SIMCROSS
       A program for haplotyping on general pedigrees
                 Written by Daniel E. Weeks
                    in collaboration with
     Eric Sobel, Jeffrey R. O'Connell, and Kenneth Lange
                          (c) 1995
                              
We are maintaining a user e-mail list, so please register by
sending e-mail to dweeks@watson.hgen.pitt.edu or
daniel.weeks@well.ox.ac.uk.

Given a set of codominant markers with known order, simcross
carries out haplotyping by simulated annealing.  The
original program was developed as a research project with
Dr. Kenneth Lange in 1987 when I was a graduate student.  We
were originally trying to order loci by using simulated
annealing to minimize cross-over counts within each order --
this problem had too many layers of complexity to work well,
and so the project was abandoned until it was revived in
this more useful context.

Important Note:
  Since simcross uses simulated annealing to search a space of often
  immense size, it may not converge to the best answer on the first
  run.  It may be necessary to run simcross several times on your
  data in order to be assured of finding the optimal haplotype configuration.

Input:  Two files in MENDEL-format
          locus.dat
          pedm.dat
Interactively input:
          locus order
          recombination fractions
Output:
          out.out     - Summary file
          recomb.first - Haplotype configuration with the
                         minimum energy
          recomb.ped  - Haplotype configuration that simcross
			converged to                                      			
The recomb.first and recomb.ped files are pedigree files in
MENDEL-format, and may be easily converted to Ped/Draw format
for graphical display on the Macintosh using my program
PedPrep (available by anonymous ftp to
watson.hgen.pitt.edu).  For each person, the maternal
chromosome is drawn on the left, and the paternal chromosome
is drawn on the right.  In order to make it easy to find the
crossovers on the pedigree drawing, we have added the
following symbols:

Key to symbols used in recomb.first and recomb.ped:
     | = No crossovers in the next interval
     \ = Crossover in the next interval in the right
(paternal) chromosome
     / = Crossover in the next interval in the left
(maternal) chromosome
     + = Crossovers in the next interval in both
chromosomes.
     * = Phase not determined by parental genotypes.

Since there are often several states with the same minimum
energy, each time a new minimum energy is encountered, we
record that state in recomb.first.  However, the simulated
annealing routine may continue to search the space after
this state is encountered, and so may often converge to
another state with the same energy.  The file 'recomb.first'
contains the first state encountered with the minimum
energy.

Usage:
     To use 'simcross' on data in LINKAGE-format, first
extract only the codominant marker loci using lsp to create
a 'datafile.dat' and a 'pedfile.dat'.  Then run 'linkmend'
to convert from LINKAGE-format to MENDEL-format.
     This will create a 'locus.dat' and a 'pedm.dat' file.
Then run 'simcross'.  If the order of the markers in the
datafiles differs from the order you'd like to analyze
under, you will have to input the new order (as integers)
when prompted to do so.

Note:
'linkmend' may also be obtained by anonymous ftp to
watson.hgen.pitt.edu

If you publish results generated by simcross, please cite
these articles:

Sobel E, Lange K, O'Connell JR, Weeks DE (1995) Haplotyping
algorithms. In: Speed TP, Waterman MS (eds) Genetic mapping
and DNA sequencing. Springer-Verlag, New York, in press.

Weeks DE, Sobel E, O'Connell JR, Lange K (1995) Computer
programs for multilocus haplotyping of general pedigrees.
American Journal of Human Genetics 56:1506-1507.

Please address any bug reports, queries, or comments to me
(see addresses below).

Don't forget to register by sending me an e-mail message.

Thank you,
     -- Dan Weeks --
________________________________
 Daniel E. Weeks, Ph.D.
 The Wellcome Trust Centre      Department of Human Genetics
 for Human Genetics             University of Pittsburgh
 University of Oxford           Crabtree Hall, Room A310
 Windmill Road                  130 DeSoto Street
 Oxford OX3 7BN                 Pittsburgh, PA 15261
 (+44) 865 740 043 (desk)
 (+44) 865 742 441 (main)            1 412 624-3066
 FAX: (+44) 865 742 196         FAX: 1 412 624-3020
 daniel.weeks@well.ox.ac.uk     dweeks@watson.hgen.pitt.edu

Files in distribution:
     The files are available by anonymous ftp from
watson.hgen.pitt.edu.  There are three different files
available:

1) simcross.tar.Z:
simcross.doc   Documentation file
simcross.f     Source code (main module)
rsub.f         Source code (subroutines)
Makefile       Unix makefile for compiling programs
locus.dat      Sample locus file (Krabbe disease pedigree)
pedm.dat       Sample pedigree file (Krabbe disease pedigree)
simcross.sh    Unix shell script for running simcross on
               Krabbe data.
out.out        Sample output file
recomb.first   Sample output file
recomb.ped     Sample output file

2) simcross.SUNOS.tar.Z:
simcross.SUNOS simcross executable compiled for SunOS 4.1.3
simcross.doc   Documentation file

3) simcross.SOL.tar.Z:
simcross.SOL   simcross executable compiled for Solaris (SunOS 5.3)
simcross.doc   Documentation file

Compilation Instructions:
     Our program is written in standard FORTRAN 77 and
should be portable across different operating systems.  To
compile on a Unix system, simply type 'make'.  This should
generate an executable file called 'simcross'.
     If this does not work, try

f77 -o simcross  simcross.f rsub.f