Preface.

Contributors.

1. Basic Concepts in Genetics and Linkage Analysis (Elizabeth C. Melvin and Marcy C. Speer).

Introduction.

Historical Contributions.

Segregation and Linkage Analysis.

Hardy–Weinberg Equilibrium.

DNA, Genes, and Chromosomes.

Structure of DNA.

Genes and Alleles.

Genes and Chromosomes.

Inheritance Patterns in Mendelian Disease.

Genetic Changes Associated with Disease/Trait Phenotypes.

Point Mutations.

Deletion/Insertion Mutations/

Novel Mechanisms of Mutation: Unstable DNA and Trinucleotide Repeats.

Susceptibility Versus Causative Genes.

Genes, Mitosis, and Meiosis.

When Genes and Chromosomes Segregate Abnormally.

Ordering and Spacing of Loci by Mapping Techniques.

Physical Mapping.

Genetic Mapping.

Interference and Genetic Mapping.

Meiotic Breakpoint Mapping.

Disease Gene Discovery.

Information Content in a Pedigree.

Disease Gene Localization.

Extensions to Complex Disease.

Summary.

References.

2. Defining Disease Phenotypes (Arthur S. Aylsworth).

Introduction.

Exceptions to Traditional Mendelian Inheritance Patterns.

Pseudodominant Transmission of a Recessive.

Pseudorecessive Transmission of a Dominant.

Mosaicism.

Mitochondrial Inheritance.

Incomplete Penetrance and Variable Expressivity.

Genomic Imprinting.

Phenocopies and Other Environmentally Related Effects.

Heterogeneity.

Genetic Heterogeneity.

Phenotypic Heterogeneity.

Complex Inheritance.

Polygenic and Multifactorial Models.

Role of Environment.

Role of Chance in Phenotype Expression.

Phenotype Definition.

Classification of Disease.

Nonsyndromic Phenotypes.

Syndromic Phenotypes.

Associations and Syndromes of Unknown Cause.

Importance of Chromosomal Rearrangements in Mapping.

Qualitative (Discontinuous) and Quantitative (Continuous) Traits.

Defining Phenotypes for Analysis of Complex Genetic Disorders.

Select Most Biologically Meaningful Phenotype.

Partition Phenotype or Dataset by Cause and Associated Pathology.

Summary: Approach to Phenotype Definition.

Resources for Information about Clinical Genetics and Phenotype Definition.

References.

3. Determining Genetic Component of a Disease (Allison Ashley-Koch).

Introduction .

Study Design .

Selecting a Study Population .

Ascertainment.

Approaches to Determining the Genetic Component of a Disease.

Cosegregation with Chromosomal Abnormalities and Other Genetic Disorders.

Familial Aggregation.

Twin and Adoption Studies.

Recurrence Risk in Relatives of Affected Individuals.

Heritability.

Segregation Analysis.

Summary.

References.

4. Patient and Family Participation in Genetic Research Studies Chantelle Wolpert, Amy Baryk Crunk, and Susan Estabrooks Hahn).

Introduction.

Step 1: Preparing to Initiate a Family Study.

Confidentiality.

Certificate of Confidentiality.

Need for a Family Studies Director.

Working with Human Subjects.

Step 2: Ascertainment of Families for Studies.

Family Recruitment.

Informed Consent and Family Participaion.

Step 3: Data Collection.

Confirmation of Diagnosis.

Art of Field Studies

Special Issues in Family Studies.

Step 4: Family Follow-Up.

Need for Additional Medical Services.

Duty to Recontact Research Participants.

Maintaining Contact with Participants.

Guidelines for Releasing Genetic Information.

Genetic Testing of Children.

Genetic Discrimination.

DNA Banking.

Future Considerations.

Appendix.

References

5. Collection of Biological Samples for DNA Analysis (effery M. Vance).

Establishing Goals of Collection.

Types of DNA Sample Collection.

Venipuncture (Blood).

Buccal Samples.

Dried Blood.

