Genetic Analysis of Complex Diseases, Second Edition PDF
Preview Genetic Analysis of Complex Diseases, Second Edition
GENETIC ANALYSIS OF COMPLEX DISEASES GENETIC ANALYSIS OF COMPLEX DISEASES SECOND EDITION Jonathan L. Haines PhD Center for Human Genetics Research Department ofMolecular Physiology and Biophysics VanderbiltUniversityMedical Center Nashville, Tennessee Margaret Pericak-Vance PhD Center for Human Genetics, SectionofMedical Genetics Duke UniversityMedical Center Durham, North Carolina A JOHN WILEY & SONS, INC., PUBLICATION Copyright#2006byJohnWiley&Sons,Inc.Allrightsreserved. PublishedbyJohnWiley&Sons,Inc.,Hoboken,NewJersey. PublishedsimultaneouslyinCanada. 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Wileyalsopublishesitsbooksinavarietyofelectronicformats.Somecontentthatappearsinprintmay notbeavailableinelectronicformats.FormoreinformationaboutWileyproducts,visitourwebsiteat www.wiley.com. LibraryofCongressCataloging-in-PublicationDataisavailable. ISBN-10:0-471-08952-4 ISBN-13:978-0-971-08952-0 PrintedintheUnitedStatesofAmerica 10 9 8 7 6 5 4 3 2 1 &CONTENTS Foreword xv Preface xvii Contributors xix 1. Basic Concepts inGenetics and Linkage Analysis 1 ElizabethC.MelvinandMarcyC.Speer Introduction 1 Historical Contributions 2 Segregationand Linkage Analysis 2 Hardy–Weinberg Equilibrium 5 DNA, Genes,and Chromosomes 5 StructureofDNA 5 Genes andAlleles 9 Genes andChromosomes 10 InheritancePatterns inMendelianDisease 13 Genetic Changes Associated with Disease/Trait Phenotypes 14 Point Mutations 14 Deletion/Insertion Mutations 17 Novel Mechanisms of Mutation: Unstable DNA and Trinucleotide Repeats 18 Susceptibility Versus Causative Genes 19 Genes, Mitosis, andMeiosis 23 When Genesand ChromosomesSegregate Abnormally 25 Ordering and Spacing ofLoci byMapping Techniques 26 Physical Mapping 26 Genetic Mapping 29 v vi CONTENTS Interference and Genetic Mapping 30 Meiotic Breakpoint Mapping 31 Disease Gene Discovery 31 InformationContentina Pedigree 41 Disease Gene Localization 42 ExtensionstoComplex Disease 45 Summary 45 References 46 2. Defining Disease Phenotypes 51 ArthurS.Aylsworth Introduction 51 Exceptionsto TraditionalMendelianInheritance Patterns 52 Pseudodominant Transmission ofa Recessive 53 Pseudorecessive Transmissionof aDominant 54 Mosaicism 55 Mitochondrial Inheritance 56 IncompletePenetrance andVariable Expressivity 58 Genomic Imprinting 61 Phenocopies andOther Environmentally Related Effects 63 Heterogeneity 64 Genetic Heterogeneity 64 PhenotypicHeterogeneity 65 Complex Inheritance 67 Polygenic and Multifactorial Models 67 Role ofEnvironment 70 Role ofChance inPhenotype Expression 70 Phenotype Definition 71 Classificationof Disease 71 NonsyndromicPhenotypes 72 SyndromicPhenotypes 72 Associations andSyndromes of Unknown Cause 73 Importanceof Chromosomal Rearrangements inMapping 74 Qualitative (Discontinuous)and Quantitative(Continuous)Traits 74 Defining Phenotypes for AnalysisofComplexGenetic Disorders 75 Select Most Biologically MeaningfulPhenotype 75 Partition PhenotypeorDataset byCauseand Associated Pathology 75 Summary: Approach toPhenotypeDefinition 80 Resources for Informationabout Clinical Genetics and Phenotype Definition 82 References 82 CONTENTS vii 3. DeterminingGenetic Component ofa Disease 91 AllisonAshley-Koch Introduction 91 Study Design 92 Selecting aStudy Population 93 Ascertainment 94 Approachesto Determiningthe Genetic Component ofa Disease 99 Cosegregation with Chromosomal Abnormalities and Other Genetic Disorders 100 Familial Aggregation 101 Twin andAdoption Studies 104 Recurrence Risk inRelatives of Affected Individuals 105 Heritability 107 SegregationAnalysis 108 Summary 110 References 111 4. Patient and Family Participation inGeneticResearch Studies 117 ChantelleWolpert,AmyBarykCrunk,andSusanEstabrooksHahn Introduction 117 Step 1:Preparing toInitiate aFamily Study 118 Confidentiality 118 Certificate ofConfidentiality 119 Need for aFamilyStudies Director 119 Working with Human Subjects 122 Step 2:AscertainmentofFamilies for Studies 124 Family Recruitment 124 Informed Consent and FamilyParticipation 128 Step 3:Data Collection 131 Confirmationof Diagnosis 131 Artof FieldStudies 132 Special IssuesinFamilyStudies 133 Step 4:FamilyFollow-Up 135 Need for AdditionalMedical Services 135 Duty toRecontact Research Participants 136 Maintaining Contact with Participants 137 Guidelinesfor Releasing Genetic Information 137 Genetic Testing