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Journal of Molecular Neuroscience

, Volume 47, Issue 2, pp 401–407 | Cite as

Intronic Tandem Repeat in the Serotonin Transporter Gene in Old World Monkeys: a New Transcriptional Regulator?

  • Ursula M. Paredes
  • Vivien J. Bubb
  • Kate Haddley
  • Gabriele A. Macho
  • John P. Quinn
Article

Abstract

The serotonin transporter gene (SLC6A4) is heavily involved in the regulation of social behaviour of primates. Old World monkeys (e.g. macaques, baboons) have been used to study interactions between variation in the SLC6A4 gene and behaviour. Correlations of variation at one polymorphism located in the promoter region (known as 5HTTLPR) and variation at SLC6A4 expression levels, serotonin turnover and behaviour has been widely studied. In Old World monkeys, the third intron of the SLC6A4 gene also presents a tandem repeat, which sequence varies across species by a few point substitutions. We predict that in these species, this repeated region also acts as transcriptional regulatory domain and that sequence variation at this polymorphic locus might result in differential levels of expression in gene–environment interactions. For testing these hypotheses, the tandem repeat of Mandrillus sphinx and Cercopithecus aethiops from the third intron were cloned into a reporter gene vector and delivered to either primary cultures of rat neonate frontal cortex or the human cell line (JAr) to analyse their transcriptional activities. These repeated sequences supported significantly different levels of gene expression only when delivered into frontal cortex cultures. Furthermore, we tested in silico if such substitutions could have an effect on their binding profile to RNA- and DNA-binding proteins and on splicing. Taken together our results suggest that the tandem repeat in the third intron of the SLC6A4 gene of Old World monkeys could constitute a second transcriptional regulator as suggested for the 5HTTLPR and therefore contribute to diversification of serotonin-related behaviour in these primates.

