iga11e_ch101

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	Preface	xiii
1	The Genetics Revolution	1
1.1	The Birth of Genetics	2
	Gregor Mendel—A monk in the garden	3
	Mendel rediscovered	5
	The central dogma of molecular biology	9
1.2	After Cracking the Code	10
	Model organisms	10
	Tools for genetic analysis	12
1.3	Genetics Today	14
	From classical genetics to medical genomics	14
	Investigating mutation and disease risk	17
	When rice gets its feet a little too wet	20
	Recent evolution in humans	23
PART I TRANSMISSION GENETICS
2	Single-Gene Inheritance	31
2.1	Single-Gene Inheritance Patterns	34
	Mendel’s pioneering experiments	34
	Mendel’s law of equal segregation	36
2.2	The Chromosomal Basis of Single-Gene Inheritance Patterns	39
	Single-gene inheritance in diploids	40
	Single-gene inheritance in haploids	44
2.3	The Molecular Basis of Mendelian Inheritance Patterns	45
	Structural differences between alleles at the molecular level	45
	Molecular aspects of gene transmission	46
	Alleles at the molecular level	48
2.4	Some Genes Discovered by Observing Segregation Ratios	50
	A gene active in the development of flower color	51
	A gene for wing development	51
	A gene for hyphal branching	52
	Predicting progeny proportions or parental genotypes by applying the principles of single-gene inheritance	53
2.5	Sex-Linked Single-Gene Inheritance Patterns	53
	Sex chromosomes	54
	Sex-linked patterns of inheritance	54
	X-linked inheritance	55
2.6	Human Pedigree Analysis	58
	Autosomal recessive disorders	59
	Autosomal dominant disorders	61
	Autosomal polymorphisms	63
	X-linked recessive disorders	65
	X-linked dominant disorders	68
	Y-linked inheritance	68
	Calculating risks in pedigree analysis	69
3	Independent Assortment of Genes	87
3.1	Mendel’s Law of Independent Assortment	89
3.2	Working with Independent Assortment	93
	Predicting progeny ratios	93
	Using the chi-square test on monohybrid and dihybrid ratios	96
	Synthesizing pure lines	98
	Hybrid vigor	99
3.3	The Chromosomal Basis of Independent Assortment	101
	Independent assortment in diploid organisms	101
	Independent assortment in haploid organisms	103
	Independent assortment of combinations of autosomal and X-linked genes	104
	Recombination	104
3.4	Polygenic Inheritance	108
3.5	Organelle Genes: Inheritance Independent of the Nucleus	110
	Patterns of inheritance in organelles	111
	Cytoplasmic segregation	113
	Cytoplasmic mutations in humans	115
	mtDNA in evolutionary studies	116
4	Mapping Eukaryote Chromosomes by Recombination	127
4.1	Diagnostics of Linkage	129
	Using recombinant frequency to recognize linkage	129
	How crossovers produce recombinants for linked genes	132
	Linkage symbolism and terminology	132
	Evidence that crossing over is a breakage-and-rejoining process	133
	Evidence that crossing over takes place at the four-chromatid stage	133
	Multiple crossovers can include more than two chromatids	134
4.2	Mapping by Recombinant Frequency	135
	Map units	136
	Three-point testcross	139
	Deducing gene order by inspection	141
	Interference	141
	Using ratios as diagnostics	142
4.3	Mapping with Molecular Markers	144
	Single nucleotide polymorphisms	144
	Simple sequence length polymorphisms	145
	Detecting simple sequence length polymorphisms	146
	Recombination analysis using molecular markers	146
4.4	Centromere Mapping with Linear Tetrads	148
4.5	Using the Chi-Square Test to Infer Linkage	150
4.6	Accounting for Unseen Multiple Crossovers	151
	A mapping function	151
	The Perkins formula	152
4.7	Using Recombination-Based Maps in Conjunction with Physical Maps	154
4.8	The Molecular Mechanism of Crossing Over	155
5	The Genetics of Bacteria and Their Viruses	173
5.1	Working with Microorganisms	176
5.2	Bacterial Conjugation	177
	Discovery of conjugation	177
