|Functional Genomics Section
DOE Human Genome Program Contractor-Grantee Workshop
138. Discovering the Genes Affected by Schizophrenia Using DNA Micro-Array
Yang Qiu, Edward M. Rubin, and Jan-Fang
Schizophrenia is a devastating psychiatric disorder that affects 1% of the population. Genetic factors make important contributions to the etiologies of this disease. It is highly likely that multiple genes and environmental factors are involved. Chromosome 6p has been shown to have linkage with schizophrenia in several independent studies. The current drugs treating schizophrenia including clozapine, risperidone and olanzapine are all far from perfect with substantial side effects. It is thus important to be able to identify the genes affected by schizophrenia, which would greatly enhance the drug discovery leading to a better treatment.
We are taking advantage of the technology of DNA micro-array at Lawrence Berkeley National Lab which can hold thousands of genes on one single glass slide and the development of the human and mouse Unigen set (uniquely expressed sequences) through the effort of genome community. The expression of thousands of genes at different physiological condition can be analyzed in parallel. New genes can be identified and biological functions of the genes can be further studied. The DNAs to be spotted on the DNA micro-array are as following:
(1) 10,000 human Unigen clones representing ~20% of expressed human genes.
(2) 309 BAC clones available from the physical mapping project covering 90% of the schizophrenia candidate region at chromosome 6p.
(3) 269 genes singly selected through thorough literature search which include neurotransmitter receptor (dopamine receptor, glutamate receptor, serotonin receptor, acetylcholine receptor, etc), brain function related genes and other possible genes involved in schizophrenia.
(4) ~ 40 clones identified to be differentially expressed in neuropsychiatric disorders by Stanley Neurovirology Laboratory at the Johns Hopkins University, School of Medicine.
The postmortem brain tissue from individuals with schizophrenia and normal controls will be obtained from Standley Foundation Neuropathology Consortium. Total RNAs are to be extracted from the different brain tissues and hybridized with the DNA micro-array. The genes that are affected in schizophrenia can be identified when using a large sample sets to minimize the individual variations in the gene expression.
Meanwhile, a mouse model for schizophrenia is underway for this study. It has been established that the mice treated with psychotic drug PCP (angel dust) mimic some symptoms of schizophrenia in which the prepulse inhibition is diminished in schizophrenia patients. We are treating mice with PCP as well as antipsychotic drugs including clozapine and risperidone. The gene expression patterns in the mouse brain will be followed at different times after each treatment using the DNA micro-array. The genes that are affected by drugs can be identified as the candidate genes for schizophrenia.
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