title: A transposon in Comt generates mRNA variants and causes widespread expression and behavioral differences among mice.
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.
  
  
  RESULTS
  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 3' UTR of Comt in C57BL/6J. This transposon introduces a premature polyadenylation signal and creates a short 3' 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 isoform. The Comt variant causes downstream differences in the expression of genes involved in synaptic function, and also modulates phenotypes such as dopamine D1 and D2 receptor binding and pharmacological responses to haloperidol.
  
  
  CONCLUSIONS
  We have precisely defined the B2 SINE as the source of variation in Comt and demonstrated that a transposon in a 3' UTR can alter mRNA isoform use and modulate behavior. The recent fixation of the variant in a subset of strains may have contributed to the rapid divergence of inbred strains.
authors.affiliation: Department of Anatomy and Neurobiology, Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Li
authors.forename: Megan K
authors.initials: MK
authors.lastname: Mulligan
authors.forename: Xusheng
authors.initials: X
authors.lastname: Wang
authors.forename: Michael F
authors.initials: MF
authors.lastname: Miles
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D004251:DNA Transposable Elements / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D014644:Genetic Variation; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics; D018626:Retroelements / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D020413:3' Untranslated Regions; D004251:DNA Transposable Elements; D012333:RNA, Messenger; D038621:Regulatory Sequences, Ribonucleic Acid; D018626:Retroelements; D002394:Catechol O-Methyltransferase
references.citation: Front Neurosci. 2009 Nov 10;3:55
references.pmid: 20582282
references.citation: Nat Rev Genet. 2005 Jul;6(7):521-32
references.pmid: 15995696
references.citation: Nucleic Acids Res. 2008 Oct;36(17):5581-90
references.pmid: 18757892
references.citation: Pharmacogenetics. 1996 Jun;6(3):243-50
references.pmid: 8807664
references.citation: Genes Brain Behav. 2006 Jun;5(4):311-28
references.pmid: 16716201
references.citation: Pharmacogenetics. 1999 Oct;9(5):607-17
references.pmid: 10591541
references.citation: Rev Physiol Biochem Pharmacol. 1992;120:1-29
references.pmid: 1519017
references.citation: Science. 1984 Nov 23;226(4677):974-7
references.pmid: 6095445
references.citation: Eur J Neurosci. 2002 Jan;15(2):246-56
references.pmid: 11849292
references.citation: Hum Genet. 2007 Feb;120(6):889-906
references.pmid: 17006672
references.citation: Neuroinformatics. 2003;1(4):299-308
references.pmid: 15043217
references.citation: Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91
references.pmid: 12716966
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12536-41
references.pmid: 17636131
references.citation: J Neurosci. 1999 Jan 15;19(2):549-61
references.pmid: 9880575
references.citation: Nat Neurosci. 2005 May;8(5):594-6
references.pmid: 15821730
references.citation: J Neurosci. 2004 Jun 9;24(23):5331-5
references.pmid: 15190105
references.citation: Mol Psychiatry. 2007 Oct;12(10):893-5, 885
references.pmid: 17895922
references.citation: Eur J Neurosci. 2004 May;19(9):2576-82
references.pmid: 15128411
references.citation: BMC Genomics. 2007 Mar 16;8:76
references.pmid: 17367521
references.citation: Mol Psychiatry. 2007 Sep;12(9):854-69
references.pmid: 17767149
references.citation: Nat Genet. 2001 May;28(1):77-81
references.pmid: 11326281
references.citation: Biol Psychiatry. 2006 Jul 15;60(2):141-51
references.pmid: 16476412
references.citation: Adv Pharmacol. 1998;42:707-11
references.pmid: 9327997
references.citation: Eur Psychiatry. 2007 Jul;22(5):276-81
references.pmid: 17419009
references.citation: Mol Cell Neurosci. 1999 Oct-Nov;14(4-5):370-84
references.pmid: 10588391
references.citation: J Pharmacol Exp Ther. 1996 May;277(2):1016-25
references.pmid: 8627512
references.citation: Mamm Genome. 2000 Aug;11(8):664-70
references.pmid: 10920237
references.citation: Am J Hum Genet. 2004 Nov;75(5):807-21
references.pmid: 15457404
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9991-6
references.pmid: 9707588
references.citation: J Neurochem. 1994 Sep;63(3):972-9
references.pmid: 7914228
references.citation: Nat Neurosci. 2004 May;7(5):485-6
references.pmid: 15114364
references.citation: Biochemistry. 1995 Apr 4;34(13):4202-10
references.pmid: 7703232
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22
references.pmid: 11381111
references.citation: Biol Psychiatry. 2002 Oct 1;52(7):701-7
references.pmid: 12372660
references.citation: EMBO J. 2000 Jun 15;19(12):2775-85
references.pmid: 10856223
references.citation: J Neurosci. 2008 Aug 27;28(35):8709-23
references.pmid: 18753372
references.citation: Nat Genet. 2005 Mar;37(3):233-42
references.pmid: 15711545
references.citation: Genes Brain Behav. 2010 Mar 1;9(2):129-59
references.pmid: 19958391
references.citation: Am J Psychiatry. 2002 Apr;159(4):652-4
references.pmid: 11925305
references.citation: Eur J Biochem. 1984 Dec 3;145(2):203-20
references.pmid: 6209137
references.citation: Biol Psychol. 2008 Sep;79(1):126-36
references.pmid: 18423838
references.citation: Nat Neurosci. 2007 Mar;10(3):376-84
references.pmid: 17277774
references.citation: Biochem J. 1993 Dec 15;296 ( Pt 3):595-600
references.pmid: 8280056
references.citation: Nature. 2002 Dec 5;420(6915):520-62
references.pmid: 12466850