	Discovery of the fertility factor (F)	178
	Hfr strains	179
	Mapping of bacterial chromosomes	184
	F plasmids that carry genomic fragments	188
	R plasmids	188
5.3	Bacterial Transformation	191
	The nature of transformation	191
	Chromosome mapping using transformation	191
5.4	Bacteriophage Genetics	192
	Infection of bacteria by phages	192
	Mapping phage chromosomes by using phage crosses	194
5.5	Transduction	196
	Discovery of transduction	196
	Generalized transduction	197
	Specialized transduction	198
	Mechanism of specialized transduction	200
5.6	Physical Maps and Linkage Maps Compared	201
6	Gene Interaction	215
6.1	Interactions Between the Alleles of a Single Gene: Variations on Dominance	216
	Complete dominance and recessiveness	216
	Incomplete dominance	218
	Codominance	219
	Recessive lethal alleles	220
6.2	Interaction of Genes in Pathways	223
	Biosynthetic pathways in Neurospora	224
	Gene interaction in other types of pathways	226
6.3	Inferring Gene Interactions	227
	Sorting mutants using the complementation test	227
	Analyzing double mutants of random mutations	231
6.4	Penetrance and Expressivity	239
PART II FROM DNA TO PHENOTYPE
7	Structure and Replication	259
7.1	DNA: The Genetic Material	260
	Discovery of transformation	261
	Hershey–Chase experiment	263
7.2	DNA Structure	264
	DNA structure before Watson and Crick	264
	The double helix	267
7.3	Semiconservative Replication	270
	Meselson–Stahl experiment	271
	The replication fork	272
	DNA polymerases	273
7.4	Overview of DNA Replication	274
7.5	The Replisome: A Remarkable Replication Machine	277
	Unwinding the double helix	279
	Assembling the replisome: replication initiation	280
7.6	Replication in Eukaryotic Organisms	280
	Eukaryotic origins of replication	280
	DNA replication and the yeast cell cycle	281
	Replication origins in higher eukaryotes	282
7.7	Telomeres and Telomerase: Replication Termination	283
8	RNA: Transcription and Processing	291
8.1	RNA	293
	Early experiments suggest an RNA intermediate	293
	Properties of RNA	294
	Classes of RNA	294
8.2	Transcription	296
	Overview: DNA as transcription template	296
	Stages of transcription	298
8.3	Transcription in Eukaryotes	301
	Transcription initiation in eukaryotes	303
	Elongation, termination, and pre-mRNA processing in eukaryotes	304
8.4	Intron Removal and Exon Splicing	307
	Small nuclear RNAs (snRNAs): the mechanism of exon splicing	307
	Self-splicing introns and the RNA world	308
8.5	Small Functional RNAs That Regulate and Protect the Eukaryotic Genome	310
	miRNAs are important regulators of gene expression	310
	siRNAs ensure genome stability	311
	Similar mechanisms generate siRNA and miRNA	314
9	Proteins and Their Synthesis	319
9.1	Protein Structure	322
9.2	The Genetic Code	324
	Overlapping versus nonoverlapping codes	325
	Number of letters in the codon	325
	Use of suppressors to demonstrate a triplet code	325
	Degeneracy of the genetic code	327
	Cracking the code	328
	Stop codons	329
9.3	tRNA: The Adapter	329
	Codon translation by tRNA	331
	Degeneracy revisited	331
9.4	Ribosomes	332
	Ribosome features	333
	Translation initiation, elongation, and termination	335
	Nonsense suppressor mutations	338
9.5	The Proteome	339
	Alternative splicing generates protein isoforms	339
	Posttranslational events	340
10	Gene Isolation and Manipulation	351
10.1	Overview: Isolating and Amplifying Specific DNA Fragments	353
10.2	Generating Recombinant DNA Molecules	354
	Genomic DNA can be cut up before cloning	355
	The polymerase chain reaction amplifies selected regions of DNA in vitro	356
	DNA copies of mRNA can be synthesized	358
	Attaching donor and vector DNA	358
	Amplification of donor DNA inside a bacterial cell	362
	Making genomic and cDNA libraries	366
