Contents
Foreword
Preface
Contributors
1. Basic Concepts in Genetics and Linkage Analysis
Elizabeth C. Melvin, M.S. and Marcy C. Speer, Ph.D.
Introduction
Historical Contributions
Segregation and Linkage Analysis
Hardy-Weinberg Equilibrium
DNA, Genes, and Chromosomes
The 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
The 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, M.D.
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
The Role of Environment
The Role of Chance in Phenotype Expression
Phenotype Definition
Classification of Disease
Nonsyndromic Phenotypes
Syndromic Phenotypes
Associations and Syndromes of Unknown Cause
The Importance of Chromosomal Rearrangements in Mapping
Qualitative (Discontinuous) and Quantitative (Continuous) Traits
Defining Phenotypes for Analysis of Complex Genetic Disorders
Select the 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 the 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
Co-segregation 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 Bazyk Crunk, Susan Estabrooks Hahn
Introduction
Step One: Preparing to Initiate a Family Study
Confidentiality
Certificate of Confidentiality
The Need for a Family Studies Director
Working with Human Subjects
Step Two: Ascertainment of Families for Studies
Family Recruitment
Informed Consent and Family Participation
Step Three: Data Collection
Confirmation of Diagnosis
The Art of Field Studies
Special Issues in Family Studies
Step Four: 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
References
5. The Collection of Biological Samples for DNA Analysis
Jeffery M. Vance
Establishing the Goals of the 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
A Brief Historical Review of Markers Used for Genotyping
Restriction Fragment Length Polymorphisms (RFLPs)
Variable Number of Tandem Repeat (VNTR) Markers
Short Tandem Repeats (STRs) or Microsatellites
Single Nucleotide Polymorphisms (SNP)
Sources of Markers
RFLPs
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 Non-Sequencer Genotyping
Loading Variants
DNA Pooling and Homozygosity Mapping
Detection Methods
Radioactive Methods (32P or 33P)
Silver Stain
Fluorescence
SNP detection
DNA Array or "Chip"
Oligonucleotide Ligation Assay (OLA)
Fluorescent Polarization (FP)
Taqman
Single Base Pair Extension (SBE)
Pyrosequencing
Matrix Assisted Laser Desorption/Ionization Time of Flight Spectrometry (MALDI-TOF)
Invader( and PCR-Invader( Assays
Single Strand Conformational Polymorphism (SSCP)
Denaturing High Pressure Liquid Chromatography (DHPLC)
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 (SAGE)
Analysis of SAGE Libraries
Microarray Analysis
Data Preparation
Expression Data Matrix
Dimension Reduction of the 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 Haines and Colette Blach
Information Planning
Needs Assessment
Information Flow
Plan the 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, Ph.D.
Introduction to Quantitative Traits
Genetic Architecture
Study Design
Haseman-Elston Regression
The Multipoint IBD Method
Variance Components 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 Misspecifying Mode of Inheritance
Impact of Misspecified Disease Penetrances
Impact of Misspecifying Marker Allele Frequency
Control of Scoring Errors
Genetic Heterogeneity
Multipoint Analysis
Practical Approaches for Model-Based Linkage Analysis of Complex Traits
Affecteds-only Analysis
MMLS
HLOD
MFLINK
Summary
References
11. Non-parametric 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 (ASP)
Methods Incorporating Affected Relative Pairs
Nonparametric Quantitative Trait Linkage Analysis
Power and Sampling Considerations for Mapping Quantitative Trait Loci
Examples of Application of Sib Pair Methods for Mapping Complex Traits
Additional Considerations in Nonparametric Linkage Analysis
WPC Analysis
Software Available for Nonparametric Linkage Analysis
Summary
References
12. Linkage Disequilibrium and Association Analysis
Eden R. Martin
Introduction
Linkage Disequilibrium
Measures of Allelic Association
Causes of Allelic Association
Mapping Genes Using Linkage Disequilibrium
Tests for Association
Case-control Tests
Family-based Tests of Association
Analysis of Haplotype Data
Association Tests For Quantitative Traits
Association and Genomic Screening
Special Populations
Summary
References
13. Sample Size and Power
Yi-Ju Li, Susan Shao, Marcy Speer
Introduction
Power Studies for Linkage Analysis - Mendelian Disease
The Information Content of Pedigrees
Computer Simulation Methods
Definitions for Power Assessments
Power Studies for Linkage Analysis - Complex Disease
Discrete Traits
Quantitative Traits
Power Studies for Association Analysis
The Transmission/Disequilibrium Test (TDT) for discrete traits
Transmission/Disequilibrium Tests for Quantitative Traits
Case-Control Study Design
DNA Pooling
Genomic Screening Strategies for Association Studies
Simulation of Linkage and Association (SIMLA) Program
Summary
References
Appendices
Appendix 13.1: Example of Monte Carlo Simulation Assuming that the Trait and Marker Loci Are Unlinked to Each Other
Appendix 13.2: Example Lod Score Results for Pedigree in Figure 13.2
Appendix 13.3: Example of Simulation of Genetic Marker Genotypes Conditional on Trait Phenotypes Allowing for Complete and Reduced Penetrance
14. Complex Genetic Interactions
William K. Scott and Joellen M. Schildkraut
Introduction
Evidence for Complex Genetic Interactions
Genetic Heterogeneity
Gene-Gene Interaction (Epistasis)
Gene-Environment Interaction
Analytic Approaches to the Detection of Complex Interactions
Segregation Analysis
Linkage Analysis
Association Analysis
Potential Biases
Conclusion
References
15. Genomics and Bioinformatics
Judith E. Stenger and Simon G. Gregory
Introduction
The Era of the Genome
Mapping the Human Genome
Genetic Mapping
Radiation Hybrid Mapping
Physical Mapping
Public Data Repositories and Genome Browsers
Single Nucleotide Polymorphisms (SNPs)
SNP Discovery
Utilizing SNPs
Computational SNP Resources
Model Organisms
Identifying Candidate Genes by Genomic Convergence
De Novo Annotation of Genes
Software Suites
On-line Sequence Analysis Resources
Understanding the Molecular Mechanism of the Disease
Assigning gene function
Looking Beyond the Genome Sequence
Other Databases
Summary
Acknowledgments
References
16. Designing a Study for Identifying Genes in Complex Traits
Jonathan L. Haines & Margaret A. Pericak-Vance
Introduction
The Components of a Disease Gene Discovery Study
Define Phenotype
Develop Study Design
Analysis
Follow-Up
Keys to a Successful Study
Foster Interaction of the Necessary Expertise
Develop a Careful Study Design
References
Glossary
Index