INTRODUCTION TO GENETIC ANALYSIS - …

1 INTRODUCTION TOGENETIC ANALYSISN inth EditionAnthony J. F. GriffithsUniversity of British ColumbiaSusan R. WesslerUniversity of GeorgiaRichard C. LewontinHarvard UniversitySean B. CarrollHoward Hughes Medical InstituteUniversity of WisconsinIS W. H. Freeman and Company New YorkContents in Briefi234567891011121314151617181920 PrefaceThe GENETIC Approach to BiologyPART 1 TRANSMISSION GENETICSS ingle-Gene InheritanceIndependent Assortment of GenesMapping Eukaryote Chromosomes byRecombinationThe Genetics of Bacteria and TheirVirusesGene InteractionPART II FROM DNA TO PHENOTYPEDNA: Structure and ReplicationRNA.

2 Transcription and ProcessingProteins and Their SynthesisRegulation of Gene Expression inBacteria and Their VirusesRegulation of Gene Expressionin EukaryotesThe GENETIC Control of DevelopmentGenomes and GenomicsPART III MUTATION, VARIATION,AND EVOLUTIONThe Dynamic GenomeMutation, Repair, and RecombinationLarge-Scale Chromosomal ChangesPopulation GeneticsQuantitative GeneticsEvolutionary GeneticsPART IV TECHNIQUESGene Isolation and ManipulationA Brief Guide to Model OrganismsAppendix A: GENETIC NomenclatureAppendix B.

3 Bioinformatics Resourcesfor Genetics and GenomicsGlossaryAnswers to Selected ProblemsIndexxiii13189129181221265295319 3513854154534875135556036396797157597757 76779803815 ContentsPreface xiiiJ_ The GENETIC Approach to Biology Genetics and the Questions of Biology The Molecular Basis of GENETIC Information 5 Specifying the amino acid sequence of a protein 6 Gene regulation The Program of GENETIC Investigation 9 The necessity of variation 9 Starting with variation: Forward genetics 10 Starting with DNA: Reverse genetics Methodologies Used in Genetics 14An Overview 14 Detecting specific molecules of DNA, RNA,and protein Model Organisms 17 Lessons from the first model organisms 17 The need for a variety of model organisms Genes, the Environment, and theOrganism 21 Model I: GENETIC determination 21 Model II: Environmental determination 22 Model III.

4 Genotype-environment interaction 23 The use of genotype and phenotype 23 Developmental noise 24 Three levels of development 26 PART I TRANSMISSION GENETICSJ2j Single-Gene Genes and Chromosomes Single-Gene Inheritance Patterns 37 Mendel's law of equal segregation The Chromosomal Basis of Single-GeneInheritance Patterns 42 Single-gene inheritance in haploids 46 The molecular basis of single-gene segregationand expression Discovering Genes by ObservingSegregation Ratios 57 Discovering a gene active in the developmentof flower color 57 Discovering a gene for wing development 58 Discovering a gene for spore production 58 The results of gene discovery 59 Forward genetics 60 Predicting progeny proportions or parental genotypes byapplying the principles of single-gene influence Sex-Linked Single-Gene Inheritance Patterns 61 Sex chromosomes 61 Sex-linked patterns of inheritance 62 Model Organism Box Drosophila 63X-linked inheritance Human Pedigree ANALYSIS 66 Autosomal

5 Recessive disorders 66 Autosomal dominant disorders 68 Autosomal polymorphisms 69X-linked recessive disorders 71X-linked dominant disorders 73Y-linked inheritance 73 Calculating risks in pedigree ANALYSIS 74^ Independent Assortment of Genes Mendel's Law of Independent Assortment Working with Independent Assortment 94 Predicting progeny ratios 94 Using the chi-square test on monohybridand dihybrid ratios 97 Synthesizing pure lines 99 Hybrid vigor The Chromosomal Basis of IndependentAssortment 102 Independent assortment in diploid organisms 103 Independent assortment in haploid organisms 103 Independent assortment of combinations of autosomaland X-linked genes 105 Recombination 106 Model Organism Box Neurospora Polygenic Inheritance Organelle Genes.

