CIT/DCB/BIMAS
Genetic Linkage Analysis Software

Genetic Linkage Analysis Tools

• APM
• ASPEX
• FASTLINK 4.0P
• Genehunter
• GenoCheck 1.0
• Linkage 5.1 (See NOTE)
• MAPMAKER
• MENDEL
• MIM
• SimIBD
• Vitesse 1.0
• More Soon!

APM Version 2.0 dated March, 1994:

APM (Affected Pedigree Member) Method Linkage Analysis Programs are used to analyze pedigrees for linkage between a diseased trait and a number of marker loci. The programs come in two versions. The many-locus version analyzes any number of markers, independently, one at a time. The multiple-locus version analyzes a set of closely linked markers. Both versions accept similar input files which require numbering each pedigree from top to bottom. Both versions generate probability statistics for each marker to show the degree of linkage for three different weighting functions of the allele frequencies: f(p) = 1, f(p) = 1/p, and f(p) = "1 over the square root of p" = 1/sqrt(p) = p^(-0.5).

These programs are developed by Kenneth Lange, Daniel E. Weeks and Mark Schroeder at Department of Human Genetics, University of Pittsburgh and are Copyright (C) 1993 by Daniel E. Weeks.

ASPEX Version 1.65 dated March, 1998:

ASPEX is a set of programs for performing multipoint exclusion mapping of affected sibling pair data for discrete traits. There are five main analysis programs: sib_ibd, sib_phase, sib_map, sib_tdt, and kinship. The sib_ibd and sib_phase programs are for exclusion mapping. The sib_ibd program is faster, tailored for data sets where both parents are typed, and makes no assumptions about missing information. The sib_phase program is slower, uses allele frequencies to reconstruct missing information, and is tailored for data sets where parents are missing, but additional typed children may be used to reconstruct and phase the parents. The sib_map program is for multipoint marker distance estimation from sib pair data. The sib_tdt program is for transmission disequilibrium testing. And the kinship program is for verifying the degree of relatedness of individuals within a family.

David Hinds and Neil Risch, Stanford University

FASTLINK Version 4.0P

The FASTLINK package contains faster-executing versions of the computationally intensive general pedigree programs of LINKAGE 5.1 package, namely LODSCORE, ILINK, MLINK, and LINKMAP. The improvements were carried out starting with converting PASCAL programs to C using the p2c translation program. Improvements were made in the combinatorial part of the algorithmic code. The most recent version, 4.0P, adds additional features to more optimally process pedigrees with loops.

The FASTLINK FTP site is fastlink.nih.gov

The author of FASTLINK, Dr. Alejandro Schäffer, welcomes invitations for consultations with NIH researchers. He may be reached at schaffer@helix.nih.gov.

For more information, please refer to the following papers:

R. W. Cottingham Jr., R. M. Idury, and A. A. Schäffer, Faster Sequential Genetic Linkage Computations, American Journal of Human Genetics, 53(1993), pp. 252-263. and

A. A. Schäffer, S. K. Gupta, K. Shriram, and R. W. Cottingham, Jr., Avoiding Recomputation in Genetic Linkage Analysis, Human Heredity, 44(1994), pp. 225-237.

Dr. Alejandro Schäffer maintains a FASTLINK homepage and Wentian Li of Rockefeller University has the hypertext version of the FASTLINK README files.

GENEHUNTER Version 1.1, dated April 24, 1997 (Version 2.0 beta has been released, dated December 29, 1998):

GENEHUNTER is a package from the Whitehead Institute at MIT. It adopts a general approach using inheritance vectors. The result is a normally distributed Z-statistic for p-values.

GENEHUNTER will run on helix, Sun workstations, and most likely other UNIX workstations. Please contact BIMAS to have a copy set up for you.

Version 2.0 beta is now available. The GENEHUNTER authors have stated: This release (November 2, 1998) is the first Beta release of GENEHUNTER 2. As such, some features are not yet completed and others (such as the new 'variance components' and TDT functionality) will possibly be extended in the near future. It's been expressed that having the MAPMAKER/SIBS and TDT functionality in GENEHUNTER is sufficiently important that I am releasing this before everything that will eventually be in GENEHUNTER 2 is completed and fully tested.

The online documentation for 2.0 beta is an improvement.

GENEHUNTER 1.1 Commands

GenoCheck Version 1.0, dated April 28, 1997:

This software implements the error checking scheme that was described by M. G. Ehm (Rice University), R. W. Cottingham, Jr., and M. Kimmel. The error checking system in conjunction with FASTLINK identifies individuals and loci likely to contain errors using a likelihood based method.

