Mammalian Genome

, Volume 21, Issue 5–6, pp 231–246 | Cite as

Quantitative trait locus and haplotype mapping in closely related inbred strains identifies a locus for open field behavior

  • Amy F. Eisener-Dorman
  • Laura Grabowski-Boase
  • Brian M. Steffy
  • Tim Wiltshire
  • Lisa M. TarantinoEmail author


Quantitative trait locus (QTL) mapping in the mouse typically utilizes inbred strains that exhibit significant genetic and phenotypic diversity. The development of dense SNP panels in a large number of inbred strains has eliminated the need to maximize genetic diversity in QTL studies as plenty of SNP markers are now available for almost any combination of strains. We conducted a QTL mapping experiment using both a backcross (N2) and an intercross (F2) between two genetically similar inbred mouse strains: C57BL/6J (B6) and C57L/J (C57). A set of additive QTLs for activity behaviors was identified on Chrs 1, 9, 13, and 15. We also identified additive QTLs for anxiety-related behaviors on Chrs 7, 9, and 16. A QTL on Chr 11 is sex-specific, and we revealed pairwise interactions between QTLs on Chrs 1 and 13 and Chrs 10 and 18. The Chr 9 activity QTL accounts for the largest amount of phenotypic variance and was not present in our recent analysis of a B6 × C58/J (C58) intercross (Bailey et al. in Genes Brain Behav 7:761–769, 2008). To narrow this QTL interval, we used a dense SNP haplotype map with over 7 million real and imputed SNP markers across 74 inbred mouse strains (Szatkiewicz et al. in Mamm Genome 19(3):199–208, 2008). Evaluation of shared and divergent haplotype blocks among B6, C57, and C58 strains narrowed the Chr 9 QTL interval considerably and highlights the utility of QTL mapping in closely related inbred strains.


Quantitative Trait Locus Inbred Strain Quantitative Trait Locus Mapping Quantitative Trait Locus Region Percent Time 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank Gary Churchill and Fernando Pardo Manuel de Villena for helpful discussions about the data and for sharing SNP genotype data for IBD mapping in the QTL region. The research described herein was supported by funding from NIH NIDA Grant DA 022392 to LMT and a Novartis Grant SFP-1406 from the Genomics Institute of the Novartis Research Foundation. Genotypes for IBD mapping were generated with support from the National Institute of General Medical Sciences National Centers of Systems Biology program grant GM-076468.


