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Influence of sex on genetic regulation of “drinking in the dark” alcohol consumption

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Abstract

The ILSXISS (LXS) recombinant inbred (RI) panel of mice is a valuable resource for genetic mapping studies of complex traits, due to its genetic diversity and large number of strains. Male and female mice from this panel were used to investigate genetic influences on alcohol consumption in the “drinking in the dark” (DID) model. Male mice (38 strains) and female mice (36 strains) were given access to 20 % ethanol during the early phase of their circadian dark cycle for four consecutive days. The first principal component of alcohol consumption measures on days 2, 3, and 4 was used as a phenotype (DID phenotype) to calculate QTLs, using a SNP marker set for the LXS RI panel. Five QTLs were identified, three of which included a significant genotype by sex interaction, i.e., a significant genotype effect in males and not females. To investigate candidate genes associated with the DID phenotype, data from brain microarray analysis (Affymetrix Mouse Exon 1.0 ST Arrays) of male LXS RI strains were combined with RNA-Seq data (mouse brain transcriptome reconstruction) from the parental ILS and ISS strains in order to identify expressed mouse brain transcripts. Candidate genes were determined based on common eQTL and DID phenotype QTL regions and correlation of transcript expression levels with the DID phenotype. The resulting candidate genes (in particular, Arntl/Bmal1) focused attention on the influence of circadian regulation on the variation in the DID phenotype in this population of mice.

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References

  • Bachmanov AA, Reed DR, Li X, Li S, Beauchamp GK, Tordoff MG (2002) Voluntary ethanol consumption by mice: genome-wide analysis of quantitative trait loci and their interactions in a C57BL/6ByJ x 129P3/J F2 intercross. Genome Res 12:1257–1268

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Baez-Ruiz A, Diaz-Munoz M (2011) Chronic inhibition of endoplasmic reticulum calcium-release channels and calcium-ATPase lengthens the period of hepatic clock gene Per1. J Circadian Rhythms 9:6

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barneche F, Malapeira J, Mas P (2014) The impact of chromatin dynamics on plant light responses and circadian clock function. J Exp Bot 65:2895–2913

    Article  PubMed  Google Scholar 

  • Belknap JK, Atkins AL (2001) The replicability of QTLs for murine alcohol preference drinking behavior across eight independent studies. Mamm Genome 12:893–899

    Article  CAS  PubMed  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 57:289–300

    Google Scholar 

  • Bice PJ, Foroud T, Carr LG, Zhang L, Liu L, Grahame NJ, Lumeng L, Li TK, Belknap JK (2006) Identification of QTLs influencing alcohol preference in the High Alcohol Preferring (HAP) and Low Alcohol Preferring (LAP) mouse lines. Behav Genet 36:248–260

    Article  PubMed  Google Scholar 

  • Buhr ED, Takahashi JS (2013) Molecular components of the mammalian circadian clock. Handbook of experimental pharmacology. pp 3–27

  • Ching TT, Wang DS, Hsu AL, Lu PJ, Chen CS (1999) Identification of multiple phosphoinositide-specific phospholipases D as new regulatory enzymes for phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 274:8611–8617

    Article  CAS  PubMed  Google Scholar 

  • Crabbe JC, Metten P, Rhodes JS, Yu CH, Brown LL, Phillips TJ, Finn DA (2009) A line of mice selected for high blood ethanol concentrations shows drinking in the dark to intoxication. Biol Psychiatry 65:662–670

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Crabbe JC, Phillips TJ, Belknap JK (2010) The complexity of alcohol drinking: studies in rodent genetic models. Behav Genet 40:737–750

    Article  PubMed Central  PubMed  Google Scholar 

  • Crabbe JC, Spence SE, Brown LL, Metten P (2011) Alcohol preference drinking in a mouse line selectively bred for high drinking in the dark. Alcohol 45:427–440

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Crepaldi L, Policarpi C, Coatti A, Sherlock WT, Jongbloets BC, Down TA, Riccio A (2013) Binding of TFIIIC to sine elements controls the relocation of activity-dependent neuronal genes to transcription factories. PLoS Genet 9:e1003699

