LINKAGE(5)

NAME
LINKAGE - general information about LINKAGE's file formats

DESCRIPTION
The input data consist of pedigree and genotypic information contained in one file, and locus descriptions, recombination rates and locus order contained in a second file. These files are entitled PEDFILE(5) and DATAFILE(5), respectivly.

  Phenotypes and Genotypes
To understand the format of the input files, you must know what kinds of phenotypic data can be interpreted by the LINKAGE programs. Phenotype data can be one of the following types:

•   Numbered alleles. These are codominant alleles at a single locus. The numbers run consecutively from 1 to the maximum number of alleles observed. The phenotype consists of two allele numbers corresponding to a genotype. An unknown genotype is coded as 0 0.

•   Binary factors. In this coding scheme a series of binary codes (1 or 0) indicates the presence or absence of a phenotype factor. This system is useful for describing either codominant or recessive/dominant systems. The phenotype is entered as a binary string.

•   Affection status. The presence or absence of disease (or other qualitative phenotypes) is described by a numbered code. A risk or liability class can also be included as a separate numeric code.

•   Quantitative traits. One or more quantitative measurements can be used as a phenotype description.

The phenotypic codes for each of these types of data are described in more detail below.

NOTE:
    The present version of LINKAGE does not allow mixtures of affection status and quantitative variables, except in the case of sex-linked traits as described below. A future version will incorporate a modification allowing such mixtures for autosomal data.

  Numbered Allies
Numbering alleles is the simplest way to code codominant marker data. A homozygote is indicated by repeating the allele number; thus 1 2 indicates that the alleles are 1 and 2 (a heterozygotea) while 1 1 indicates the alleles are 1 and 1 (a homozygote). An unknown genotype is coded as 0 0. For sex-linked loci, males have a single allele. With the allele 1, for example, the phenotype can be coded 1 0 or 1 1.

  Binary Factors
Binary factors (sometimes called "factor-union" notation) can also represent phenotypes for codominant marker data, but this coding is most useful with recessive alleles or with complex systems such as Rh, ABO, and Gm. Each allele is assigned a set of properties, called factors, in such a way that all phenotypes can be specified as the union of two allele sets. For codominant loci, each allele can be associated with one factor. If n alleles are present, the ith allele is represented by a series of n binary codes with a 0 in all locations, except in the ith position, which contains a 1. For example, in a two allele system the allelic codes are:
1 | 0 | (allele 1)
0 | 1 | (allele 2)
The three possible phenotypes are:
1 | 0 | (union of alleles 1 and 1)
1 | 1 | (union of alleles 1 and 2)
0 | 1 | (union of alleles 2 and 2)
An unknown phenotype is coded as 0 0. Spaces between the codes are very important; they must be included when entering the phenotypes into the pedigree file as described below. A locus with three codominant alleles is coded as:
1 | 0 | 0 | (allele 1)
0 | 1 | 0 | (allele 2)
0 | 0 | 1 | (allele 3)
The six possible phenotypes are:
1 | 0 | 0 | (union of alleles 1 and 1)
1 | 1 | 0 | (union of alleles 1 and 2)
1 | 0 | 1 | (union of alleles 1 and 3)
0 | 1 | 0 | (union of alleles 2 and 2)
0 | 1 | 1 | (union of alleles 2 and 3)
0 | 0 | 1 | (union of alleles 3 and 3)
and an unknown phenotype is 0 0 0. The advantage of the binary factor coding scheme is evident when a recessive disease gene is under study. To code such a system, we could indicate the normal gene by the presence of a single factor (1) and the disease gene by the absence of this factor (0). The phenotype 1 (unaffected) now corresponds to two possible genotypes, either the union of allele 1 and allele 1 (noncarrier) or the union of allele 1 and allele 0 (carrier). This simple coding is usually not sufficient because both homozygote recessive and unknown phenotypes are coded as 0. To account for this, we introduce a second factor for which a 1 indicates that the phenotype is known, and a 0 that the phenotype is unknown. The allelic codes are:
1 | 1 | (allele 1)
0 | 1 | (allele 2)
and the possible phenotypes are:
1 | 1 | (union of alleles 1 and 1, or alleles 1 and 2)
0 | 1 | (union of alleles 2 and 2)
0 | 0 | (unknown)

  Affected Status
"Affection status" refers to the presence or absence of disease. The programs assume that an affected individual will have the phenotype code "2" and that an unknown individual will have the code "0." By convention, "1" is used to designate unaffected status (in fact, this code can be any integer value other than 0 and 2). If necessary, the unknown and affected codes can be changed in the program code, and the programs recompiled. For an "affection-status" locus, each genotype has an associated penetrance; this is the probability that an individual with a particular genotype will be affected. Penetrance can also be defined as a function of liability classes. In this case, one penetrance is given for each genotype in each liability class. The classes are numbered sequentially starting from 1. With two or more liability classes, the phenotype is the affection status plus the class number. When a single affection status class is defined, the class number is not included as part of the phenotype. With sex-linked traits, different penetrances must be given for females and males. One penetrance in males is specified for each allele in each liability class.

  Quantitative Variables
Phenotypic information is sometimes presented in the form of quantitative measurements, e.g. creatine kinase for carrier detection in Duchenne muscular dystrophy. The phenotype is then the quantitative value. Unknown phenotypes are entered as 0.0. (The code for unknown quantitative values is a program constant that can be changed.) The genotypic means, the variance of the trait in homozygotes, and the ratio of the variances in heterozygotes and homozygotes must be specified. If several traits are measured for the same locus, the phenotype is the list of all the variables. A single value of 0.0 in the list is interpreted as an unknown phenotype. The means must be given for each variable as a function of genotype, along with the variance-covariance matrix. The variance matrices for homozygotes and heterozygotes can differ by a constant factor. For sex-linked traits it is assumed that males will have an affection-status variable rather than a quantitative value. If several variables have been measured (ntrait), a male phenotype consists of affection status followed by ntrait-1 arbitrary entries (for example, zeros). The present version of the programs supports only one affection status class, with full penetrance of the disease allele for sex-linked traits.

NOTES
The information contained herein was gleaned, often-times verbatim, from the LINKAGE User's Guide (http://linkage.rockefeller.edu/soft/linkage/) on the web by kind permission of Jurg Ott, Ph.D.

AUTHORS
Mark Lathrop and Jurg Ott.

This manual page was written by Elizabeth Barham <lizzy@soggytrousers.net> for the Debian GNU/Linux distribution.

WORLD-WIDE-WEB
http://linkage.rockefeller.edu/soft/linkage/ (http://linkage.rockefeller.edu/soft/linkage/)

SEE ALSO
DATAFILE(5), PEDFILE(5), ilink(1), linkmap(1), lodscore(1), mlink(1), and unknown(1).