of Children 139 Genetic Discrimination 139 DNA Banking 141 viii CONTENTS Future Considerations 142 Appendix 142 References 148 5. Collection ofBiological Samples for DNA Analysis 153 JefferyM.Vance EstablishingGoalsofCollection 153 Types of DNA Sample Collection 153 Venipuncture (Blood) 153 Buccal Samples 155 Dried Blood 156 Tissue 156 DNA Extractionand Processing 157 Blood 157 Quantitation 157 Tissue Culture 159 Buccal Brushes 160 Dried Blood Cards 161 Fixed Tissue 161 Whole-Genome Amplification 161 Sample Management 162 Informed Consent/Security 164 References 164 6. Methods ofGenotyping 167 JefferyM.Vance Brief Historical Reviewof Markers Used for Genotyping 167 Restriction Fragment Length Polymorphisms 167 Variable Number ofTandem Repeat Markers 168 Short Tandem Repeatsor Microsatellites 168 Single-Nucleotide Polymorphisms 168 Sources ofMarkers 168 Restriction Fragment Length Polymorphisms 169 Microsatellites 169 Single-Nucleotide Polymorphisms 171 PCRand Genotyping 171 Laboratory and Methodology Optimization 171 Optimization ofReagents 172 “ICan’t Read aMarker, What ShouldIDo?” 173 CONTENTS ix Marker Separation 175 Manual orNonsequencer Genotyping 175 Loading Variants 176 DNA Pooling and Homozygosity Mapping 177 DetectionMethods 178 Radioactive Methods (32P or 33P) 178 Silver Stain 178 Fluorescence 179 SNPDetection 181 DNA Array or“Chip” 181 Oligonucleotide Ligation Assay 181 Fluorescent Polarization 182 Taqman 182 Single-Base-Pair Extension 184 Pyrosequencing 184 Matrix-Assisted Laser Desorption/IonizationTime-of-Flight Spectrometry 184 Invader andPCR-InvaderAssays 184 Single-Strand Conformational Polymorphism 186 Denaturing High-Pressure Liquid Chromatography 186 Data Management 186 Objectivity 187 GenotypeIntegrity 187 Scoring 187 Standards 187 Quality Control 188 References 189 7. Data Analysis Issuesin ExpressionProfiling 193 SimonLinandMichaelHauser Introduction 193 Serial Analysis of Gene Expression 194 AnalysisofSAGE Libraries 195 Microarray Analysis 196 Data Preparation 197 Expression Data Matrix 198 DimensionReduction of Features 198 Measuresof Similaritybetween Objects 200 Unsupervised Machine Learning: Clustering 201 Supervised Machine Learning 204 x CONTENTS Data Visualization 207 Other Types ofGene Expression Data Analysis 207 Biological Applications ofExpression Profiling 209 References 212 8. Information Management 219 CarolHaynesandColetteBlach InformationPlanning 220 Needs Assessment 220 InformationFlow 222 Plan Logical Database Model 223 Hardware and Software Requirements 225 Software Selection 226 System Administration 226 Database Administration 226 Database Implementation 227 Conversion 227 Performance Tuning 228 Data Integrity 228 User Interfaces 231 Security 231 TransmissionSecurity 231 System Security 233 Patient Confidentiality 233 Pedigree Plotting andData Manipulation Software 234 Summary 235 9. QuantitativeTrait LinkageAnalysis 237 JasonH.Moore Introductionto QuantitativeTraits 237 Genetic Architecture 238 Study Design 240 Haseman–ElstonRegression 240 MultipointIBD Method 242 Variance Component LinkageAnalysis 243 Nonparametric Methods 246 CONTENTS xi Future Directions 247 Summary 249 References 250 10. AdvancedParametric Linkage Analysis 255 SilkeSchmidt Two-PointAnalysis 256 Example ofLOD Score Calculation and Interpretation 259 Effects ofMisspecified Model Parametersin LOD Score Analysis 260 Impact ofMisspecified Disease Allele Frequency 261 Impact ofMisspecified Mode of Inheritance 262 Impact ofMisspecified Disease Penetrances 263 Impact ofMisspecified Marker Allele Frequency 264 ControlofScoringErrors 265 Genetic Heterogeneity 266 MultipointAnalysis 269 Practical Approaches for Model-Based LinkageAnalysis ofComplexTraits 273 Affecteds-OnlyAnalysis 274 Maximized Maximum LOD Score 275 Heterogeneity LOD 275 MFLINK 276 Summary 277 References 277 11. Nonparametric Linkage Analysis 283 ElizabethR.Hauser,JonathanHaines,andDavidE.Goldgar Introduction 283 Background andHistorical Framework 284 Identity by State and Identityby Descent 286 Measuresof Familiality 289 QualitativeTraits 289 Measuring Genetic Effects in QuantitativeTraits 293 Summaryof Basic Concepts 295 Methods for Nonparametric Linkage Analysis 295 Tests for LinkageUsing Affected SiblingPairs (ASPs) 295 Methods IncorporatingAffected RelativePairs 301 Power AnalysisandExperimental Design Considerationsfor QualitativeTraits 311
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