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gill K, Desaulniers N, Desjardins P, Lake K (1998) Alcohol preference in AXB/BXA recombinant inbred mice: gender differences and gender-specific quantitative trait loci. Mamm Genome 9:929–935

    Article  CAS  PubMed  Google Scholar 

  • Gossan NC, Zhang F, Guo B, Jin D, Yoshitane H, Yao A, Glossop N, Zhang YQ, Fukada Y, Meng QJ (2014) The E3 ubiquitin ligase UBE3A is an integral component of the molecular circadian clock through regulating the BMAL1 transcription factor. Nucleic Acids Res 42:5765–5775

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hamada T, Liou SY, Fukushima T, Maruyama T, Watanabe S, Mikoshiba K, Ishida N (1999) The role of inositol trisphosphate-induced Ca2+ release from IP3-receptor in the rat suprachiasmatic nucleus on circadian entrainment mechanism. Neurosci Lett 263:125–128

    Article  CAS  PubMed  Google Scholar 

  • Hardin PE, Panda S (2013) Circadian timekeeping and output mechanisms in animals. Curr Opin Neurobiol 23:724–731

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hatanaka F, Matsubara C, Myung J, Yoritaka T, Kamimura N, Tsutsumi S, Kanai A, Suzuki Y, Sassone-Corsi P, Aburatani H, Sugano S, Takumi T (2010) Genome-wide profiling of the core clock protein BMAL1 targets reveals a strict relationship with metabolism. Mol Cell Biol 30:5636–5648

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hemmeryckx B, Himmelreich U, Hoylaerts MF, Lijnen HR (2011) Impact of clock gene Bmal1 deficiency on nutritionally induced obesity in mice. Obesity 19:659–661

    Article  CAS  PubMed  Google Scholar 

  • Hofstetter JR, Grahame NJ, Mayeda AR (2003) Circadian activity rhythms in high-alcohol-preferring and low-alcohol-preferring mice. Alcohol 30:81–85

    Article  CAS  PubMed  Google Scholar 

  • Huang F, Xiao H, Sun BL, Yang RG (2013) Characterization of TRIM62 as a RING finger E3 ubiquitin ligase and its subcellular localization. Biochem Biophys Res Commun 432:208–213

    Article  CAS  PubMed  Google Scholar 

  • Iancu OD, Oberbeck D, Darakjian P, Metten P, McWeeney S, Crabbe JC, Hitzemann R (2013) Selection for drinking in the dark alters brain gene coexpression networks. Alcohol Clin Exp Res 37:1295–1303

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Izidio GS, Oliveira LC, Oliveira LF, Pereira E, Wehrmeister TD, Ramos A (2011) The influence of sex and estrous cycle on QTL for emotionality and ethanol consumption. Mamm Genome 22:329–340

    Article  CAS  PubMed  Google Scholar 

  • Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14:R36

    Article  PubMed Central  PubMed  Google Scholar 

  • Mason R, Biello SM (1992) A neurophysiological study of a lithium-sensitive phosphoinositide system in the hamster suprachiasmatic (SCN) biological clock in vitro. Neurosci Lett 144:135–138

    Article  CAS  PubMed  Google Scholar 

  • McClearn GE, Kakihana R (1981) Selective breeding for ethanol sensitivity: short-sleep and long-sleep mice. In: McClearn GE, Deitrich RA, Erwin VG (eds) Development of animal models of pharmacogenetic tools. U.S. Government Printing Office, Washington, DC, pp 81–113

    Google Scholar 

  • McCulley WD 3rd, Ascheid S, Crabbe JC, Rosenwasser AM (2013) Selective breeding for ethanol-related traits alters circadian phenotype. Alcohol 47:187–194

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Melo JA, Shendure J, Pociask K, Silver LM (1996) Identification of sex-specific quantitative trait loci controlling alcohol preference in C57BL/6 mice. Nat Genet 13:147–153

    Article  CAS  PubMed  Google Scholar 

  • Menet JS, Pescatore S, Rosbash M (2014) CLOCK:BMAL1 is a pioneer-like transcription factor. Genes Dev 28:8–13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mieda M, Sakurai T (2011) Bmal1 in the nervous system is essential for normal adaptation of circadian locomotor activity and food intake to periodic feeding. J Neurosci 31:15391–15396