Keywords

Serotonin transporter Old World monkeys Tandem repeat Gene expression Behaviour 

References

  1. Ali FR, Vasiliou SA, Haddley K, Paredes UM, Roberts JC, Miyajima F, Klenova E, Bubb VJ, Quinn JP (2010) Combinatorial interaction between two human serotonin transporter gene variable number tandem repeats and their regulation by CTCF. J Neurochem 112(1):296–306PubMedCrossRefGoogle Scholar
  2. Battersby S, Ogilvie AD, Smith CA, Blackwood DH, Muir WJ, Quinn JP, Fink G, Goodwin GM, Harmar AJ (1996) Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder. Psychiatr Genet 6(4):177–181PubMedCrossRefGoogle Scholar
  3. Bell GI, Jurka J (1997) The length distribution of perfect dimer repetitive DNA is consistent with its evolution by an unbiased single-step mutation process. J Mol Evol 44(4):414–421PubMedCrossRefGoogle Scholar
  4. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extract. Anal Biochem 162(1):156–159PubMedCrossRefGoogle Scholar
  5. Fairbanks LA, Jorgensen MJ, Huff A, Blau K, Hung YY, Mann JJ (2004a) Adolescent impulsivity predicts adult dominance attainment in male vervet monkeys. Am J Primatol 64:1–17PubMedCrossRefGoogle Scholar
  6. Fairbanks LA, Newman TK, Bailey JN, Jorgensen MJ, Breidenthal SE, Ophoff RA, Comuzzie AG, Martin LJ, Rogers J (2004b) Genetic contributions to social impulsivity and aggressiveness in vervet monkeys. Biol Psychiatry 55(6):642–647PubMedCrossRefGoogle Scholar
  7. Faustino NA, Cooper TA (2003) Pre mRNA splicing and human disease. Genes Dev 17:419–437PubMedCrossRefGoogle Scholar
  8. Fiskerstrand CE, Lovejoy EA, Quinn JP (1999) An intronic polymorphic domain often associated with susceptibility to affective disorders has allele dependent differential enhancer activity in embryonic stem cells. FEBS Lett 458(2):171–174PubMedCrossRefGoogle Scholar
  9. Gabellini N (2001) A polymorphic GT repeat from the human cardiac Na+Ca2+ exchanger intron 2 activates splicing. Eur J Biochem 268(4):1076–1083PubMedCrossRefGoogle Scholar
  10. Gelernter J, Cubells JF, Kidd JR, Pakstis AJ, Kidd KK (1999) Population studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet 88:61–66PubMedCrossRefGoogle Scholar
  11. Giresi PG, Lieb JD (2009) Isolation of active regulatory elements from eukaryotic chromatin using FAIRE (Formaldehyde Assisted Isolation of Regulatory Elements). Methods 48(3):233–239PubMedCrossRefGoogle Scholar
  12. Goren A, Ram O, Amit M, Keren H, Lev-Maor G, Vig I, Pukpo T, Ast G (2006) Comparative analysis identifies exonic splicing regulatory sequences—the complex definition of enhancers and silencers. Mol Cell 22(6):769–781PubMedCrossRefGoogle Scholar
  13. Haddley K, Vasiliou AS, Ali FR, Paredes UM, Bubb VJ, Quinn JP (2008) Molecular genetics of monoamine transporters: relevance to brain disorders. Neurochem Res 33(4):652–670PubMedCrossRefGoogle Scholar
  14. Han DH, Park DB, Na C, Kee BS, Lee YS (2004) Association of aggressive behavior in Korean male schizophrenic patients with polymorphisms in the serotonin transporter promoter and catecholamine-O-methyltransferase genes. Psychiatry Res 129(1):29–37PubMedCrossRefGoogle Scholar
  15. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, Egan MF, Weinberger DR (2002) Serotonin transporter genetic variation and the response of the human amygdala. Science 297(5580):400–403PubMedCrossRefGoogle Scholar
  16. Heinz A, Higley JD, Gorey JG, Saunders RC, Jones DW, Hommer D, Zajicek K, Suomi SJ, Lesch KP, Weinberger DR, Linnoila M (1998) In vivo association between alcohol intoxication, aggression, and serotonin transporter availability in nonhuman primates. Am J Psychiatry 155:1023–1028PubMedGoogle Scholar
  17. Heinz A, Jones DW, Mazzanti C, Goldman D, Ragan P, Hommer D, Linnoila M, Weinberger DR (2000) A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 47(7):643–649PubMedCrossRefGoogle Scholar
  18. Heinz A, Jones DW, Gorey JG, Bennet A, Suomi SJ, Weinberger DR, Higley JD (2003) Serotonin transporter availability correlates with alcohol intake in non-human primates. Mol Psychiatry 8:231–234PubMedCrossRefGoogle Scholar
  19. Higley JD, Suomi SJ, Linnoila M (1996) A nonhuman primate model of type II excessive alcohol consumption? Part 1. Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and diminished social competence correlate with excessive alcohol consumption. Alcohol Clin Exp Res 20(4):629–642PubMedCrossRefGoogle Scholar
  20. Hranilovic D, Stefulj J, Schwab S, Borrmann-Hassenbach M, Albus M, Jernej B, Wildenauer D (2004) Serotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression. Biol Psychiatry 55(11):1090–1094PubMedCrossRefGoogle Scholar
  21. Inoue-Murayama M, Hibino E, Iwatsuki H, Inoue E, Hong KW, Nishida T, Hayasaka I, Ito S, Murayama Y (2008) Interspecies and intraspecies variations in the serotonin transporter gene intron 3 VNTR in nonhuman primates. Primates 49(2):139–142PubMedCrossRefGoogle Scholar
  22. Izquierdo A, Newman TK, Higley JD, Murray EA (2007) Genetic modulation of cognitive flexibility and socioemotional behavior in rhesus monkeys. Proc Natl Acad Sci U S A 104(35):14128–14133PubMedCrossRefGoogle Scholar