10.3	Using Molecular Probes to Find and Analyze a Specific Clone of Interest	367
	Finding specific clones by using probes	367
	Finding specific clones by functional complementation	369
	Southern- and Northern-blot analysis of DNA	371
10.4	Determining the Base Sequence of a DNA Segment	374
10.5	Aligning Genetic and Physical Maps to Isolate Specific Genes	377
	Using positional cloning to identify a human-disease gene	378
	Using fine mapping to identify genes	379
10.6	Genetic Engineering	382
	Genetic engineering in Saccharomyces cerevisiae	383
	Genetic engineering in plants	383
	Genetic engineering in animals	386
11	Regulation of Gene Expression in Bacteria and Their Viruses	397
11.1	Gene Regulation	399
	The basics of prokaryotic transcriptional regulation: genetic switches	400
	A first look at the lac regulatory circuit	401
11.2	*Discovery of the lac* System: Negative Control**	404
	Genes controlled together	405
	Genetic evidence for the operator and repressor	405
	Genetic evidence for allostery	407
	Genetic analysis of the lac promoter	408
	Molecular characterization of the Lac repressor and the lac operator	408
	Genetic analysis of the lac promoter	408
	Molecular characterization of the Lac repressor and the lac operator	408
11.3	*Catabolite Repression of the lac* Operon: Positive Control**	409
	The basics of lac catabolite repression: choosing the best sugar to metabolize	410
	The structures of target DNA sites	410
	A summary of the lac operon	411
11.4	Dual Positive and Negative Control: The Arabinose Operon	413
11.5	Metabolic Pathways and Additional Levels of Regulation: Attenuation	414
11.6	Bacteriophage Life Cycles: More Regulators, Complex Operons	417
	Molecular anatomy of the genetic switch	421
	Sequence-specific binding of regulatory proteins to DNA	422
11.7	Alternative Sigma Factors Regulate Large Sets of Genes	423
12	Regulation of Gene Expression in Eukaryotes	431
12.1	Transcriptional Regulation in Eukaryotes: An Overview	432
12.2	Lessons from Yeast: The GAL System	436
	Gal4 regulates multiple genes through upstream activation sequences	436
	The Gal4 protein has separable DNA-binding and activation domains	438
	Gal4 activity is physiologically regulated	439
	Gal4 functions in most eukaryotes	439
	Activators recruit the transcriptional machinery	440
	The control of yeast mating type: combinatorial interactions	440
12.3	Dynamic Chromatin	443
	Chromatin-remodeling proteins and gene activation	444
	Modification of histones	445
	Histone methylation can activate or repress gene expression	448
	The inheritance of histone modifications and chromatin structure	448
	Histone variants	449
	DNA methylation: another heritable mark that influences chromatin structure	449
12.4	Activation of Genes in a Chromatin Environment	450
	The β-interferon enhanceosome	451
	Enhancer-blocking insulators	452
12.5	Long-Term Inactivation of Genes in a Chromatin Environment	454
	Mating-type switching and gene silencing	454
	Heterochromatin and euchromatin compared	455
	Position-effect variegation in Drosophila reveals genomic neighborhoods	456
	Genetic analysis of PEV reveals proteins necessary for heterochromatin formation	457
12.6	Gender-Specific Silencing of Genes and Whole Chromosomes	460
	Genomic imprinting explains some unusual patterns of inheritance	460
	But what about Dolly and other cloned mammals?	461
	Silencing an entire chromosome: X-chromosome inactivation	462
12.7	Post-Transcriptional Gene Repression by miRNAs	463
13	The Genetic Control of Development	469
13.1	The Genetic Approach to Development	471
13.2	*The Genetic Toolkit for Drosophila* Development**	474
	Classification of genes by developmental function	474
	Homeotic genes and segmental identity	474
	Organization and expression of Hox genes	476
	The homeobox	478
