Characterization of a Functional Comt1 Haplotype in Inbred Strains of Mice

We have pursued a genome-wide approach to examining strain-specific variations in gene expression in the brain of 29 inbred strains of mice. The highest association was found within the locus of the Catechol-O-Methyltransferase (Comt1) gene, coding for an ubiquitously expressed enzyme that maintains basic biologic functions by inactivating catecholamines. In human and mouse, COMT has been associated with multiple behavioral phenotypes, including pain sensitivity and stress response. Multiple brain regions in 29 inbred strains of mice were analyzed for Comt1 expression levels using a genome wide array. Differential expression levels, validated with qPCR, were observed for Comt1. A B2 Short Interspersed Nucleotide Element (SINE) was identified as an insertion in the 3'UTR of Comt1 in 14 strains of a shared haplotype. Experiments using mammalian expression vectors of full length cDNA clones with and without the SINE element present demonstrate the SINE haplotype (+SINE) to have greater Comt1 enzymatic activity. Within strains examined to date, +SINE mice have increased enzymatic function, decreased sensitivity for thermal and chemical- induced pain assays and behavioral differences in several anxiety assays. These results suggest that a haplotype, defined by a 3'UTR B2 SINE element, regulates Comt1 expression and mouse behavior