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Pedigree Selection and Information Content

Elizabeth R. Hauser¹, Daniel E. Weeks²

¹Duke University Medical Center, Durham, North Carolina
²University of Pittsburgh, Pittsburgh, Pennsylvania

Publication Name:

Current Protocols in Human Genetics

Unit Number:

Unit 1.2

DOI:

10.1002/0471142905.hg0102s29

Online Posting Date:

August, 2001

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Abstract

This unit covers the important criteria and methods for appropriately selecting pedigrees for linkage analysis. It includes methods for determining the power of a dataset to detect genetic loci for both model-based (lod score) and model-free (affected sib-pair, affected-relative pair) analyses.This unit covers the important criteria and methods for appropriately selecting pedigrees for linkage analysis.

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Introduction
Key Concepts
Strategic Approach: Pedigree Selection and Evaluation of Pedigree Data for Information Content
Commentary
Bibliography
Figures
Tables

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Figures

Figure 1.2.1

Flow chart showing initial steps in a linkage study.

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Figure 1.2.2

Three-generation family segregating for an autosomal dominant disease. The mother (person 3) is a phase-known double heterozygote. Circles represent females and squares represent males, in this and all subsequent pedigree diagrams. Darkened symbols represent affected individuals.

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Figure 1.2.3

Nuclear family segregating for an autosomal dominant disease. The mother is a phase-unknown double heterozygote.

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Figure 1.2.4

A nuclear family with one offspring contains no information for linkage. This family is segregating for a rare autosomal dominant disease.

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Figure 1.2.5

Expected lod score as function of number of offspring for phase-known and phase-unknown nuclear families.

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Figure 1.2.6

Nuclear families segregating for an autosomal recessive disease. The father has a 1/2 marker genotype, while the mother has a 3/4 marker genotype. Figure 1.2.7 shows the expected lod scores for each family.

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Figure 1.2.7

The expected lod score as a function of the recombination fraction ( and pedigree structure (shown in Fig. 1.2.6).

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Figure 1.2.8

Two pedigrees segregating for a rare autosomal dominant disease with full penetrance. See Table 1.2.2 and Figure 1.2.12 for simulation results.

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Figure 1.2.9

Example pedigree indicating four possible extensions.

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Figure 1.2.10

A three-generation family in which persons 1, 2, and 6 are considered founders.

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Figure 1.2.11

A sample pedigree used for illustration of the SLINK simulation algorithm. Person 2 is known to have the AB marker genotype.

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Figure 1.2.12

Sample simdata.dat file containing parameters for SLINK simulation and sample simped.dat file containing data from the two pedigrees in Figure 1.2.8. The line identifying columns has been added for clarity. Columns of the simped.dat file are as follows: (1) Pedigree ID. (2) Person ID. (3) Father ID. If a father is not in the pedigree drawing, then a zero is used as the ID. (4) Mother ID. (5) First offspring ID. (6) Next paternal sibling ID. (7) Next maternal sibling ID. (8) Sex—a “1” indicates a male while a “2” indicates a female. (9) Proband column. The proband has a “1” in this column, and the remaining members of the pedigree have a “0.” (10) Disease-status column, where 1 means normal, 2 means affected, and 0 indicates unknown disease status. (11) First marker allele. Because, in this particular example, no prior marker data are known, each person is given the “unknown” genotype, as indicated by a zero in this column. (12) Second marker allele. See note to column 11. (13) Availability code (always the last column of a simped.dat file). A code of 2 indicates that the individual is available for marker typing, but that the original disease phenotype should be retained. In our example, all individuals are available for marker typing and so have a code of 2. A code of 0 would indicate that the individual is unavailable for marker typing, but that the original disease phenotype should be retained. See the SLINK documentation for a detailed discussion of these codes.

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