A transposon in Comt generates mRNA variants and causes widespread expression and behavioral differences among mice.
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.
Li
Zhengsheng
Z
Department of Anatomy and Neurobiology, Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
Mulligan
Megan K
MK
Wang
Xusheng
X
Miles
Michael F
MF
Lu
Lu
L
Williams
Robert W
RW
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
D020413:3' Untranslated Regions; D004251:DNA Transposable Elements; D012333:RNA, Messenger; D038621:Regulatory Sequences, Ribonucleic Acid; D018626:Retroelements; D002394:Catechol O-Methyltransferase
Front Neurosci. 2009 Nov 10;3:55
20582282
Nat Rev Genet. 2005 Jul;6(7):521-32
15995696
Nucleic Acids Res. 2008 Oct;36(17):5581-90
18757892
Pharmacogenetics. 1996 Jun;6(3):243-50
8807664
Genes Brain Behav. 2006 Jun;5(4):311-28
16716201
Pharmacogenetics. 1999 Oct;9(5):607-17
10591541
Rev Physiol Biochem Pharmacol. 1992;120:1-29
1519017
Science. 1984 Nov 23;226(4677):974-7
6095445
Eur J Neurosci. 2002 Jan;15(2):246-56
11849292
Hum Genet. 2007 Feb;120(6):889-906
17006672
Neuroinformatics. 2003;1(4):299-308
15043217
Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91
12716966
Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12536-41
17636131
J Neurosci. 1999 Jan 15;19(2):549-61
9880575
Nat Neurosci. 2005 May;8(5):594-6
15821730
J Neurosci. 2004 Jun 9;24(23):5331-5
15190105
Mol Psychiatry. 2007 Oct;12(10):893-5, 885
17895922
Eur J Neurosci. 2004 May;19(9):2576-82
15128411
BMC Genomics. 2007 Mar 16;8:76
17367521
Mol Psychiatry. 2007 Sep;12(9):854-69
17767149
Nat Genet. 2001 May;28(1):77-81
11326281
Biol Psychiatry. 2006 Jul 15;60(2):141-51
16476412
Adv Pharmacol. 1998;42:707-11
9327997
Eur Psychiatry. 2007 Jul;22(5):276-81
17419009
Mol Cell Neurosci. 1999 Oct-Nov;14(4-5):370-84
10588391
J Pharmacol Exp Ther. 1996 May;277(2):1016-25
8627512
Mamm Genome. 2000 Aug;11(8):664-70
10920237
Am J Hum Genet. 2004 Nov;75(5):807-21
15457404
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9991-6
9707588
J Neurochem. 1994 Sep;63(3):972-9
7914228
Nat Neurosci. 2004 May;7(5):485-6
15114364
Biochemistry. 1995 Apr 4;34(13):4202-10
7703232
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22
11381111
Biol Psychiatry. 2002 Oct 1;52(7):701-7
12372660
EMBO J. 2000 Jun 15;19(12):2775-85
10856223
J Neurosci. 2008 Aug 27;28(35):8709-23
18753372
Nat Genet. 2005 Mar;37(3):233-42
15711545
Genes Brain Behav. 2010 Mar 1;9(2):129-59
19958391
Am J Psychiatry. 2002 Apr;159(4):652-4
11925305
Eur J Biochem. 1984 Dec 3;145(2):203-20
6209137
Biol Psychol. 2008 Sep;79(1):126-36
18423838
Nat Neurosci. 2007 Mar;10(3):376-84
17277774
Biochem J. 1993 Dec 15;296 ( Pt 3):595-600
8280056
Nature. 2002 Dec 5;420(6915):520-62
12466850