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UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL

Contribution of Cis-acting regulatory polymorphisms to Psychiatric Disorders, AR Differences in gene expression patterns between individuals are common, and it has been suggested that the polymorphisms responsible for these differences may account for the majority of human phenotypic variability. Gene expression is likely determined by the combined impact of environmental factors and inherited polymorphisms in regulatory regions of genes that modulate transcription or affect mRNA processing. Abundant polymorphisms in cis-acting sequences have been identified in genes implicated in psychiatric disorders. However, the elucidation of the contributions of these polymorphisms, both alone and when inherited in combination with polymorphisms at other loci, has been extremely difficult. The lack of progress in this area contrasts sharply with the progress that has been made in the evaluation of polymorphisms that alter protein structure. Mouse lines have been generated in which coding variants identified in patients have been introduced into the orthologous mouse gene using what are now standard genetic engineering techniques. These lines have provided important information regarding the functional importance of these polymorphisms. However, this method can rarely be used to study regulatory variants, as generally these polymorphisms are in regions that are less well conserved between mouse and human. The goal of this project is to utilize a novel approach for evaluation of the functionality of polymorphisms in non-coding regions of genes believed to act in cis to regulate gene expression. We will generate mouse lines in which the mouse ortholog of the human polymorphic gene is excised and then replaced with the syntenic human locus carrying either the disease associated or protective allele. The expected outcome is the generation of a panel of mouse lines which can be used to determine the impact of the polymorphisms present in human populations on gene expression during all stages of development, both during normal rearing and in response to imposed environmental stresses. In addition, these lines will provide an opportunity to follow epigenetic changes at the human loci and to determine whether expression changes manifest as alterations in the behavior of the mouse. The lines we are generating will allow us to assess the functionality of polymorphisms in the genes encoding the dopamine receptor D4, DRD4, the dopamine transporter (SLC6A3), the serotonin transporter (SLC6A4 gene) and in MAOA, a key regulator of serotonin metabolism.

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