Mammalian Genome

, Volume 17, Issue 6, pp 669–688

Candidate genes and their regulatory elements: alcohol preference and tolerance

  • Laura Saba
  • Sanjiv V. Bhave
  • Nicholas Grahame
  • Paula Bice
  • Razvan Lapadat
  • John Belknap
  • Paula L. Hoffman
  • Boris Tabakoff
Article

Abstract

QTL analysis of behavioral traits and mouse brain gene expression studies were combined to identify candidate genes involved in the traits of alcohol preference and acute functional alcohol tolerance. The systematic application of normalization and statistical analysis of differential gene expression, behavioral and expression QTL location, and informatics methodologies resulted in identification of 8 candidate genes for the trait of alcohol preference and 22 candidate genes for acute functional tolerance. Pathway analysis, combined with clustering by ontology, indicated the importance of transcriptional regulation and DNA and protein binding elements in the acute functional tolerance trait, and protein kinases and intracellular signal transduction elements in the alcohol preference trait. A rudimentary search for transcription control elements that could indicate coregulation of the panels of candidate genes produced modest results, implicating SMAD-3 in the regulation of four of the eight candidate genes for alcohol preference. However, the realization of the many caveats related to transcription factor binding site analysis, and attempts to correlate between transcription factor binding and function, forestalled any definitive global analysis of transcriptional control of differentially expressed candidate genes.