    Article  CAS  PubMed  Google Scholar 

  • Napolitano LM, Meroni G (2012) TRIM family: pleiotropy and diversification through homomultimer and heteromultimer formation. IUBMB Life 64:64–71

    Article  CAS  PubMed  Google Scholar 

  • Nerou EP, Riley AM, Potter BV, Taylor CW (2001) Selective recognition of inositol phosphates by subtypes of the inositol trisphosphate receptor. Biochem J 355:59–69

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patro R, Mount SM, Kingsford C (2014) Sailfish enables alignment-free isoform quantification from RNA-seq reads using lightweight algorithms. Nat Biotechnol 32:462–464

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ (2010) High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains. Genes Brain Behav 9:129–159

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Phillips TJ, Crabbe JC, Metten P, Belknap JK (1994) Localization of genes affecting alcohol drinking in mice. Alcohol Clin Exp Res 18:931–941

    Article  CAS  PubMed  Google Scholar 

  • Rhodes JS, Best K, Belknap JK, Finn DA, Crabbe JC (2005) Evaluation of a simple model of ethanol drinking to intoxication in C57BL/6J mice. Physiol Behav 84:53–63

    Article  CAS  PubMed  Google Scholar 

  • Rhodes JS, Ford MM, Yu CH, Brown LL, Finn DA, Garland T Jr, Crabbe JC (2007) Mouse inbred strain differences in ethanol drinking to intoxication. Genes Brain Behav 6:1–18

    Article  CAS  PubMed  Google Scholar 

  • Rieseberg LH, Archer MA, Wayne RK (1999) Transgressive segregation, adaptation and speciation. Heredity 83(Pt 4):363–372

    Article  PubMed  Google Scholar 

  • Rodriguez LA, Plomin R, Blizard DA, Jones BC, McClearn GE (1995) Alcohol acceptance, preference, and sensitivity in mice. II. Quantitative trait loci mapping analysis using BXD recombinant inbred strains. Alcohol Clin Exp Res 19:367–373

    Article  CAS  PubMed  Google Scholar 

  • Rosenwasser AM, Fecteau ME, Logan RW, Reed JD, Cotter SJ, Seggio JA (2005) Circadian activity rhythms in selectively bred ethanol-preferring and nonpreferring rats. Alcohol 36:69–81

    Article  CAS  PubMed  Google Scholar 

  • Ryabinin AE, Galvan-Rosas A, Bachtell RK, Risinger FO (2003) High alcohol/sucrose consumption during dark circadian phase in C57BL/6J mice: involvement of hippocampus, lateral septum and urocortin-positive cells of the Edinger-Westphal nucleus. Psychopharmacology 165:296–305

    CAS  PubMed  Google Scholar 

  • Saba LM, Bennett B, Hoffman PL, Barcomb K, Ishii T, Kechris K, Tabakoff B (2011) A systems genetic analysis of alcohol drinking by mice, rats and men: influence of brain GABAergic transmission. Neuropharmacology 60:1269–1280

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shakya K, Ruskin HJ, Kerr G, Crane M, Becker J (2010) Comparison of microarray preprocessing methods. Adv Exp Med Biol 680:139–147

    Article  CAS  PubMed  Google Scholar 

  • Tabakoff B, Saba L, Kechris K, Hu W, Bhave SV, Finn DA, Grahame NJ, Hoffman PL (2008) The genomic determinants of alcohol preference in mice. Mamm Genome 19:352–365

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tabakoff B, Saba L, Printz M, Flodman P, Hodgkinson C, Goldman D, Koob G, Richardson HN, Kechris K, Bell RL, Hubner N, Heinig M, Pravenec M, Mangion J, Legault L, Dongier M, Conigrave KM, Whitfield JB, Saunders J, Grant B, Hoffman PL, State WISo, Trait Markers of A (2009) Genetical genomic determinants of alcohol consumption in rats and humans. BMC Biol 7:70

