-1
Finding Genes that Make Us
Human 770 Index I-1
About the Authors
Mark F. Sanders has been a faculty John L. Bowman is a professor
member in the Department of Molecular in the School of Biological Sciences at
and Cellular Biology at the University Monash University in Melbourne, Aus-
of California, Davis, since 1985. In that tralia, and an adjunct professor in the
time, he has taught more than 150 genet- Department of Plant Biology at the Uni-
ics courses to nearly 35,000 undergradu- versity of California, Davis, in the United
ate students. Although he specializes in States. He received a B.S. in Biochem-
teaching the genetics course for which this book is written, istry at the University of Illinois at Urbana-Champaign in
his genetics teaching experience also includes a genetics 1986 and a Ph.D. in Biology from the California Institute
laboratory course, an advanced human genetics course for of Technology in Pasadena, California. His Ph.D. research
biology majors, and a human heredity course for nonscience focused on how the identities of floral organs are specified
majors, as well as introductory biology and courses in popu- in Arabidopsis (described in Chapter 18), and he conducted
lation genetics and evolution. He has also served as an advi- postdoctoral research at Monash University on the regulation
sor to undergraduate students and in undergraduate education of floral development. From 1996 to 2006, his laboratory
administration, and he has directed several undergraduate at UC Davis investigated developmental genetics of plants,
education programs. focusing on how leaves are patterned. From 2006 to 2011,
Dr. Sanders received his B.A. degree in Anthropology he was a Federation Fellow at Monash University, where his
from San Francisco State University, his M.A. and Ph.D. laboratory is studying land plant evolution using a develop-
degrees in Biological Anthropology from the University of mental genetics approach. He was elected a Fellow of the
California, Los Angeles, and 4 years of training as a postdoc- Australian Academy of Science in 2014. At UC Davis he
toral researcher studying inherited susceptibility to human taught genetics, “from Mendel to cancer,” to undergradu-
breast and ovarian cancer at the University of California, ate students, and he continues to teach genetics courses at
Berkeley. Monash University.

Dedication
To my extraordinary wife and partner Ita. She is a treasure For my parents, Lois and Noel, who taught me to love and
whose support, patience, and encouragement throughout revere nature, and Tizita, my partner in our personal genet-
this ongoing project make me very fortunate. To my won- ics experiments. And to all my genetics students who have
derful children Jana and Nick, to their spouses John and inspired me over the years, I hope that the inspiration was
Molly, to my grandson Lincoln, and to all my students, mutual.
from whom I have learned as much as I have taught.
John L. Bowman
Mark F. Sanders

We dedicate this third edition of Genetic Analysis: An Integrated Approach to our friend and
colleague Mel Green, who passed away in October 2017 at the age of 101. Mel was a stellar
geneticist and was engaged in genetics until the end. Over his long career, he made numerous
important contributions to genetics, ­inspiring scores of geneticists including the authors of this
textbook.

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