Abstract
Catechol-O-methyltransferase (COMT) is a key enzyme for dopamine catabolism and COMT 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 Comt1 which is present in C57BL/6J (Comt1B2i) and other strains including 129 (multiple sublines), but is not found in DBA/2J (Comt1+) and many other strains including wild-derived Mus domesticus, M. musculus, M. molossinus, M.castaneus and M. spretus. Comt1B2i 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 Comt1B2i 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 Comt1B2i (a B2 SINE insertion) results in a relatively modest difference in Comt1 expression and enzyme activity (comparable to the human Val-Met polymorphism) which has a demonstrable behavioral phenotype across a variety of outbred genetic backgrounds.
Highlights
Catechol-O-methyltransferase (COMT) plays a regulatory role in catecholamine neurotransmission, in the case of dopamine, by facilitating degradation (Tunbridge et al 2004)
A length polymorphism of nearly 200 bp was identified in the 3 untranslated region (UTR) of Comt1 between C57BL/6J and DBA/2J, possessing the long and the short alleles, respectively
We have found that a B2 SINE in Comt1 (Comt1B2i ) present in some inbred strains but not others is the likely cause of the expression difference between these strains, being the only confirmed variation within the gene between C57BL/6J and DBA/2J
Summary
Catechol-O-methyltransferase (COMT) plays a regulatory role in catecholamine neurotransmission, in the case of dopamine, by facilitating degradation (Tunbridge et al 2004). Research in mice has shown a link between Comt expression and cognitive (Papaleo et al 2008) and aggressive phenotypes (Fernandes et al 2004; Filipenko et al 2001; Gogos et al 1998). In Comt knockout mice a variety of phenotypic changes have been reported, including increased anxiety (Gogos et al 1998), improved working memory, set-shifting performance and greater acoustic startle reactivity (Papaleo et al 2008) and lower weight and greater motor activity (Haasio et al 2003). We examine whether this Comt polymorphism is associated with a behavioral phenotype using the HS mouse stock
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