Viral and Immune Hypotheses In Schizophrenia: An Epigenetic Perspective

Neurogenetics Section, Clarke Institute of Psychiatry, Toronto,

action of viral infection have been suggested in schizophrenia

including the integration of retroviral sequences into the host

genome. Integration of retroviral DNA may be pathogenic in two

ways: I) the insertion of viral DNA in a functioning gene may

lead to disruption of the host’s gene sequence, and II)

integrated viral DNA may produce new viruses and toxic

substances. Viral-host genome interaction to a large extent

depends on epigenetic factors. Firstly, the integration of any

exogenous genome is not random but depends on the chromatin

conformation and other epigenetic conditions at the specific

locus of the host genome. Only some loci are

“receptive” and can incorporate a strand of foreign

DNA. Secondly, the activity of integrated viruses is under the

control of epigenetic modification of viral DNA. Numerous

experimental data have shown that DNA methylation plays a role in

silencing or activating various types of viruses including

herpesvirus, lentivirus, cytomegalovirus, hepatitis B virus, and

human immunodeficiency virus. The findings that the majority of

proviral DNA and transposable elements were methylated and

transcriptionally inactive in the genomes of fungi, plants and

mammals, have provided the basis for concluding that DNA

methylation is part of the host defence system (Bestor 1996). In

comparison to other epigenetic mechanisms, DNA methylation seems

to be of key importance in genomic defence because Drosophila,

which is known to have no DNA methylation, exhibits a

significantly higher degree of insertional mutagenesis caused by

exogenous sequences than other organisms which have DNA

play a role in the development of autoimmune reactions. Foetal

carriers of genetic risk factors to insulin dependent diabetes

mellitus exhibited decreased expression of the insulin gene in

thymus, a critical site for tolerance induction to self proteins.

It can be hypothesized that insufficient expression of insulin

during embryogenesis may lead to inefficient negative selection

of insulin-specific T-lymphocytes, and eventually to an

autoimmune reaction against the insulin. The insufficient

expression of the insulin gene during embryogenesis at least

partially could be determined by epigenetic regulation of the

insulin gene. This autoimmune mechanism can be extrapolated to

shed a new light on the understanding of viral and autoimmune