  1. Adriani W, Felici A, Sargolini F, Roullet P, Usiello A et al (1998) N-methyl-D-aspartate and dopamine receptor involvement in the modulation of locomotor activity and memory processes. Exp Brain Res 123:52–59CrossRefPubMedGoogle Scholar
  2. Alttoa A, Eller M, Herm L, Rinken A, Harro J (2007) Amphetamine-induced locomotion, behavioral sensitization to amphetamine, and striatal D2 receptor function in rats with high or low spontaneous exploratory activity: differences in the role of locus coeruleus. Brain Res 1131:138–148CrossRefPubMedGoogle Scholar
  3. Bailey JS, Grabowski-Boase L, Steffy BM, Wiltshire T, Churchill GA et al (2008) Identification of quantitative trait loci for locomotor activation and anxiety using closely-related inbred strains. Genes Brain Behav 7:761–769CrossRefGoogle Scholar
  4. Beavis W (1994) The power and deceit of QTL experiments: lessons from comparative QTL studies. In: 49th Annual corn and sorghum research conference. American Seed Trade Association, Washington, DC, pp 252-268 Google Scholar
  5. Beck JA, Lloyd S, Hafezparast M, Lennon-Pierce M, Eppig JT et al (2000) Genealogies of mouse inbred strains. Nat Genet 24:23–25CrossRefPubMedGoogle Scholar
  6. Bolivar VJ, Caldarone BJ, Reilly AA, Flaherty L (2000) Habituation of activity in an open field: a survey of inbred strains and F1 hybrids. Behav Genet 30:285–293CrossRefPubMedGoogle Scholar
  7. Boone EM, Hawks BW, Li W, Garlow SJ (2008) Genetic regulation of hypothalamic cocaine and amphetamine-regulated transcript (CART) in BxD inbred mice. Brain Res 1194:1–7CrossRefPubMedGoogle Scholar
  8. Bothe GW, Bolivar VJ, Vedder MJ, Geistfeld JG (2005) Behavioral differences among fourteen inbred mouse strains commonly used as disease models. Comp Med 55:326–334PubMedGoogle Scholar
  9. Boyle AE, Gill KJ (2009) A verification of previously identified QTLs for cocaine-induced activation using a panel of B6A chromosome substitution strains (CSS) and A/J × C57Bl/6 J F2 mice. Psychopharmacology (Berl) 207(2):325–334CrossRefGoogle Scholar
  10. Burgess-Herbert SL, Cox A, Tsaih SW, Paigen B (2008) Practical applications of the bioinformatics toolbox for narrowing quantitative trait loci. Genetics 180:2227–2235CrossRefPubMedGoogle Scholar
  11. Cabib S, Puglisi-Allegra S, Ventura R (2002) The contribution of comparative studies in inbred strains of mice to understanding of the hyperactive phenotype. Behav Brain Res 130:103–109CrossRefPubMedGoogle Scholar
  12. Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138:963–971PubMedGoogle Scholar
  13. Couceyro PR, Evans C, McKinzie A, Mitchell D, Dube M et al (2005) Cocaine- and amphetamine-regulated transcript (CART) peptides modulate the locomotor and motivational properties of psychostimulants. J Pharmacol Exp Ther 315:1091–1100CrossRefPubMedGoogle Scholar
  14. Cox A, Ackert-Bicknell CL, Dumont BL, Ding Y, Bell JT et al (2009) A new standard genetic map for the laboratory mouse. Genetics 182:1335–1344CrossRefPubMedGoogle Scholar
  15. Crabbe JC, Wahlsten D, Dudek BC (1999) Genetics of mouse behavior: interactions with laboratory environment. Science 284:1670–1672CrossRefPubMedGoogle Scholar
  16. de Mooij-van Malsen JG, van Lith HA, Oppelaar H, Olivier B, Kas MJ (2009) Evidence for epigenetic interactions for loci on mouse chromosome 1 regulating open field activity. Behav Genet 39:176–182CrossRefPubMedGoogle Scholar
  17. DeFries JC, Gervais MC, Thomas EA (1978) Response to 30 generations of selection for open-field activity in laboratory mice. Behav Genet 8:3–13CrossRefPubMedGoogle Scholar
  18. DiPetrillo K, Wang X, Stylianou IM, Paigen B (2005) Bioinformatics toolbox for narrowing rodent quantitative trait loci. Trends Genet 21:683–692CrossRefPubMedGoogle Scholar
  19. Flint J (2003) Analysis of quantitative trait loci that influence animal behavior. J Neurobiol 54:46–77CrossRefPubMedGoogle Scholar
  20. Flint J (2004) The genetic basis of neuroticism. Neurosci Biobehav Rev 28:307–316CrossRefPubMedGoogle Scholar
