STUDIES ON MS-RELATED
SEQUENCES IDENTIFIED BY AMPLICON-BASED RDA FROM AFFECTED MEMBERS
OF MONOZGOTIC TWIN PAIRS DISCORDANT FOR SCHIZOPHRENIA
P. Deb1, T.A.
Klempan1, R.L. OReilly1, E.F. Torrey2,
and S.M. Singh1*. University of Western Ontario1,
London, Ontario, Canada and NIMH2
The retroviral hypothesis accommodates
most of the family and population distribution patterns for
schizophrenia. Experimental demonstration for the direct
involvement of retroviruses in schizophrenia however, has
remained a challenge and is complicated by two factors. First,
retroviruses are hypothesized to have incorporated during hominid
evolution as a major evolutionary force. They are an integral and
stable part of the human genome, some with the potential to
transpose. Second, retroviruses are a highly heterogeneous, yet
related group of viruses that could enter the cell and integrate
in the host genome with or without any effect to the host. Their
disease implication therefore is not always related to their
presence, rather it may be due to their occurrence at specific
genomic site(s) resulting in insertional mutagenesis or a direct
toxic effect on the host.
We have attempted to isolate
retroviral-related sequences from genomic DNA of affected members
of monozygotic twin pairs discordant for schizophrenia using
amplicon based representational differences analysis
(RDA). Amplicons specific to the reverse transcriptase gene
sequence were obtained from three pairs of twin samples by PCR.
They were used in four to five rounds of RDA where the ill twin
was used as “tester” and the well twin as
“driver”. A 127 bp sequence repeatedly isolated from
all three twin pairs matched with a sequence in the Genbank
specified as multiple sclerosis associated retroviral sequence
(acc # AF009668). An attempt to establish an association of this
relatively small sequence with schizophrenia was not possible. We
used Genome Walker to obtain a larger continuous stretch of this
sequence (2.3 kb). This is currently being assessed in two sets
of experiments: (a) genetic features in the human genome and (b)
possible association with schizophrenia. The results available to
date suggest that this sequence is present in multiple copies in
human genomes, as Southern blots yield 15 20 bands. The
genomic locations of this sequence appear stable in DNA from
control individuals analyzed to date. Given the sequence
features, it is logical to suggest that at least some of these
may have the potential to transpose. It could provide a basis for
genetic predisposition for insertional mutagenesis by endogenous
or exogenous retroviral-related sequences that may lead to the
development of schizophrenia. The actual role of these sequences
in the causation of schizophrenia or any other disease however,
remains to be established.