Jurg Ott 17 Dec 1993 Columbia University, Unit 58 Tel (212) 960-2507 722 West 168 Street Fax (212) 568-2750 New York, NY 10032 e-mail: jurg.ott@columbia.edu LINKAGE programs for 2-locus traits (TLINKAGE) NDP Pascal for OS/2 - Turbo Pascal for DOS Contents INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . 1 IMPLEMENTATION. . . . . . . . . . . . . . . . . . . . . . 2 KNOWN BUGS. . . . . . . . . . . . . . . . . . . . . . . . 3 SAMPLE INPUT. . . . . . . . . . . . . . . . . . . . . . . 3 LITERATURE. . . . . . . . . . . . . . . . . . . . . . . . 4 INTRODUCTION The programs described here are an extension of the general LINKAGE programs for genetic linkage analysis. The extension consists of allowing for a disease phenotype to be under the control of two loci. The manual describing the use of the general programs is furnished as file USER.W51 (in WordPerfect 5.1 format) and file USER.TXT (in ASCII format); these files reside in DOC.ZIP. Version for DOS: This version is for compilation with Turbo Pascal. The relevant compiler switches may be set in the file SWITCHES.PAS. As shipped, the programs sense a coprocessor when it is installed and emulate it if none is installed. In the presence of a faulty coprocessor, this test may fail leading to cryptic error messag- es. The programs may then be forced to emulate the coprocessor by issuing the DOS command, set 87=no, before running the pro- grams. The programs should be compiled with the batch program COMPILE, not with the Turbo Pascal compiler directly. Version for OS/2: This program version is written in NDP Pascal (available from Microway Inc.), which is essentially the same as Vax Pascal. A batch file, COMPILE.CMD, is furnished for easy compilation of the programs. NOTE: As shipped, the programs do not check whether array bounds are exceeded at run time. It is the user's responsibility to ensure that array bounds are large enough, or else the programs should be compiled with the appropriate switch- es. It might be best to compile with array bound checking (-cg1 switch) and, before a long production run, compile without array bound checking. NDP Pascal does not recognize ^Z (Ctrl-Z) as an end-of-file character. If ^Z is present at the end of a file it will be treated as a character. The LINKAGE programs typically test for end of file to see, for example, if all individuals have been read. Presence of ^Z may lead to a cryptic error message (eg. "invalid integer"). Thus, please be sure to use an editor that does not leave a trailing ^Z when saving a file. Unfortunately, the OS/2 editors (system and enhanced editor) have this undesir- able property and are thus unsuitable for preparing input files unless ^Z is removed afterwards by another editor. IMPLEMENTATION ----------------------------- Program name Corresponds to ----------------------------- TUNK UNKNOWN TMLINK MLINK TLINKM LINKMAP TILINK ILINK ----------------------------- The TLINKAGE programs implement a new locus type #4, called the null type because it may have no associated phenotype in the pedigree file. Each null locus is associated with the same phenotype. The number of null loci corresponds to the number of loci jointly responsible for a disease phenotype. That number is indicated as the last entry on the first line of the datafile (after the program number). In this version of TLINKAGE, you must have two null loci, or zero null loci. If two null loci are defined, there are thus two consecutive locus descriptions for these null loci in the datafile, but they correspond to only one phenotype in the pedfile. That phenotype must be an affection status phenotype, and it may be at any position among the phenotypes (ie, the null loci are not restricted to be the first two loci in the datafile). NOTE, however, the following restriction: if the two null loci are loci 1 and 2, their order must be 1 2 and not 2 1. For example, with loci 3 and 4 being markers, the orders 1 3 2 4 and 4 1 3 2 are all right but the orders 2 3 1 4 and 4 2 3 1 are not. An analogous restriction on order applies when the null loci are numbered other than 1 and 2. In the datafile, the description of a null locus contains only the number of alleles and gene frequencies, eg: 4 2 << null locus, number of alleles 0.9 0.1 << allele frequencies except that after the last null locus, a line specifying the number of liability classes must be present, followed by one or more tables of penetrances (as many tables as the number of liability classes). Each such table (see example below) has a single entry for each genotype combination at the two loci and is arranged as shown in the example below. The numbers to be entered in each table are only the penetrances, in this case the 3x3=9 numbers in the body of the table (do not enter any of the genotypes such as 1/2 or 2/2). Repeat this table with different entries for different liability classes. Remember that only the last null locus has an associated phenotype in the pedfile. An example may look as follows: ----------------------------- First Second null locus null ----------------- locus 1/1 1/2 2/2 ----------------------------- 1/1 0 0 0 1/2 0 0.8 0.8 2/2 0 0.8 1 ----------------------------- The current 2-locus version of LINKAGE allows analysis of autosomal loci only. Please make sure you do not use these programs for X chromosomal loci -- there is no check in the programs to ensure that you are adhering to this restriction. KNOWN BUGS In releases prior to 13 Feb 1991, two bugs were present in these programs: the programs did not work right when individuals with unknown disease status were present and when more than one liability class was used. Both bugs were fixed by Joseph Terwil- liger. SAMPLE INPUT FILES The files TESTML.DAT, TESTLM.DAT, and TESTIL.DAT are sample datafiles for TMLINK, TLINKM, and TILINK, respectively. A test pedigree file (before processing by MAKEPED) is included as TEST.PRE. The corresponding pedfile suitable for input to the programs is TEST.PED. To run the test example for TMLINK, copy the test files to your current directory in which you want to carry out the TLINKAGE runs. Then give the following commands: copy testml.dat datafile.dat copy test.ped pedfile.dat tunk tmlink In the regular LINKAGE programs, various utility programs such as LCP and PREPLINK may be used for the creation of the input files. Presently, these programs have not been adapted to the TLINKAGE programs. Therefore, you must create your input files with a text editor. LITERATURE Lathrop GM, Ott J (1990) Analysis of complex diseases under oligogenic models and intrafamilial heterogeneity by the LINKAGE programs. Am J Hum Genet 47, A188 (abstr) Schork NJ, Boehnke M, Terwilliger JD, Ott J (1993) Two trait locus linkage analysis: a powerful strategy for mapping complex genetic traits. Am J Hum Genet 53, 1127-1136