Tissue.

DNA Extraction and Processing .

Blood.

Quantitation.

Tissue Culture.

Buccal Brushes.

Dried Blood Cards.

Fixed Tissue.

Whole-Genome Amplification.

Sample Management.

Informed Consent/Security.

References.

6. Methods of Genotyping (Jeffery M. Vance).

Brief Historical Review of Markers Used for Genotyping.

Restriction Fragment Length Polymorphisms.

Variable Number of Tandem Repeat Markers.

Short Tandem Repeats or Microsatellites.

Single-Nucleotide Polymorphisms.

Sources of Markers.

Restriction Fragment Length Polymorphisms.

Microsatellites.

Single-Nucleotide Polymorphisms.

PCR and Genotyping.

Laboratory and Methodology Optimization,

Optimization of Reagents.

“I Can’t Read a Marker, What Should I Do?”

Marker Separation.

Manual or Nonsequencer Genotyping.

Loading Variants.

DNA Pooling and Homozygosity Mapping/Detection Methode.

Radioactive Methods (32P or 33P).

Silver Stain.

Fluorescence.

SNP Detection.

DNA Array or "Chip".

Oligonucleotide Ligation Assay.

Fluorescent Polarization.

Taqman.

Single-Base-Pair Extension.

Pyrosequencing.

Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Spectrometry.

Invader and PCR-Invader Assays.

Single-Strand Conformational Polymorphism.

Denaturing High-Pressure Liquid Chromatography.

Data Management.

Objectivity.

Genotype Integrity.

Scoring.

Standards.

Quality Control.

References.

7. Data Analysis Issues in Expression Profiling.(Simon Lin and Michael Hauser).

Introduction.

Serial Analysis of Gene Expression.

Analysis of SAGE Libraries.

Microarray Analysis.

Data Preparation.

Expression Data Matrix.

Dimension Reduction of Features.

Measures of Similarity between Objects.

Unsupervised Machine Learning: Clustering.

Supervised Machine Learning

Data Visualization

Other Types of Gene Expression Data Analysis.

Biological Applications of Expression Profiling.

References.

8. Information Management (Carol Haynes and Colette Blach).

Information Planning.

Needs Assessment.

Information Flow.

Plan Logical Database Model.

Hardware and Software Requirements.

Software Selection.

System Administration.

Database Administration.

Database Implementation.

Conversion.

Performance Tuning.

Data Integrity.

User Interfaces.

Security.

Transmission Security.

System Security.

Patient Confidentiality.

Pedigree Plotting and Data Manipulation Software.

Summary.

9. Quantitative Trait Linkage Analysis (Jason H. Moore).

Introduction to Quantitative Traits.

Genetic Architecture.

Study Design.

Haseman–Elston Regression .

Multipoint IBD Method.

Variance Component Linkage Analysis.

Nonparametric Methods.

Future Directions.

Summary.

References.

10. Advanced Parametric Linkage Analysis (Silke Schmidt).

Two-Point Analysis.

Example of LOD Score Calculation and Interpretation.

Effects of Misspecified Model Parameters in LOD Score Analysis.

Impact of Misspecified Disease Allele Frequency.

Impact of Misspecified Mode of Inheritance.

Impact of Misspecified Disease Penetrances.

Impact of Misspecified Marker Allele Frequency.

Control of Scoring Errors.

Genetic Heterogeneity.

Multipoint Analysis.

Practical Approaches for Model-Based Linkage Analysis of Complex Traits.

Affecteds-Only Analysis.

Maximized Maximum LOD Score.

Heterogeneity LOD.

MFLINK.

Summary.

References.

11. Nonparametric Linkage Analysis (Elizabeth R. Hauser, Jonathan Haines, and David E. Goldgar).

Introduction.

Background and Historical Framework.

Identity by State and Identity by Descent.

Measures of Familiality.

Qualitative Traits.

Measuring Genetic Effects in Quantitative Traits.

Summary of Basic Concepts.

