Linkage Newsletter

Jurg Ott OTTSR%CUVMB at CUVMB.CC.COLUMBIA.EDU
Sat Jul 31 10:35:59 EST 1993


   It seems that by mistake this
newsletter has not yet been sub-
mitted to the gene-linkage news-
group.  Sorry for the delay.


                       Linkage Newsletter

                  Vol. 7   No. 2   June 1993


Published by Jurg Ott, Columbia University, New York

Editorial Assistant:  Katherine Montague
      Fax: +1-212-568-2750
      Tel. 212-960-2507 or 718-960-2507 (there have been some
             problems recently with our telephone and we are not
             quite sure which one works best right now)
      e-mail:  ott at nyspi.bitnet  or  jurg.ott at columbia.edu

Postal address:
      Columbia University, Unit 58
      722 West 168th Street, New York, NY 10032



EDITORIAL

      Finally - we have made a major step into the electronic age.
Up until now, our programs have been distributed only on diskettes.
We have now set up an anonymous ftp site from which interested
researchers can obtain programs and other materials (see below for
details).


LINKAGE COURSES

      There are still a few places available for the next Advanced
Linkage Course.  It will be held in Zurich (Switzerland), at the
Computing Center of the University of Zurich Irchel campus,
September 27 - October 1, 1993.  Maximum number of participants is
12.  For information and application forms please write to the
address above, preferably by fax.

      The Columbia University Advanced Course for the academic year
1993/4 will be held in January of 1994 but a date has not been
fixed yet.


MEETING ANNOUNCEMENT
      (contributed by Dr. Robert Elston)

      Second Annual meeting of the INTERNATIONAL GENETIC EPIDEMI-
      OLOGY SOCIETY, October 10-11, 1993 - New Orleans, Louisiana.
      The meeting will be held in the Monteleone Hotel (French
      Quarter) and will begin on Sunday, Oct. 10th with a joint
      symposium with the American Society of Human Genetics on
      "Genetic & Environmental Aspects of Disease."  For further
      information and abstract forms please contact Louisiana State
      University Medical Center Foundation, Division of Professional
      Education, 433 Bolivar Street, New Orleans, LA 70112 - Phone
      #(504) 568-3712/FAX #(504) 568-3460.


NEW ANONYMOUS ftp SITE

      An anonymous ftp site (Login: anonymous;  no password) is
being made available for use by people interested in genetic
linkage analysis.  We are in the process of uploading all our
programs to this ftp site.  All programs distributed by us will
eventually be made available on this site.  The DOS version of
LINKAGE version 5.20 is now also available from us (see below).
For those people who are unable to access our ftp site, we will
still distribute programs on floppy disks.

      The ftp site presently works fine as far as we can tell.
However, because of local network congestion in the afternoon,
please access the site during off-peak hours as transfer may be
impossible during periods of heavy network activity.  To access our
site, use the command

      ftp york.ccc.columbia.edu    or    ftp 128.59.97.32

When asked for a login name, enter ANONYMOUS.  A password is not
required.  For reports on problems please send e-mail to

      joe at york.ccc.columbia.edu (Joe Terwilliger).

      The host computer, YORK.CCC.COLUMBIA.EDU, is running Desktop-
VMS Version 1.2, so the directory syntax must be specified in VMS
format, which is different from UNIX-based ftp sites.  When you
reach our computer, you will be in directory [anonymous], which is
the root directory for the ftp site.  All higher directories are
off-limits, and any attempt to access such directories will block
any further activity for you.  That root directory contains a file,
README.TXT, which contains a description of the directory structure
and a list of all files available from the ftp site.

      Each of the subdirectories in the ftp site contains a file
with the directory name and extension .TXT.  This file briefly
describes the contents of the subdirectory.  As an example, the
directory [anonymous.pub.newsletter] contains the current and past
issues of the Linkage Newsletter.  Eventually, it will contain all
newsletters published by us since the first issue of August 1987.
Please note:  We are still sending out the newsletter by e-mail.
If you want to receive it by e-mail as soon as a new issue is
ready, send a message to:  jurg.ott at columbia.edu

      When you logon, you will notice that there are some files in
the root directory.  These are all account specific files, which
are read/write protected.  You must go to the subdirectory PUB.DIR,
with VMS syntax [anonymous.pub].  You can get there by typing CD
[.pub], for example, if your computer is running UNIX ftp software.
A directory name preceded by a "." means a subdirectory.  If the
"." is not given, the computer will think you are trying to access
a higher-level directory, and will block further access to the
system.  If, for example, you are in the directory [anony-
mous.pub.linkage.dos], and you want to move to the directory
[anonymous.pub.linkage], you could enter CD [-], where the "-" sign
means to go back one directory level.  To move to the directory
[anonymous.pub.tlinkage.dos], you could enter CD [--.tlinkage.dos],
meaning back up two levels, and then move forward to subdirectory
[.tlinkage.dos].  If you have any further questions about VMS
directory syntax, or are having difficulty navigating around the
ftp site, please send e-mail to Joseph Terwilliger
(JOE at YORK.CCC.COLUMBIA.EDU).

      To get any files other than ASCII files (*.EXE or *.W51 files,
for example, are non-ASCII), please make sure you do this in binary
mode.  Typically, one should type SET TYPE BINARY at the ftp
prompt, though the exact syntax may vary from system to system.  If
you further must use communications software like KERMIT to get the
binary files from a UNIX or VMS machine to your PC, be sure to do
those transfers in BINARY format as well.


