Handbook of Human Genetic Linkage

Joseph Terwilliger and Jürg Ott

Johns Hopkins University Press, 1994

TABLE OF CONTENTS

  1. Background Material

    1. The purpose of this book
    2. Notation and definitions
    3. A review of the principles of linkage analysis
    4. Installing the LINKAGE programs

    Part I. TWO-POINT LINKAGE ANALYSIS

  2. The File System Used by LINKAGE

    1. Pedigree drawing
    2. Pedigree files
    3. MAKEPED
    4. Parameter files (PREPLINK)

  3. Running the LINKAGE Programs MLINK and ILINK

    1. Theoretical analysis
    2. MLINK
    3. ILINK

  4. Setting Up a Linkage Analysis Using LCP

    1. LCP

  5. Elementary Usage of the Affected Status Locus Type

    1. Autosomal dominant disease
    2. Autosomal recessive disease
    3. Incomplete penetrance

  6. Sex-linked Recessive Diseases

    1. Sex-linked diseases
    2. The preparation of pedigree and parameter files
    3. Performing the linkage analysis

  7. Loops

    1. Consanguinity loops
    2. Marriage loops
    3. The LOOP program

  8. Locus Types I: Allele Number and Binary Factor

    1. Codominance
    2. Multiple factors: two alleles (the CEPH database)
    3. Dominance and recessivity
    4. Systems with dominance and codominance: the ABO blood group

  9. Advanced Applications of Affected Status I: Incomplete Penetrance Revisited

    1. Age-dependent penetrance
    2. Distribution functions versus density functions
    3. Phenocopies

  10. Advanced Applications of the Affection Status Locus Type II

    1. Generalized definition of the 2 phenotype
    2. Codominant marker loci
    3. Carrier status
    4. Diagnostic uncertainty
    5. ABO blood group revisited

  11. The LIPED Program

    1. Characteristics of LIPED
    2. An example: monozygotic twins

  12. Solutions to the Exercises in Part I

    Part II. MULTIPOINT LINKAGE ANALYSIS WITH THE LINKAGE PACKAGE

  13. Gene Mapping in CEPH Families

    1. What is CEPH?
    2. Why use the CEPH panel?
    3. CLINKAGE
    4. General strategies for map construction

  14. The Locus-ordering Problems: CILINK

    1. How to order a set of loci?
    2. CILINK

  15. CMAP and Adding a New Locus

    1. Multipoint lod score
    2. Computing multipoint lod scores with CMAP
    3. Map distance

  16. Mapping a Disease Locus against a Fixed Map of Markers

    1. Multipoint testing and estimating linkage with disease
    2. Disease gene mapping

  17. Exclusive Mapping

    1. Using negative test results
    2. Two-point exclusion mapping
    3. Multipoint exclusion mapping
    4. Model errors and exclusion mapping

  18. Sex Difference in Recombination Rates: Multipoint Case

    1. Estimating sex-specific recombination rates
    2. Constant female-to-male map distance ration
    3. Using sex difference in general pedigree data
    4. Using sex difference in recombination fraction in LINKMAP

  19. Introduction to Interference

    1. What is interference?
    2. Three-point analysis of interference
    3. Sex-specific interference analysis

  20. Solutions to the Exercises in Part II

    Part III. ADVANCED TOPICS IN LINKAGE ANALYSIS

  21. Mutation Rates and the LINKAGE Programs

    1. Mutations
    2. Allowing for mutation rates in LINKAGE
    3. Mutation-selection equilibrium
    4. Sex-linked lethal recessive disease

  22. Gene Frequencies and LINKAGE

    1. How are gene frequencies used in the LINKAGE programs?
    2. The consequences of using incorrect gene frequencies
    3. Estimation of gene frequencies

  23. Linkage Disequilibrium between Alleles at Marker Loci

    1. What is linkage disequilibrium?
    2. Population-based sampling and the EH program
    3. Estimating disequilibrium from pedigree data

  24. Linkage Disequilibrium and Disease Loci

    1. Case-control sampling
    2. More complicated penetrance models
    3. The theory behind the haplotype relative risk
    4. The application of the HRR and the CONTING program
    5. Paired sampling and the CHIPROB program
    6. Haplotype-based haplotype relative risk
    7. Using ILINK to estimate linkage disequilibrium with disease
    8. Using linkage disequilibrium in the LINKAGE programs

  25. Parametric Analysis of Complex Diseases

    1. Complex diseases
    2. Entering data for multiple diagnostic schemes
    3. Choosing an appropriate single-locus parametric model
    4. Interpreting lod score maximized over models
    5. Combining diagnostic criteria in a single model
    6. Affecteds-only analysis

  26. Nonparametric Methods of Linkage Analysis

    1. Identity by descent versus identity by state
    2. Affected sib-pair analysis
    3. Affected pedigree member method
    4. When to use nonparametric methods
    5. How to do sib-pair analysis
    6. Extended sib-pair analysis and the ESPA program
    7. Using the ESPA program

  27. Genetic Heterogeneity

    1. Genetic heterogeneity
    2. Test for homogeneity given linkage
    3. Using the HOMOG program

  28. Computer Simulation Method

    1. Random numbers and simulation
    2. Pedigree simulation by tossing a coin
    3. The SIMULATE program
    4. Possible applications of simulation under H0
    5. How to use the SIMULATE program
    6. Analyzing the simulated replicates with MLINK and ILINK
    7. Analyzing the simulated replicates with MSIM
    8. ISIM
    9. SLINK
    10. LSIM

  29. Solution to the Exercise in Part III

APPENDICES