Methods for Nonparametric Linkage Analysis.

Tests for Linkage Using Affected Sibling Pairs (ASPs).

Methods Incorporating Affected Relative Pairs.

Power Analysis and Experimental Design Considerations for Qualitative Traits.

Nonparametric Quantitative Trait Linkage Analysis.

Power and Sampling Considerations for Mapping.Quantitative Trait Loci.

Examples of Application of Sibpair Methods for Mapping Complex Traits.

Additional Considerations in Nonparametric Linkage Analysis.

WPC Analysis 319

Software Available for Nonparametric Linkage Analysis 322

Summary 323

References 323

12. Linkage Disequilibrium and Association Analysis 329

Eden R. Martin

Introduction 329

Linkage Disequilibrium 330

Measures of Allelic Association 330

Causes of Allelic Association 331

Mapping Genes Using Linkage Disequilibrium 334

Tests for Association 335

Case–Control Tests 335

Family-Based Tests of Association 340

Analysis of Haplotype Data 345

Association Tests for Quantitative Traits 347

Association and Genomic Screening 347

Special Populations 348

Summary 349

References 349

13. Sample Size and Power 355

Yi-Ju Li, Susan Shao, and Marcy Speer

Introduction 355

Power Studies for Linkage Analysis:

Mendelian Disease 358

Information Content of Pedigrees 358

Computer Simulation Methods 359

Definitions for Power Assessments 363

xii CONTENTS

Power Studies for Linkage Analysis: Complex Disease 365

Discrete Traits 367

Quantitative Traits 373

Power Studies for Association Analysis 376

Transmission/Disequilibrium Test for Discrete Traits 378

Transmission/Disequilibrium Test for Quantitative Traits 380

Case–Control Study Design 380

DNA Pooling 381

Genomic Screening Strategies for Association Studies 381

Simulation of Linkage and Association Program 382

Summary 383

Appendix 13.1: Example of Monte Carlo Simulation Assuming

That Trait and Marker Loci Are Unlinked to Each Other 384

Appendix 13.2: Example LOD Score Results for Pedigree

in Figure 13.2 385

Appendix 13.3: Example of Simulation of Genetic Marker

Genotypes Conditional on Trait Phenotypes Allowing for

Complete and Reduced Penetrance 386

References 393

14. Complex Genetic Interactions 397

William K. Scott and Joellen M. Schildkraut

Introduction 397

Evidence for Complex Genetic Interactions Genetic

Heterogeneity 398

Genetic Heterogeneity 398

Gene–Gene Interaction (Epistasis) 399

Gene–Environment Interaction 400

Analytic Approaches to Detection of Complex Interactions 401

Segregation Analysis 402

Linkage Analysis 402

Association Analysis 406

Potential Biases 414

Conclusion 415

References 415

15. Genomics and Bioinformatics 423

Judith E. Stenger and Simon G. Gregory

Introduction 423

Era of the Genome 423

CONTENTS xiii

Mapping the Human Genome 424

Genetic Mapping 425

Radiation Hybrid Mapping 427

Physical Mapping 428

Public Data Repositories and Genome Browsers.

Single-Nucleotide Polymorphisms.

SNP Discovery.

Utilizing SNPs.

Computational SNP Resources.

Model Organisms.

Identifying Candidate Genes by Genomic Convergence.

De Novo Annotation of Genes.

Software Suites.

Online Sequence Analysis Resources.

Understanding Molecular Mechanisms of Disease.

Assigning Gene Function.

Looking Beyond Genome Sequence.

Other Databases.

Summary.

References.

16. Designing a Study for Identifying. Genes in Complex Traits (Jonathan L. Haines and Margaret A. Pericak-Vance).

Introduction.

Components of a Disease Gene Discovery Study.

Define Phenotype.

Develop Study Design.

Analysis.

Follow-Up.

Keys to a Successful Study.

Foster Interaction of Necessary Expertise.

Develop Careful Study Design.

References.

Index.