a transposon in comt generates mrna variants and causes widespread expression and behavioral differences among mice转座子在comt的信使rna产生变异,导致广泛的表达和行为差异的老鼠.pdfVIP

A Transposon in Comt Generates mRNA Variants and Causes Widespread Expression and Behavioral Differences among Mice 1. 1. 1 2 1 1 Zhengsheng Li , Megan K. Mulligan , Xusheng Wang , Michael F. Miles , Lu Lu , Robert W. Williams * 1 Department of Anatomy and Neurobiology, Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America, 2 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America Abstract Background: Catechol-O-methyltransferase (COMT) is a key enzyme responsible for the degradation of dopamine and norepinephrine. COMT activity influences cognitive and emotional states in humans and aggression and drug responses in mice. This study identifies the key sequence variant that leads to differences in Comt mRNA and protein levels among mice, and that modulates synaptic function and pharmacological and behavioral traits. Methodology/Principal Findings: We examined Comt expression in multiple tissues in over 100 diverse strains and several genetic crosses. Differences in expression map back to Comt and are generated by a 230 nt insertion of a B2 short interspersed element (B2 SINE) in the proximal 39 UTR of Comt in C57BL/6J. This transposon introduces a premature polyadenylation signal and creates a short 39 UTR isoform. The B2 SINE is shared by a subset of strains, including C57BL/6J, A/J, BALB/cByJ, and AKR/J, but is absent in others, including DBA/2J, FVB/NJ, SJL/J, and wild subspecies. The short isoform is associated with increased protein expression in prefrontal cortex and hippocampus relative to the longer ancestral is