    Article  PubMed Central  PubMed  Google Scholar 

  • Takimoto K, Okada M, Matsuda Y, Nakagawa H (1985) Purification and properties of myo-inositol-1-phosphatase from rat brain. J Biochem 98:363–370

    CAS  PubMed  Google Scholar 

  • Thiele TE, Navarro M (2014) “Drinking in the dark” (DID) procedures: a model of binge-like ethanol drinking in non-dependent mice. Alcohol 48:235–241

    Article  CAS  PubMed  Google Scholar 

  • Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, Salzberg SL, Wold BJ, Pachter L (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 28:511–515

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Turaga RV, Paquet ER, Sild M, Vignard J, Garand C, Johnson FB, Masson JY, Lebel M (2009) The Werner syndrome protein affects the expression of genes involved in adipogenesis and inflammation in addition to cell cycle and DNA damage responses. Cell Cycle 8:2080–2092

    Article  CAS  PubMed  Google Scholar 

  • Van Bortle K, Corces VG (2012) tDNA insulators and the emerging role of TFIIIC in genome organization. Transcription 3:277–284

    Article  PubMed Central  PubMed  Google Scholar 

  • van Nas A, Ingram-Drake L, Sinsheimer JS, Wang SS, Schadt EE, Drake T, Lusis AJ (2010) Expression quantitative trait loci: replication, tissue- and sex-specificity in mice. Genetics 185:1059–1068

    Article  PubMed Central  PubMed  Google Scholar 

  • Vanderlinden LA, Saba LM, Kechris K, Miles MF, Hoffman PL, Tabakoff B (2013) Whole brain and brain regional coexpression network interactions associated with predisposition to alcohol consumption. PLoS ONE 8:e68878

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vendruscolo LF, Terenina-Rigaldie E, Raba F, Ramos A, Takahashi RN, Mormede P (2006) Evidence for a female-specific effect of a chromosome 4 locus on anxiety-related behaviors and ethanol drinking in rats. Genes Brain Behav 5:441–450

    Article  CAS  PubMed  Google Scholar 

  • Verwey M, Amir S (2009) Food-entrainable circadian oscillators in the brain. Eur J Neurosci 30:1650–1657

    Article  CAS  PubMed  Google Scholar 

  • Williams RW, Bennett B, Lu L, Gu J, DeFries JC, Carosone-Link PJ, Rikke BA, Belknap JK, Johnson TE (2004) Genetic structure of the LXS panel of recombinant inbred mouse strains: a powerful resource for complex trait analysis. Mamm Genome 15:637–647

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Abraham D, Lin ST, Oster H, Eichele G, Fu YH, Ptacek LJ (2012) PKCgamma participates in food entrainment by regulating BMAL1. Proc Natl Acad Sci USA 109:20679–20684

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by NIAAA/NIH (R24AA013162, U01AA16649) and the Banbury Fund. We thank Dr. Tom Johnson, Institute for Behavioral Genetics, University of Colorado, Boulder, CO and Dr. Gary Churchill, Jackson Laboratory, Bar Harbor, ME, for providing SNP information on the LXS panel. We thank Yinni Yu and Adam Chapman for expert technical assistance with the microarray experiments.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Blvd., Campus Box: C238, Aurora, CO, 80045, USA

    Lauren A. Vanderlinden, Laura M. Saba, Paula L. Hoffman & Boris Tabakoff

  2. Institute for Behavioral Genetics, University of Colorado at Boulder, F420 AMCA, Boulder, CO, 80309, USA

    Beth Bennett

  3. Department of Pharmacology, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, 12800 E. 19 Ave., MS 8303, Aurora, CO, 80045, USA

    Paula L. Hoffman

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  1. Lauren A. Vanderlinden
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  2. Laura M. Saba
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  3. Beth Bennett
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Correspondence to Paula L. Hoffman.

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Vanderlinden, L.A., Saba, L.M., Bennett, B. et al. Influence of sex on genetic regulation of “drinking in the dark” alcohol consumption. Mamm Genome 26, 43–56 (2015). https://doi.org/10.1007/s00335-014-9553-8

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