Studies on MS-Related Sequences Identified by Amplicon-Based RDA From Affected Members of Monozygotic Twin Pairs Discordant for Schizophrenia




P. Deb1, T.A.

Klempan1, R.L. O’Reilly1, 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.