A Human-Specific Gene (G72/G30) in Transgenic Mice

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DESCRIPTION (provided by applicant): G72/G30, a sense-antisense gene complex on chromosome 13q33.2 also known as DAOA (D-amino acid oxidase activator), has been associated with schizophrenia and bipolar disorder in multiple studies. The disease association and its characteristic of being one of the very few primate-specific genes make G72/G30 a very intriguing target in the biological study of human brain and mental diseases. Our most recent meta-analysis of schizophrenia indicates that two SNPs in G72/G30 show gene-wide significant association in Asians. In this application, we propose to screen Asian schizophrenia patients (DNAs have been collected by the NIMH Genetics Initiative) for an individual carrying the allele that shows association with schizophrenia. Then, we will use the Transformation Associated Recombination (TAR) Cloning method to isolate G72 Bacterial Artificial Chromosome (BAC) clones from the selected schizophrenia patient. The isolated clone will be introduced into a mouse genome to produce a transgenic mouse line. We will then perform biochemical, gene expression, and behavioral tests on three types of mice: the new transgenic mouse line produced in this study, our existing G72 transgenic mouse line that carries the non-risk allele, and wild type mice. Comprehensive use of genetic, functional genomics and behavioral genetics approaches should lead us to an improved understanding of the biology of G72 in brain function and in schizophrenia susceptibility. We will create a transgenic mouse line that carries a human G72/G30 gene complex with a schizophrenia risk allele. G72 (as we refer to the complex) is one of the most consistently associated genes with both bipolar disorder and schizophrenia. Because G72 is a primate-specific gene with low expression levels in human, biological study of G72 in humans is particularly challenging. With the new transgenic mouse generated in this application, and our existing G72 transgenic mouse without the schizophrenia risk allele, we can perform in vivo tests on G72 biological and behavioral functions. We expect these results will ultimately lead to a better understanding of G72 and its role in both normal human brain function and psychiatric disease states.