It is recommended that GenoCheck be used to identify potential genotyping errors and other data errors before a large investment of time is made to perform linkage analysis computations.

GenoCheck Documentation

LINKAGE Version 5.1, dated January 19, 1994:

NOTE: It is strongly recommended that the use of the LINKAGE program be discontinued and FASTLINK (and/or VITESSE) be used in it's place. The functionality of FASTLINK is designed to supercede LINKAGE, and FASTLINK's performance benefits are very great. And for those problems which VITESSE can accomodate, the additional performance has the potential for being still greater.

LINKAGE is an integrated system of programs designed to perform linkage analysis and genetic risk calculation for an arbitrary number of loci. These programs are subdivided as "Linkage Analysis" programs and "Linkage Support" programs.

LINKAGE's Linkage Analysis programs

Linkage Analysis programs consist of a core of programs, which perform such tasks as maximum likelihood estimation of recombination rates, calculation of lod score tables, and analysis of genetic risk.

• MLINK: This program performs n-point linkage and risk calculations in general pedigrees. This program can be used to construct lod score tables.
• LODSCORE: This program performs iterative maximum likelihood estimation of recombination fractions from two-locus data in general pedigrees.
• ILINK: This program performs iterative maximum likelihood estimations in general pedigrees.
• LINKMAP: This program calculates location scores in general pedigrees.
• UNKNOWN: This program infers possible genotypes for unknown individuals. Prepares input files for ILINK, LINKMAP, MLINK and LODSCORE programs.
• CILINK: This program performs iterative maximum likelihood estimations in nuclear pedigrees (nuclear families with the possible addition of grandparents).
• CMAP: This program calculates likelihoods for genetic location in nuclear pedigrees.
• CINFER: This program infers genotypes for unknown individuals whenever possible. Works on nuclear pedigrees only. Prepares the input file for the CFACTOR program.
• CFACTOR: This program applies factorization and transformation rules to genotypes in nuclear pedigrees prior to analysis with the CMAP and CILINK programs. CFACTOR works on nuclear pedigrees only.

LINKAGE's Linkage Support Programs

Linkage Support programs form an interactive "shell" or "front-end" around the core programs. In addition, they also provide the user with linkage file preparation, data checking facilities and report generation from the linkage results.

• LCP: Linkage Control Program (LCP) is an interactive menu program for building command files to perform linkage analysis.
• LRP: Linkage Report Program (LRP) is an interactive menu program for displaying and formatting the stream output from the linkage analysis programs.
• MAKEPED: converts pedigree files of the form: pedigree number, ID number, father ID, mother ID to a form that includes offspring and sib-pointers.
• PREPLINK: interactively defines locus descriptions; stores descriptions in a parameter file for input into computational programs.

LINKAGE references:

G. M. Lathrop, J.-M. Lalouel, C. Julier, and J. Ott, Strategies for Multilocus Analysis in Humans, PNAS 81(1984), pp. 3443-3446.

G. M. Lathrop and J.-M. Lalouel, Easy Calculations of LOD Scores and Genetic Risks on Small Computers, American Journal of Human Genetics, 36(1984), pp. 460-465.

G. M. Lathrop, J.-M. Lalouel, and R. L. White, Construction of Human Genetic Linkage Maps: Likelihood Calculations for Multilocus Analysis, Genetic Epidemiology 3(1986), pp. 39-52.

For more information, look at genetic linkage analysis software at Rockefeller University.

MAPMAKER dated February 10, 1993:

MAPMAKER is a linkage analysis package designed to help construct primary linkage maps of markers segregating in both experimental crosses as well as simple natural populations (e.g. two and three generation nuclear families). mapmaker performs full multipoint linkage analyses (simultaneous estimation of all recombination fractions from the primary data) for dominant, recessive, and co-dominant (e.g. RFLP-like) markers. qtl is a companion program to mapmaker which allows one to map genes controlling polygenic quantitative traits in F2 intercrosses and BC1 backcrosses relative to a genetic linkage map.

MAPMAKER was written by Stephen E. Lincoln, Mark J. Daly, and Eric S. Lander of the Whitehead Institute for Biomedical Research and the MIT center for Genome Research at MIT Department of Biology.

Tutorials are available directly from MIT Genome Center and also locally.