	Clusters of Hox genes control development in most animals	479
13.3	Defining the Entire Toolkit	482
	The anteroposterior and dorsoventral axes	483
	Expression of toolkit genes	484
13.4	Spatial Regulation of Gene Expression in Development	487
	Maternal gradients and gene activation	488
	Drawing stripes: integration of gap-protein inputs	489
	Making segments different: integration of Hox inputs	491
13.5	Post-transcriptional Regulation of Gene Expression in Development	494
	RNA splicing and sex determination in Drosophila	494
	Regulation of mRNA translation and cell lineage in C. elegans	496
	Translational control in the early embryo	496
	miRNA control of developmental timing in C. elegans and other species	499
13.6	From Flies to Fingers, Feathers, and Floor Plates: The Many Roles of Individual Toolkit Genes	500
13.7	Development and Disease	501
	Polydactyly	501
	Holoprosencephaly	502
	Cancer as a developmental disease	502
14	Genomes and Genomics	507
14.1	The Genomics Revolution	510
14.2	Obtaining the Sequence of a Genome	511
	Turning sequence reads into an assembled sequence	511
	Whole-genome sequencing	513
	Traditional WGS	513
	Next-generation whole-genome shotgun sequencing	514
	Whole-genome-sequence assembly	517
14.3	Bioinformatics: Meaning from Genomic Sequence	519
	The nature of the information content of DNA	519
	Deducing the protein-encoding genes from genomic sequence	520
14.4	The Structure of the Human Genome	524
	Noncoding functional elements in the genome	525
14.5	The Comparative Genomics of Humans with Other Species	527
	Phylogenetic inference	527
	Of mice and humans	530
	Comparative genomics of chimpanzees and humans	532
14.6	Comparative Genomics and Human Medicine	532
	The exome and personalized genomics	533
	Comparative genomics of nonpathogenic and pathogenic E. coli	534
14.7	Functional Genomics and Reverse Genetics	536
	“’Omics”	536
	Reverse genetics	539
PART III MUTATION, VARIATION, AND EVOLUTION
15	The Dynamic Genome: Transposable Elements	547
15.1	Discovery of Transposable Elements in Maize	549
	McClintock’s experiments: the Ds element	549
	Autonomous and nonautonomous elements	550
	Transposable elements: only in maize?	552
15.2	Transposable Elements in Prokaryotes	553
	Bacterial insertion sequences	553
	Prokaryotic transposons	554
	Mechanism of transposition	556
15.3	Transposable Elements in Eukaryotes	558
	Class 1: retrotransposons	558
	Class 2: DNA transposons	562
	Utility of DNA transposons for gene discovery	564
15.4	The Dynamic Genome: More Transposable Elements Than Ever Imagined	566
	Large genomes are largely transposable elements	567
	Transposable elements in the human genome	568
	The grasses: LTR-retrotransposons thrive in large genomes	569
	Safe havens	569
15.5	Regulation of Transposable Element Movement by the Host	571
	Genome surveillance in animals and bacteria	573
16	Mutation, Repair, and Recombination	581
16.1	The Phenotypic Consequences of DNA Mutations	583
	Types of point mutation	583
	The molecular consequences of point mutations in a coding region	584
	The molecular consequences of point mutations in a noncoding region	586
16.2	The Molecular Basis of Spontaneous Mutations	586
	Luria and Delbrück fluctuation test	586
	Mechanisms of spontaneous mutations	588
	Spontaneous mutations in humans: trinucleotiderepeat diseases	591
16.3	The Molecular Basis of Induced Mutations	593
	Mechanisms of mutagenesis	593
	The Ames test: evaluating mutagens in our environment	595
16.4	Biological Repair Mechanisms	596
	Direct reversal of damaged DNA	597
	Base-excision repair	598
	Nucleotide-excision repair	599
	Postreplication repair: mismatch repair	602
	Error-prone repair: translesion DNA synthesis	604
	Repair of double-strand breaks	606
	The involvement of DSB repair in meiotic recombination	608