Supplementary material

supp.pdf (1.2 mb)
Supplementary material

References

  1. Affymetrix (2001) Statistical algorithms reference guide (Santa Clara, CA: Affymetrix, Inc.)Google Scholar
  2. Affymetrix (2004) GeneChip ® expression analysis. Data analysis fundamentals (Santa Clara, CA: Affymetrix, Inc.)Google Scholar
  3. Backström P, Hyytia P (2004) Ionotropic glutamate receptor antagonists modulate cue-induced reinstatement of ethanol-seeking behavior. Alcohol Clin Exp Res 28:558–565PubMedGoogle Scholar
  4. Behm A, Lumeng L, Li T-K, Grahame N (2003) Selective breeding for replicate line 2 high and low alcohol preferring mice. Alcohol Clin Exp Res 27:49AGoogle Scholar
  5. Belknap JK, Atkins AL (2001) The replicability of QTLs for murine alcohol preference drinking behavior across eight independent studies. Mamm Genome 12:893–899PubMedCrossRefGoogle Scholar
  6. Bice PJ, Foroud T, Carr LG, Zhang L, Liu L, et al. (2006) Identification of QTLs influencing alcohol preference in the high alcohol preferring (HAP) and low alcohol preferring (LAP) mouse lines. Behav Genet 36, 248–260PubMedCrossRefGoogle Scholar
  7. Boehm SL 2nd, Peden L, Chang R, Harris RA, Blednov YA (2003) Deletion of the fyn-kinase gene alters behavioral sensitivity to ethanol. Alcohol Clin Exp Res 27:1033–1040PubMedCrossRefGoogle Scholar
  8. Broman KW, Wu H, Sen S, Churchill GA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19:889–890PubMedCrossRefGoogle Scholar
  9. Bustin SA, Nolan T (2004) Pitfalls of quantitative real-time reverse-transcription polymerase chain reaction. J Biomol Tech 15:155–166PubMedGoogle Scholar
  10. Carlborg O, De Koning DJ, Manly KF, Chesler E, Williams RW, et al. (2005) Methodological aspects of the genetic dissection of gene expression. Bioinformatics 21:2383–2393PubMedCrossRefGoogle Scholar
  11. Chesler EJ, Lu L, Shou S, Qu Y, Gu J, et al. (2005) Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 37:233–242PubMedCrossRefGoogle Scholar
  12. Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138:963–971PubMedGoogle Scholar
  13. Churchill GA, Airey DC, Allayee H, Angel JM, Attie AD, et al. (2004) The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet 36:1133–1137PubMedCrossRefGoogle Scholar
  14. Crabbe JC, Phillips TJ, Feller DJ, Hen R, Wenger CD, et al. (1996) Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors. Nat Genet 14:98–101PubMedCrossRefGoogle Scholar
  15. Culverhouse R, Klein T, Shannon W (2004) Detecting epistatic interactions contributing to quantitative traits. Genet Epidemiol 27:141–152PubMedCrossRefGoogle Scholar
  16. Draghici S, Khatri P, Bhavsar P, Shah A, Krawetz SA, et al. (2003) Onto-Tools, the toolkit of the modern biologist: Onto-Express, Onto-Compare, Onto-Design and Onto-Translate. Nucleic Acids Res 31:3775–3781PubMedCrossRefGoogle Scholar
  17. Dudoit S, Yang YH, Callow MJ, Speed TP (2000) Statistical methods for identifying differentially expressed genes in replicate cDNA microarray experiments. Available at http://www.stat.berkeley.edu/users/terry/zarray/TechReport/578.pdf
  18. Eaves IA, Wicker LS, Ghandour G, Lyons PA, Peterson LB, et al. (2002) Combining mouse congenic strains and microarray gene expression analyses to study a complex trait: the NOD model of type 1 diabetes. Genome Res 12:232–243PubMedCrossRefGoogle Scholar
  19. Erwin VG, Deitrich RA (1996) Genetic selection and characterization of mouse lines for acute functional tolerance to ethanol. J Pharmacol Exp Ther 279:1310–1317PubMedGoogle Scholar
  20. Falconer DS (1996) Introduction to Quantitative Genetics (Essex, UK: Longman)Google Scholar
  21. Georges M, Drinkwater R, King T, Mishra A, Moore SS, et al. (1993) Microsatellite mapping of a gene affecting horn development in Bos taurus. Nat Genet 4:206–210PubMedCrossRefGoogle Scholar
  22. Grahame NJ, Li TK, Lumeng L (1999) Selective breeding for high and low alcohol preference in mice. Behav Genet 29:47–57PubMedCrossRefGoogle Scholar
  23. Heinemeyer T, Chen X, Karas H, Kel AE, Kel OV, et al. (1999) Expanding the TRANSFAC database towards an expert system of regulatory molecular mechanisms. Nucleic Acids Res 27:318–322PubMedCrossRefGoogle Scholar
  24. Hensler JG, Ladenheim EE, Lyons WE (2003) Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (±) mice. J Neurochem 85:1139–1147PubMedCrossRefGoogle Scholar
  25. Hitzemann R, Reed C, Malmanger B, Lawler M, Hitzemann B, et al. (2004) On the integration of alcohol-related quantitative trait loci and gene expression analyses. Alcohol Clin Exp Res 28:1437–1448PubMedCrossRefGoogle Scholar
  26. Hodge CW, Slawecki CJ, Aiken AS (1996) Norepinephrine and serotonin receptors in the paraventricular nucleus interactively modulate ethanol consumption. Alcohol Clin Exp Res 20:1669–1674PubMedCrossRefGoogle Scholar
  27. Hou Y, Chang V, Capper AB, Taussig R, Gautam N (2001) G protein beta subunit types differentially interact with a muscarinic receptor but not adenylyl cyclase type II or phospholipase C-beta 2/3. J Biol Chem 276:19982–19988PubMedCrossRefGoogle Scholar
  28. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, et al. (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4:249–264PubMedCrossRefGoogle Scholar
  29. Jurka J (1994) Approaches to identification and analysis of interspersed repetitive DNA sequences. In Automated DNA Sequencing and Analysis, Adams MD, Fields C, Venter JC (eds) (San Diego, CA: Academic Press), pp 294–298Google Scholar
  30. Jurka J (1998) Repeats in genomic DNA: mining and meaning. Curr Opin Struct Biol 8:333–337PubMedCrossRefGoogle Scholar
  31. Kel AE, Gossling E, Reuter I, Cheremushkin E, Kel-Margoulis OV, et al. (2003) MATCH: A tool for searching transcription factor binding sites in DNA sequences. Nucleic Acids Res 31:3576–3579PubMedCrossRefGoogle Scholar
