A B2 SINE insertion in the <i>Comt1</i> gene (<i>Comt1</i>^<i>B2i</i>) results in an overexpressing, behavior modifying allele present in classical inbred mouse strains

<jats:p> <jats:bold>Catechol‐O‐methyltransferase (COMT) is a key enzyme for dopamine catabolism and <jats:italic>COMT</jats:italic> is a candidate gene for human psychiatric disorders. In mouse it is located on chromosome 16 in a large genomic region of extremely low variation among the classical inbred strains, with no confirmed single nucleotide polymorphisms (SNPs) between strains C57BL/6J and DBA/2J within a 600‐kB window. We found a B2 SINE in the 3′ untranslated region (UTR) of <jats:italic>Comt1</jats:italic> which is present in C57BL/6J (<jats:italic>Comt1</jats:italic><jats:sup><jats:italic>B2i</jats:italic></jats:sup>) and other strains including 129 (multiple sublines), but is not found in DBA/2J (<jats:italic>Comt1</jats:italic><jats:sup>+</jats:sup>) and many other strains including wild‐derived <jats:italic>Mus domesticus, M. musculus, M. molossinus</jats:italic>, <jats:italic>M.castaneus</jats:italic> and <jats:italic>M. spretus. Comt1</jats:italic><jats:sup><jats:italic>B2i</jats:italic></jats:sup> is absent in strains closely related to C57BL/6, such as C57L and C57BR, indicating that it was polymorphic in the cross that gave rise to these strains. The strain distribution of <jats:italic>Comt1</jats:italic><jats:sup><jats:italic>B2i</jats:italic></jats:sup> indicates a likely origin of the allele in the parental Lathrop stock. A stringent association test, using 670 highly outbred mice (Boulder Heterogeneous Stock), indicates that this insertion allele may be responsible for a difference in behavior related to exploration. Gene expression differences at the mRNA and enzyme activity level (1.7‐fold relative to wild type) indicate a mechanism for this behavioral effect. Taken together, these findings show that <jats:italic>Comt1</jats:italic><jats:sup><jats:italic>B2i</jats:italic></jats:sup> (a B2 SINE insertion) results in a relatively modest difference in <jats:italic>Comt1</jats:italic> expression and enzyme activity (comparable to the human Val‐Met polymorphism) which has a demonstrable behavioral phenotype across a variety of outbred genetic backgrounds.</jats:bold> </jats:p>