A transposon in Comt generates mRNA variants and causes widespread expression and behavioral differences among mice

Zhengsheng Li, Megan Mulligan, Xusheng Wang, Michael F. Miles, Lu Lu, Robert Williams

Research output: Contribution to journalArticle

32 Citations (Scopus)

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 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/Significance: We have precisely defined the B2 SINE as the source of variation in Comt and demonstrated that a transposon in a 39 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.

Original languageEnglish (US)
Article numbere12181
JournalPloS one
Volume5
Issue number8
DOIs
StatePublished - Oct 19 2010

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Untranslated Regions
transposons
Catechol O-Methyltransferase
Protein Isoforms
catechol O-methyltransferase
Messenger RNA
mice
dopamine
Genetic Crosses
Pharmacology
RNA Isoforms
Dopamine D1 Receptors
Polyadenylation
Dopamine D2 Receptors
Haloperidol
haloperidol
Prefrontal Cortex
Aggression
Hippocampus
Dopamine

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

A transposon in Comt generates mRNA variants and causes widespread expression and behavioral differences among mice. / Li, Zhengsheng; Mulligan, Megan; Wang, Xusheng; Miles, Michael F.; Lu, Lu; Williams, Robert.

In: PloS one, Vol. 5, No. 8, e12181, 19.10.2010.

Research output: Contribution to journalArticle

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