16.5	Cancer: An Important Phenotypic Consequence of Mutation	609
	How cancer cells differ from normal cells	609
	Mutations in cancer cells	609
17	Large-Scale Chromosomal Changes	617
17.1	Changes in Chromosome Number	618
	Aberrant euploidy	619
	Aneuploidy	627
	The concept of gene balance	632
17.2	Changes in Chromosome Structure	634
	Deletions	637
	Duplications	640
	Inversions	642
	Reciprocal translocations	645
	Robertsonian translocations	647
	Applications of inversions and translocations	648
	Rearrangements and cancer	649
	Identifying chromosome mutations by genomics	650
17.3	Overall Incidence of Human Chromosome Mutations	651
18	Population Genetics	665
18.1	Detecting Genetic Variation	666
	Single nucleotide polymorphisms (SNPs)	667
	Microsatellites	668
	Haplotypes	669
	Other sources and forms of variation	670
	The HapMap Project	671
18.2	The Gene-Pool Concept and the Hardy–Weinberg Law	672
18.3	Mating Systems	677
	Assortative mating	677
	Isolation by distance	678
	Inbreeding	679
	The inbreeding coefficient	680
	Population size and inbreeding	682
18.4	Genetic Variation and Its Measurement	684
18.5	The Modulation of Genetic Variation	687
	New alleles enter the population: mutation and migration	687
	Recombination and linkage disequilibrium	689
	Genetic drift and population size	691
	Selection	696
	Forms of selection	698
	Balance between mutation and drift	702
	Balance between mutation and selection	703
18.6	Biological and Social Applications	704
	Conservation genetics	704
	Calculating disease risks	705
	DNA forensics	706
	Googling your DNA mates	707
19	The Inheritance of Complex Traits	715
19.1	Measuring Quantitative Variation	717
	Types of traits and inheritance	717
	The mean	718
	The variance	719
	The normal distribution	721
19.2	A Simple Genetic Model for Quantitative Traits	722
	Genetic and environmental deviations	722
	Genetic and environmental variances	724
	Correlation between variables	725
19.3	Broad-Sense Heritability: Nature Versus Nurture	727
	Measuring heritability in humans using twin studies	728
19.4	Narrow-Sense Heritability: Predicting Phenotypes	731
	Gene action and the transmission of genetic variation	732
	The additive and dominance effects	733
	A model with additivity and dominance	734
	Narrow-sense heritability	736
	Predicting offspring phenotypes	739
	Selection on complex traits	740
19.5	Mapping QTL in Populations with Known Pedigrees	742
	The basic method	743
	From QTL to gene	747
19.6	Association Mapping in Random-Mating Populations	742
	The basic method	751
	GWA, genes, disease, and heritability	752
20	Evolution of Genes and Traits	761
20.1	Evolution by Natural Selection	764
20.2	Natural Selection in Action: An Exemplary Case	766
	The selective advantage of Hb^S	768
	The molecular origins of Hb^S	770
20.3	Molecular Evolution: The Neutral Theory	771
	The development of the neutral theory	771
	The rate of neutral substitutions	772
	The signature of purifying selection on DNA	772
20.4	Cumulative Selection and Multistep Paths to Functional Change	774
	Multistep pathways in evolution	774
	The signature of positive selection on DNA sequences	778
20.5	Morphological Evolution	779
	Adaptive changes in a pigment-regulating protein	779
	Gene inactivation	781
	Regulatory-sequence evolution	782
	Loss of characters through regulatory-sequence evolution	783
	Regulatory evolution in humans	785
20.6	The Origin of New Genes and Protein Functions	786
	Expanding gene number	787
	The fate of duplicated genes	788
A Brief Guide to Model Organisms		793
Appendix A: Genetic Nomenclature		809
Appendix B: Bioinformatics Resources for Genetics and Genomics		810
Glossary		813
Answers to Selected Problems		833
Index		845

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Contents

Contents