  32. Kirstein SL, Davidson KL, Ehringer MA, Sikela JM, Erwin VG, et al. (2002) Quantitative trait loci affecting initial sensitivity and acute functional tolerance to ethanol-induced ataxia and brain cAMP signaling in BXD recombinant inbred mice. J Pharmacol Exp Ther 302:1238–1245PubMedCrossRefGoogle Scholar
  33. Kitanaka N, Kitanaka J, Walther D, Wang XB, Uhl GR (2003) Comparative inter-strain sequence analysis of the putative regulatory region of murine psychostimulant-regulated gene GNB1 (G protein beta 1 subunit gene). DNA Seq 14:257–263PubMedGoogle Scholar
  34. Klingenhoff A, Frech K, Quandt K, Werner T (1999) Functional promoter modules can be detected by formal models independent of overall nucleotide sequence similarity. Bioinformatics 15:180–186PubMedCrossRefGoogle Scholar
  35. Lander ES, Botstein D (1989) Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121:185–199PubMedGoogle Scholar
  36. Liang T, Habegger K, Spence JP, Foroud T, Ellison JA, et al. (2004) Glutathione S-transferase 8-8 expression is lower in alcohol-preferring than in alcohol-nonpreferring rats. Alcohol Clin Exp Res 28:1622–1628PubMedGoogle Scholar
  37. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408PubMedCrossRefGoogle Scholar
  38. Lu J, Wu Y, Sousa N, Almeida OF (2005) SMAD pathway mediation of BDNF and TGF beta 2 regulation of proliferation and differentiation of hippocampal granule neurons. Development 132:3231–3242PubMedCrossRefGoogle Scholar
  39. Matys V, Fricke E, Geffers R, Gossling E, Haubrock M, et al. (2003) TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res 31:37437–37438CrossRefGoogle Scholar
  40. McClearn GE, Wilson JR, Meredith W (1970) The use of isogenic and heterogenic mouse stocks in behavioral research. In Contributions to Behavior-Genetic Analysis: The Mouse As a Prototype, Lindzey G, Thiessen DD. (eds) (New York: Appleton–Century–Crofts), pp 3–22Google Scholar
  41. Miyakawa T, Yagi T, Kitazawa H, Yasuda M, Kawai N, et al. (1997) Fyn-kinase as a determinant of ethanol sensitivity: relation to NMDA-receptor function. Science 278:698–701PubMedCrossRefGoogle Scholar
  42. Newlin DB, Thomson JB ( 1990) Alcohol challenge with sons of alcoholics: a critical review and analysis. Psychol Bull 108:383–402PubMedCrossRefGoogle Scholar
  43. Nikitin A, Egorov S, Daraselia N, Mazo I (2003) Pathway studio—the analysis and navigation of molecular networks. Bioinformatics 19:2155–2157PubMedCrossRefGoogle Scholar
  44. Qiu P (2003) Recent advances in computational promoter analysis in understanding the transcriptional regulatory network. Biochem Biophys Res Commun 309:495–501PubMedCrossRefGoogle Scholar
  45. Roberts AJ, McDonald JS, Heyser CJ, Kieffer BL, Matthes HW, et al. (2000) mu-Opioid receptor knockout mice do not self-administer alcohol. J Pharmacol Exp Ther 293:1002–1008PubMedGoogle Scholar
  46. Rockett JC, Hellmann GM (2004) Confirming microarray data–is it really necessary? Genomics 83:541–549PubMedCrossRefGoogle Scholar
  47. Rodriguez LA, Plomin R, Blizard DA, Jones BC, McClearn GE (1994) Alcohol acceptance, preference, and sensitivity in mice. I. Quantitative genetic analysis using BXD recombinant inbred strains. Alcohol Clin Exp Res 18:1416–1422PubMedCrossRefGoogle Scholar
  48. Schadt EE, Monks SA, Drake TA, Lusis AJ, Che N, et al. (2003) Genetics of gene expression surveyed in maize, mouse and man. Nature 422:297–302PubMedCrossRefGoogle Scholar
  49. Spanagel R (2003) Alcohol addiction research: from animal models to clinics. Best Pract Res Clin Gastroenterol 17:507–518PubMedCrossRefGoogle Scholar
  50. Tabakoff B, Bhave SV, Hoffman PL (2003) Selective breeding, quantitative trait locus analysis, and gene arrays identify candidate genes for complex drug-related behaviors. J Neurosci 23:4491–4498PubMedGoogle Scholar
  51. Tanaka K, Miyazaki I, Fujita N, Haque ME, Asanuma M, et al. (2001) Molecular mechanism in activation of glutathione system by ropinirole, a selective dopamine D2 agonist. Neurochem Res 26:31–36PubMedCrossRefGoogle Scholar
  52. Tanaka K, Yoshioka M, Miyazaki I, Fujita N, Ogawa N (2002) GPI1046 prevents dopaminergic dysfunction by activating glutathione system in the mouse striatum. Neurosci Lett 321:45–48PubMedCrossRefGoogle Scholar
  53. Thanos PK, Taintor NB, Rivera SN, Umegaki H, Ikari H, et al. (2004) DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and nonpreferring rats attenuates alcohol drinking. Alcohol Clin Exp Res 28:720–728PubMedGoogle Scholar
  54. The FANTOM Consortium and RIKEN Genome Exploration Research Group and Genome Science Group (2005) The transcriptional landscape of the mammalian genome. Science 309:1559–1563CrossRefGoogle Scholar
  55. Thoday JM (1961) Location of polygenes. Nature 191:368–370Google Scholar
  56. Traynor JR, Neubig RR (2005) Regulators of G protein signaling & drugs of abuse. Mol Interv 5:30–41PubMedCrossRefGoogle Scholar
  57. Visscher PM, Thompson R, Haley CS (1996) Confidence intervals in QTL mapping by bootstrapping. Genetics 143:1013–1020PubMedGoogle Scholar
  58. Wilson CL, Miller CJ (2005) Simpleaffy: a BioConductor package for Affymetrix Quality Control and data analysis. Bioinformatics 21:3683–3685PubMedCrossRefGoogle Scholar
  59. Wong ML, Medrano JF (2005) Real-time PCR for mRNA quantitation. Biotechniques 39:75–85PubMedCrossRefGoogle Scholar
  60. Zamore PD, Haley B (2005) Ribo-gnome: the big world of small RNAs. Science 309:1519–1524PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Laura Saba
    • 1
  • Sanjiv V. Bhave
    • 1
  • Nicholas Grahame
    • 3
  • Paula Bice
    • 4
  • Razvan Lapadat
    • 1
  • John Belknap
    • 2
  • Paula L. Hoffman
    • 1
  • Boris Tabakoff
    • 1
    • 5
  1. 1.Department of PharmacologyUniversity of Colorado at Denver and Health Sciences CenterAuroraUSA
  2. 2.Research Service R&D-5VA Medical CenterPortlandUSA
  3. 3.Department of PsychologyIndiana University School of MedicineIndianapolisUSA
  4. 4.Department of MedicineIndiana UniversityIndianapolisUSA
  5. 5.Department of PharmacologyBoris TabakoffAuroraUSA

Personalised recommendations