DescriptionSecond Edition features the latest tools for uncovering the genetic basis of human disease
The Second Edition of this landmark publication brings together a team of leading experts in the field to thoroughly update the publication. Readers will discover the tremendous advances made in human genetics in the seven years that have elapsed since the First Edition. Once again, the editors have assembled a comprehensive introduction to the strategies, designs, and methods of analysis for the discovery of genes in common and genetically complex traits. The growing social, legal, and ethical issues surrounding the field are thoroughly examined as well.
Rather than focusing on technical details or particular methodologies, the editors take a broader approach that emphasizes concepts and experimental design. Readers familiar with the First Edition will find new and cutting-edge material incorporated into the text:
- Updated presentations of bioinformatics, multiple comparisons, sample size requirements, parametric linkage analysis, case-control and family-based approaches, and genomic screening
- New methods for analysis of gene-gene and gene-environment interactions
- A completely rewritten and updated chapter on determining genetic components of disease
- New chapters covering molecular genomic approaches such as microarray and SAGE analyses using single nucleotide polymorphism (SNP) and cDNA expression data, as well as quantitative trait loci (QTL) mapping
The editors, two of the world's leading genetic epidemiologists, have ensured that each chapter adheres to a consistent and high standard. Each one includes all-new discussion questions and practical examples. Chapter summaries highlight key points, and a list of references for each chapter opens the door to further investigation of specific topics.
Molecular biologists, human geneticists, genetic epidemiologists, and clinical and pharmaceutical researchers will find the Second Edition a helpful guide to understanding the genetic basis of human disease, with its new tools for detecting risk factors and discovering treatment strategies.
1. Basic Concepts in Genetics and Linkage Analysis (Elizabeth C. Melvin and Marcy C. Speer).
Segregation and Linkage Analysis.
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.
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.
Interference and Genetic Mapping.
Meiotic Breakpoint Mapping.
Disease Gene Discovery.
Information Content in a Pedigree.
Disease Gene Localization.
Extensions to Complex Disease.
2. Defining Disease Phenotypes (Arthur S. Aylsworth).
Exceptions to Traditional Mendelian Inheritance Patterns.
Pseudodominant Transmission of a Recessive.
Pseudorecessive Transmission of a Dominant.
Incomplete Penetrance and Variable Expressivity.
Phenocopies and Other Environmentally Related Effects.
Polygenic and Multifactorial Models.
Role of Environment.
Role of Chance in Phenotype Expression.
Classification of Disease.
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.
3. Determining Genetic Component of a Disease (Allison Ashley-Koch).
Study Design .
Selecting a Study Population .
Approaches to Determining the Genetic Component of a Disease.
Cosegregation with Chromosomal Abnormalities and Other Genetic Disorders.
Twin and Adoption Studies.
Recurrence Risk in Relatives of Affected Individuals.
4. Patient and Family Participation in Genetic Research Studies Chantelle Wolpert, Amy Baryk Crunk, and Susan Estabrooks Hahn).
Step 1: Preparing to Initiate a Family Study.
Certificate of Confidentiality.
Need for a Family Studies Director.
Working with Human Subjects.
Step 2: Ascertainment of Families for Studies.
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.
5. Collection of Biological Samples for DNA Analysis (effery M. Vance).
Establishing Goals of Collection.
Types of DNA Sample Collection.
DNA Extraction and Processing .
Dried Blood Cards.
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.
Sources of Markers.
Restriction Fragment Length Polymorphisms.
PCR and Genotyping.
Laboratory and Methodology Optimization,
Optimization of Reagents.
“I Can’t Read a Marker, What Should I Do?”
Manual or Nonsequencer Genotyping.
DNA Pooling and Homozygosity Mapping/Detection Methode.
Radioactive Methods (32P or 33P).
DNA Array or ""Chip"".
Oligonucleotide Ligation Assay.
Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Spectrometry.
Invader and PCR-Invader Assays.
Single-Strand Conformational Polymorphism.
Denaturing High-Pressure Liquid Chromatography.
7. Data Analysis Issues in Expression Profiling.(Simon Lin and Michael Hauser).
Serial Analysis of Gene Expression.
Analysis of SAGE Libraries.
Expression Data Matrix.
Dimension Reduction of Features.
Measures of Similarity between Objects.
Unsupervised Machine Learning: Clustering.
Supervised Machine Learning
Other Types of Gene Expression Data Analysis.
Biological Applications of Expression Profiling.
8. Information Management (Carol Haynes and Colette Blach).
Plan Logical Database Model.
Hardware and Software Requirements.
Pedigree Plotting and Data Manipulation Software.
9. Quantitative Trait Linkage Analysis (Jason H. Moore).
Introduction to Quantitative Traits.
Haseman–Elston Regression .
Multipoint IBD Method.
Variance Component Linkage Analysis.
10. Advanced Parametric Linkage Analysis (Silke Schmidt).
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.
Practical Approaches for Model-Based Linkage Analysis of Complex Traits.
Maximized Maximum LOD Score.
11. Nonparametric Linkage Analysis (Elizabeth R. Hauser, Jonathan Haines, and David E. Goldgar).
Background and Historical Framework.
Identity by State and Identity by Descent.
Measures of Familiality.
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
12. Linkage Disequilibrium and Association Analysis 329
Eden R. Martin
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
13. Sample Size and Power 355
Yi-Ju Li, Susan Shao, and Marcy Speer
Power Studies for Linkage Analysis:
Mendelian Disease 358
Information Content of Pedigrees 358
Computer Simulation Methods 359
Definitions for Power Assessments 363
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
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
14. Complex Genetic Interactions 397
William K. Scott and Joellen M. Schildkraut
Evidence for Complex Genetic Interactions Genetic
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
15. Genomics and Bioinformatics 423
Judith E. Stenger and Simon G. Gregory
Era of the Genome 423
Mapping the Human Genome 424
Genetic Mapping 425
Radiation Hybrid Mapping 427
Physical Mapping 428
Public Data Repositories and Genome Browsers.
Computational SNP Resources.
Identifying Candidate Genes by Genomic Convergence.
De Novo Annotation of Genes.
Online Sequence Analysis Resources.
Understanding Molecular Mechanisms of Disease.
Assigning Gene Function.
Looking Beyond Genome Sequence.
16. Designing a Study for Identifying. Genes in Complex Traits (Jonathan L. Haines and Margaret A. Pericak-Vance).
Components of a Disease Gene Discovery Study.
Develop Study Design.
Keys to a Successful Study.
Foster Interaction of Necessary Expertise.
Develop Careful Study Design.