SOFTWARE NEWS

PC version 5.2 of LINKAGE

      The PC version of LINKAGE version 5.20 is now also available
from us.  It is essentially the same as the one you may obtain from
Paris with the following exceptions:  We have added a few more
error checks, the program manual is included not for Postscript
printers but as ASCII and WordPerfect files, and the COMPILE batch
file of version 5.10 has been adapted to version 5.20.  We are also
in the process of adapting the Turbo Pascal version to Borland
Pascal such that, for example, it can run under Windows and use
more memory than under DOS.  This adaptation, however, may take
some time to become available.

      The OS/2 version of LINKAGE version 5.2 is in preparation and
should be available in August.  It is being adapted to NDP Pascal
for OS/2, which is just now becoming available from Microway, Inc.
(tel. (508 746 7341, fax (508) 746 4678).  The previous, pre-
release version already had excellent qualitites (see Linkage
Newsletter of February 1993).


Modified LINKAGE programs in C

      Robert Cottingham at Baylor College of Medicine has translated
some of the LINKAGE version 5.1 programs into C and rewritten
several procedures resulting in a program version with much
improved execution speed.  A paper describing these modifications
will appear in the Amer J Hum Genet.  The programs may be obtained
from the anonymous ftp site, gc.bcm.tmc.edu.  Robert Cottingham may
be reached at bwc at bcm.tmc.edu.


Estimating allele and haplotype frequencies - BEWARE!

      As more and more people estimate allele and haplotype
frequencies using the LINKAGE programs, in particular, the ILINK
program, it is important to be aware of the following two steps
required for reliable estimation:
      1) The program constant, fitmodel, must be set to true and the
program recompiled.
      2) Whenever all individuals in a pedigree are untyped for a
marker, the UNKNOWN program makes those individuals homozygous for
the 1 allele at that marker.  While this speeds up calculations
considerably, it leads to wrong results in the estimation of allele
and haplotype frequencies.  A possible solution is simply not to
use the UNKNOWN program.  We have slightly amended the UNKNOWN
program such that it contains a program constant, makehomozygous,
which should be set to false if no unknown phenotypes should be
turned into homozygotes 1 1.  A compiled version of UNKNOWN with
makehomozygous set to false is furnished in executable form as
UNKNOWN1.EXE.


FORTRAN programs

      While most of our programs are written in Pascal, a few
programs are in FORTRAN.  This includes PC-LIPED and NOCOM
(estimation of mixture of distributions).  All our FORTRAN programs
are now compiled with Microsoft FORTRAN 5.1 and bound in such a way
that the same executable code runs under DOS or OS/2 (the LIPED
version allowing for 12 alleles runs only under OS/2).


URP program for downcoding alleles

      URP is a computer program which reduces the number of alleles
at a marker locus by re-labeling ("down-coding") them.  The
original version of this program was designed and written by
Michael Braverman in PL/I computer language in the early 1980's and
was implemented on an IBM Series/1 minicomputer in Dr. Kenneth K.
Kidd's lab at Yale University.  In 1984 Randy Holmes converted this
program into primary PASCAL language, and in 1985 Matthew Hawley
adapted it to a VMS/VAX machine.  We recently obtained a copy of
URP from Dr. Andrew Pakstis at Yale University, and Xiaoli Xie
converted it to Turbo Pascal.  Xiaoli Xie tried it out on nine CEPH
families with chromosome 13 marker data;  her experiences with the
program are given below.

      The input file to the URP program has a format similar to the
one used in the LIPED program.  However, genotypes can only be
coded with alphabet letters, so there are up to 52 different allele
codes as upper and lower case letters distinguishable.  Besides,
the URP program only recodes one marker at a time.  Since genotypes
in input files to the LINKAGE programs are coded with numbers, one
must replace these numbers by letters.  As the URP program only
recodes one marker at a time, repeatedly modifying the input file
for URP is inevitable.  If one wants to use the output file
resulting from URP as input to a linkage program other than LIPED,
one must change the letters back to numbers.  Since the whole
procedure is very time consuming, we only tested the program with
two-point analysis.

      We used nine families in the pedigree file, each family with
approximately 14 individuals.  There were two markers with 12 and
9 alleles, respectively.  All but seven individuals were untyped.
We ran MLINK (PC version) and LIPED based on the original dataset,
and then reduced the number of alleles by running the URP program,
which reduced the number of alleles in the first marker from 12 to
4, and in the second one from 9 to 3.  We assigned equal allele
frequencies to the recoded makers and then ran MLINK and LIPED
again.  The results turned out to be identical.  The elapsed time
for the recoded dataset was much shorter than for the original data
set, for example, 3 seconds versus 125 seconds.  Note, however,
that not knowing the allele frequencies can create problems for the
analysis (J. Ott, Am J Hum Genet 51:283-290, 1992).

      DISCLAIMER:  The above investigation was carried out because
we keep receiving requests regarding the availability of such
programs.  We do not endorse the URP program in any way.  Its
application may be problematic in several respects that we are not
pursuing any further.  For example, with untyped individuals
present in a pedigree, exact solutions become extremely cumbersome
(Ott [1979] Cytogenet Cell Genet 25:196).  Also, the algorithm
applied in the URP program focuses on twopoint analysis, but cases
are known in which pairwise comparisons are uninformative yet the
multipoint analysis is not.  The most urgent need for downcoding
alleles is in multipoint analysis, but it is not clear whether the
procedure employed in URP  consistently works fine for multipoint
analysis.  For the time being, we choose to carry out downcoding by
hand even though it may be tedious.

Support through grant HG00008 from the National Center for Human
      Genome Research is gratefully acknowledged.



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