Hello,
I received a query from a user regarding some results he got when doing a
two-point linkage analysis. Here follows the query:
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I have a problem with a simple two point linkage analysis.
I have done many such analyses in the past and experience has taught me
to expect that, with any fully penetrant dominant phenotype, a marker
that detects a crossover will always give negative infinity at a theta
of zero. However I now have a family with about 40 meioses in 60 or so
individuals in which this is not happening. Is this possible? The single
crossover is between branches of the family separated by seven unsampled
meioses (the people involved are dead) but it is quite unambiguously
there. The disease segregates with one allele in all the rest of the
family and with another in a small branch. This is only clearly visable
in two individuals but nevertheless it is there.The lod score in
question rises to a peak of over 5 at about three centimorgans then
falls to 3.4 at zero. I've checked it, I've run it on both a PC and the
HGMP facility, I've played with allele frequencies of both the linked
marker and the disease, I've run both two point (MLINK) and multipoint
(LINKMAP), I've even typed the whole thing in again from scratch, and
still it is there. The lod score goes up and down, but is always still
posative at a theta of zero. Have I made a mistake, or is this a real
result? Any help or advice would be gratefully recieved.
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So, is it possible to get such a result for a fully penetrant dominant
phenotype? Or is more detailed knowledge of the pedigree
necessary? Is
something wrong with the model? I tried to figure it out for myself
but am not sure. Intuitively I would say that something is wrong, but I
do not have any idea where to start to look. Any information, discussion,
pointers to literature, etc. gladly welcomed. All information will be passed
on to the user.
Frank
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F. R. Visser
HGMP-Resource Centre
Hinxton, UK
Phone : +44 (0)1223 494526
e-mail: fvisser at hgmp.mrc.ac.uk