  23. Kaplan J, Fontenot MB, Berard J, Manuck SB, Mann JJ (1995) Delayed dispersal and elevated monoaminergic activity in free-ranging rhesus monkeys. Am J Primatol 35(3):229–234CrossRefGoogle Scholar
  24. Kaplan JR, Phillips-Conroy J, Fontenot MB, Jolly CJ, Fairbanks LA, Mann JJ (1999) Cerebrospinal fluid monoaminergic metabolites differ in wild anubis and hybrid (Anubis hamadryas) baboons: possible relationships to life history and behavior. Neuropsychopharmacol 20(6):517–524CrossRefGoogle Scholar
  25. Kaplan JR, Manuck SB, Fontenot MB, Mann JJ (2002) Central nervous system monoamine correlates of social dominance in cynomolgus monkeys (Macaca fascicularis). Neuropsychopharmacol 26(4):431–443CrossRefGoogle Scholar
  26. Klenova E, Scott AC, Roberts J, Shamsuddin S, Lovejoy EA, Bergmann S, Bubb VJ, Royer HD, Quinn JP (2004) YB-1 and CTCF differentially regulate the 5-HTT polymorphic intron 2 enhancer which predisposes to a variety of neurological disorders. J Neurosci 24(26):5966–5973PubMedCrossRefGoogle Scholar
  27. MacKenzie A, Quinn JP (1999) A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci U S A 96(26):15251–15255PubMedCrossRefGoogle Scholar
  28. MacKenzie A, Quinn JP (2004) Post-genomic approaches to exploring neuropeptide gene mis-expression in disease. Neuropeptides 38(1):1–15PubMedCrossRefGoogle Scholar
  29. Mehlman PT, Higley JD, Faucher I, Lilly AA, Taub DM, Vickers J, Suomi SJ, Linnoila M (1995) Correlation of CSF 5-HIAA concentration with sociality and the timing of emigration in free-ranging primates. Am J Psychiatry 152:907–913PubMedGoogle Scholar
  30. Moore TM, Scarpa A, Raine A (2002) A meta-analysis of serotonin metabolite 5-HIAA and antisocial behavior. Aggressive Behav 28(4):299–316CrossRefGoogle Scholar
  31. Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwim GM, Smith CA (1996) Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 347(9003):731–733PubMedCrossRefGoogle Scholar
  32. Paredes UM, Bubb VJ, Haddley K, Macho GA, Quinn JP (2011) An evolutionary conserved region in the human dopamine receptor D4 gene supports reporter gene expression in primary cultures derived from the rat cortex. BMC Neurosci 12:46PubMedCrossRefGoogle Scholar
  33. Rogers J, Martin LJ, Comuzzie AG, Mann JJ, Manuck SB, Leland M, Kaplan JR (2004) Genetics of monoamine metabolites in baboons: overlapping sets of genes influence levels of 5-hydroxyindolacetic acid, 3-hydroxy-4-methoxyphenylglycol, and homovanillic acid. Biol Psychiatry 55(7):739–744PubMedCrossRefGoogle Scholar
  34. Sakai K, Nakamura M, Ueno S, Sano A, Sakai N, Shirai Y, Saito N (2002) The silencer activity of the novel human serotonin transporter linked polymorphic regions. Neurosci Lett 327(1):13–16PubMedCrossRefGoogle Scholar
  35. Soeby K, Larsen SA, Olsen L, Rasmussen HB, Werge T (2005) Serotonin transporter: evolution and impact of polymorphic transcriptional regulation. Am J Med Genet B Neuropsychiatr Genet 136B:53–57PubMedCrossRefGoogle Scholar
  36. Spencer EM, Chandler KE, Haddley K, Howard MR, Hughes D, Belyaev ND, Coulson JM, Stewart JP, Buckley NJ, Kipar A, Walker MC, Quinn JP (2006) Regulation and role of REST and REST4 variants in modulation of gene expression in in vivo and in vitro in epilepsy models. Neurobiol Dis 24(1):41–52PubMedCrossRefGoogle Scholar
  37. Suomi SJ (2003) Gene–environment interactions and the neurobiology of social conflict. Ann N Y Acad Sci 1008:132–139PubMedCrossRefGoogle Scholar
  38. Trefilov A, Berard J, Krawczak M, Schmidtke J (2000) Natal dispersal in rhesus macaques is related to serotonin transporter gene promoter variation. Behav Genet 30(4):295–301PubMedCrossRefGoogle Scholar
  39. Tsai SJ, Ouyang WC, Hong CJ (2002) Association for serotonin transporter gene variable number tandem repeat polymorphism and schizophrenic disorders. Neuropsychobiology 45(3):131–133PubMedCrossRefGoogle Scholar
  40. Wendland JR, Lesch KP, Newman TK, Timme A, Gachot-Neveu H, Thierry B, Suomi SJ (2006) Differential functional variability of serotonin transporter and monoamine oxidase a genes in macaque species displaying contrasting levels of aggression-related behavior. Behav Genet 36(2):163–172PubMedCrossRefGoogle Scholar
  41. Yilmaz M, Erdal ME, Herken H, Cataloluk O, Barlas O, Bayazit YA (2001) Significance of serotonin transporter gene polymorphism in migraine. J Neurol Sci 186(1–2):27–30PubMedCrossRefGoogle Scholar
  42. Ying SY, Lin SL (2004) Intron-derived microRNAs—fine tuning of gene functions. Gene 342(1):25–28PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Ursula M. Paredes
    • 1
    • 2
  • Vivien J. Bubb
    • 1
  • Kate Haddley
    • 1
  • Gabriele A. Macho
    • 1
    • 3
  • John P. Quinn
    • 1
  1. 1.Department of Molecular and Clinical Pharmacology, Institute of Translational MedicineUniversity of LiverpoolLiverpoolUK
  2. 2.MRC centre for Social, Genetic and Developmental Psychiatry Centre, Institute of PsychiatryKing’s College, LondonLondonUK
  3. 3.Institut Català de PaleontologiaCampus de la Universitat Autònoma de BarcelonaBarcelonaSpain

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