6 Inheritance Independentof the Nucleus 112 Patterns of inheritance in organelles 112 Cytoplasm ic segregation 114 Cytoplasmic mutations in humans Eukaryote Chromosomesby Recombination 129 Diagnostics of Linkage 131 Using recombinant frequency to recognize linkage 131 How crossovers produce recombinants for linkedgenes 133 Linkage symbolism and terminology 134 Evidence that crossing over is a breakage-and-rejoiningprocess 134 Evidence that crossing over takes place at the four-chromatid stage 135 Multiple crossovers can include more than twochromatids Mapping by Recombinant Frequency 137 Map units 137 Three-point testcross 140 Deducing gene order by inspection 142 Interference 143 Using ratios as diagnostics Mapping with Molecular Markers 146 Single nucleotide polymorphisms 147 Mapping by using SNP haplotypes 149 Simple sequence length polymorphisms Centromere Mapping with LinearTetrads Using the Chi-Square Test for Testing LinkageAnalysis Using Lod Scores to Assess

7 Linkage in HumanPedigrees Accounting for Unseen Multiple Crossovers 159A mapping function 160 The Perkins formula Using Recombination-Based Maps in Conjunctionwith Physical Maps 163^ The Genetics of Bacteria and TheirViruses Working with Microorganisms Bacterial Conjugation 185 Discovery of conjugation 185 Model Organism Box Escherichia coli 185 Discovery of the fertility factor (F) 187 Hfr strains 188 Mapping of bacterial chromosomes 192F plasmids that carry genomic fragments 195 Rplasmids Bacterial Transformation 198 Chromosome mapping using transformation Bacteriophage Genetics 199 Infection of bacteria by phages 200 Mapping phage chromosomes by usingphage crosses Transduction 204 Discovery of transduction 204 Generalized transduction 205 Specialized transduction 207 Mechanism of specialized transduction Physical Maps and Linkage MapsCompared 2096^ Gene Interaction

8 Interactions Between the Alleles of a Single Gene:Variations on Dominance 223 Complete dominance and recessiveness 223 Incomplete dominance 225 Codominance 225 Recessive lethal alleles 227 Model Organism Box Mouse Interaction of Genes in Pathways 230 Biosynthetic pathways in Neurospora 230 Gene interaction in other types of pathways Inferring Gene Interactions 235 Defining the set of genes by using thecomplementation test 235 Analyzing double mutants of random mutations Penetrance and Expressivity 247 PART II FROM DNA TO PHENOTYPE_7_ DNA.

9 Structure and Replication DNA: The GENETIC Material 266 Discovery of transformation 266 Hershey-Chase experiment The DNA Structure 269 DNA structure before Watson and Crick 270 The double helix Semiconservative Replication 275 Meselson-Stahl experiment 276 The replication fork 277 DNA polymerases Overview of DNA Replication The Replisome: A Remarkable ReplicationMachine 281 Unwinding the double helix 283 Assembling the replisome: Replication initiation Replication in Eukarydtic Organisms 284 The eukaryotic replisome 284 Eukaryotic origins of replication 285 DNA replication and the yeast cell cycle 286 Replication origins in higher eukaryotes Telomeres and Telomerase: ReplicationTermination 287 Telomeres, cancer, and aging 288 8_ RNA: Transcription and Processing RNA 297 Early experiments suggest an RNA intermediate 297 Properties of RNA 297 Classes of RNA Transcription 300 Overview.

10 DNA as transcription template 300 Stages of transcription Transcription in eukaryotes 304 Transcription initiation in eukaryotes 306 Elongation, termination, and pre-mRNA processingin eukaryotes Functional RNAs 309 Small nuclear RNAs (snRNAs): The mechanism of exonsplicing 310 Self-splicing introns and the RNA world 312 Small interfering RNAs (siRNAs) 3129 Proteins and Their Synthesis