MENDEL Version 3.3, dated April 4, 1995:

MENDEL is a Fortran 77 program for the genetic analysis of human pedigree data. It performs likelihood calculations for models involving a small number of loci; the companion program FISHER is designed for the analysis of polygenic models. MENDEL will be useful for segregation analysis, linkage calculations, genetic counseling, and related kinds of problems. Perhaps, it would better to think of MENDEL as a collection of programs for genetic analysis. A common framework is provided for users to develop their own applications. MENDEL and it's companion programs are available free, but copies must be acquired from and registered with Dr. Kenneth Lange at the University of Michigan.

MIM Version 1.1, dated March 5, 1996:

MIM is a program to implement the Multipoint Identity By Descent method (Goldgar 1990; Goldgar and Oniki 1992) for partitioning genetic variance of quantitative traits to specific chromosomal regions using data on nuclear families. More complex pedigrees may be decomposed into groups of nuclear families in order to use this program. MIM operates in two modes:

(a) Analysis of a quantitative traid by estimating P, the proportion of genetic variance of the trait due to a loci in a chromosomal region determined by a set of marker loci. The Null Hypothesis of P=0 is tested using a Chi-Squared approximation to the generalized likelihood ratio test.

(b) Analysis of a discrete trait by computing the average proportion shared IBD in the test region among affected pairs and comparison of this to both the expected value of 0.5 and that computed for discordant or unaffected pairs. For example, if the quantitative trait is the usual 1=unaffected, 2=affected status variable, a threshold value of 1.5 would provide the correct dichotomy.

MIM is written in C for a Unix workstation, but should be readily portable to a wide variety of computer systems.

References:

Goldgar DE (1990) Multipoint analysis of human quantitative genetic variation. Am J Hum Genet 45:957-967.

Goldgar DE and Oniki RO (1992) Comparison of a multipoint identity by descent method with parametric multipoint linkage analysis for mapping quantitative traits. Am J Hum Genet 50:598-606.

Goldgar DE, Lewis CM, Gholami K (1993) Analysis of discrete phenotypes using a multipoint identity by descent method: application to the Alzheimers data set. Genetic Epidemiology 10:383-388.

Lewis CM, Goldgar DE (1995) Screening for linkage using a mulitpoint identity- by-descent method. In Goldin LR, Bishop DT, Meyers DA, Morgan K, Rice JP, MacCluer JW (eds) Genetic Analysis Workshop 9: Analysis of Complex Oligogenic Traits. In press.

For additional information, please contact:

David E. Goldgar, Ph. D.
Genetic Epidemiology
391 Chipeta Way, D2
Salt Lake City, UT 84108
Email: gold@episun3.med.utah.edu

SimIBD Version 1.21, dated April 25, 1997:

SimIBD is the software implementation of the algorithms described in Davis et al., "Nonparametric simulation-based statistics for detecting linkage in general pedigrees," (1996) Am J Hum Genet 58:867-880.

SimIBD Documentation

Vitesse Version 1.0, dated December 13, 1995:

VITESSE is a software package that computes likelihoods with the functionality of the LINKMAP and MLINK programs from LINKAGE. Version 1 can only handle simple pedigrees with no loops, however. For some suitable datasets, VITESSE may run dramatically faster and use less memory than FASTLINK's LINKMAP program.

VITESSE uses the novel algorithms of set-recoding and fuzzy inheritance to reduce the number of genotypes needed for exact computation of the likelihood, which accelerates the calculation. It also represents multilocus genotypes locus-by-locus to reduce the memory requirements.

The algorithms in VITESSE were developed and coded by Jeff O'Connell at the University of Pittsburgh. Dan Weeks at the University of Pittsburgh and the Wellcome Trust Centre for Human Genetics at Oxford University collaborated.

Distribution: via anonymous FTP from:

• watson.hgen.pitt.edu, directory /pub/vitesse (US)
• ftp.ox.ac.uk, directory pub/users/ayoung/vitesse (UK)
• ftp.ebi.ac.uk, directory pub/software/linkage_and_mapping/hgen_pitt (UK)
• via WWW from http://info.ox.ac.uk/~ayoung/gas.html (UK)

REGISTRATION/MAILING LIST: If you wish to use VITESSE, or to be on the VITESSE mailing list to be informed of new releases, updates, bug fixes, etc, please register with jeff@sherlock.hgen.pitt.edu.

Reference: "The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance", O'Connell JR, Weeks DE, Nature Genetics 11:402-408, December 1995.

For Complete Vitesse Documentation

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