  21. Flint J, Corley R, DeFries JC, Fulker DW, Gray JA et al (1995) A simple genetic basis for a complex psychological trait in laboratory mice. Science 269:1432–1435CrossRefPubMedGoogle Scholar
  22. Garriock HA, Kraft JB, Shyn SI, Peters EJ, Yokoyama JS et al (2010) A genomewide association study of citalopram response in major depressive disorder. Biol Psychiatry 67:133–138CrossRefPubMedGoogle Scholar
  23. Gershenfeld HK, Neumann PE, Mathis C, Crawley JN, Li X et al (1997) Mapping quantitative trait loci for open-field behavior in mice. Behav Genet 27:201–210CrossRefPubMedGoogle Scholar
  24. Gill KJ, Boyle AE (2003) Confirmation of quantitative trait loci for cocaine-induced activation in the AcB/BcA series of recombinant congenic strains. Pharmacogenetics 13:329–338CrossRefPubMedGoogle Scholar
  25. Gill KJ, Boyle AE (2005) Quantitative trait loci for novelty/stress-induced locomotor activation in recombinant inbred (RI) and recombinant congenic (RC) strains of mice. Behav Brain Res 161:113–124CrossRefPubMedGoogle Scholar
  26. Gould TD, Gottesman II (2006) Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav 5:113–119CrossRefPubMedGoogle Scholar
  27. Henderson ND, Turri MG, DeFries JC, Flint J (2004) QTL analysis of multiple behavioral measures of anxiety in mice. Behav Genet 34:267–293CrossRefPubMedGoogle Scholar
  28. Hettema JM, Neale MC, Kendler KS (2001) A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 158:1568–1578CrossRefPubMedGoogle Scholar
  29. Hitzemann R, Malmanger B, Reed C, Lawler M, Hitzemann B et al (2003) A strategy for the integration of QTL, gene expression, and sequence analyses. Mamm Genome 14:733–747CrossRefPubMedGoogle Scholar
  30. Hooks MS, Juncos JL, Justice JB Jr, Meiergerd SM, Povlock SL et al (1994) Individual locomotor response to novelty predicts selective alterations in D1 and D2 receptors and mRNAs. J Neurosci 14:6144–6152PubMedGoogle Scholar
  31. Hranilovic D, Bucan M, Wang Y (2008) Emotional response in dopamine D2L receptor-deficient mice. Behav Brain Res 195:246–250CrossRefPubMedGoogle Scholar
  32. Jaworski JN, Kozel MA, Philpot KB, Kuhar MJ (2003a) Intra-accumbal injection of CART (cocaine-amphetamine regulated transcript) peptide reduces cocaine-induced locomotor activity. J Pharmacol Exp Ther 307:1038–1044CrossRefPubMedGoogle Scholar
  33. Jaworski JN, Vicentic A, Hunter RG, Kimmel HL, Kuhar MJ (2003b) CART peptides are modulators of mesolimbic dopamine and psychostimulants. Life Sci 73:741–747CrossRefPubMedGoogle Scholar
  34. Jaworski JN, Kimmel HL, Mitrano DA, Tallarida RJ, Kuhar MJ (2007) Intra-VTA CART 55–102 reduces the locomotor effect of systemic cocaine in rats: an isobolographic analysis. Neuropeptides 41:65–72CrossRefPubMedGoogle Scholar
  35. Jetten AM (2009) Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal 7:e003PubMedGoogle Scholar
  36. Jones BC, Tarantino LM, Rodriguez LA, Reed CL, McClearn GE et al (1999) Quantitative-trait loci analysis of cocaine-related behaviours and neurochemistry. Pharmacogenetics 9:607–617CrossRefPubMedGoogle Scholar
  37. Kao CH, Zeng ZB, Teasdale RD (1999) Multiple interval mapping for quantitative trait loci. Genetics 152:1203–1216PubMedGoogle Scholar
  38. Kelly MA, Low MJ, Phillips TJ, Wakeland EK, Yanagisawa M (2003) The mapping of quantitative trait loci underlying strain differences in locomotor activity between 129S6 and C57BL/6 J mice. Mamm Genome 14:692–702CrossRefPubMedGoogle Scholar
  39. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR et al (2005) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry 62:593–602CrossRefPubMedGoogle Scholar
  40. Kimmel HL, Gong W, Vechia SD, Hunter RG, Kuhar MJ (2000) Intra-ventral tegmental area injection of rat cocaine and amphetamine-regulated transcript peptide 55–102 induces locomotor activity and promotes conditioned place preference. J Pharmacol Exp Ther 294:784–792PubMedGoogle Scholar
  41. Koyner J, Demarest K, McCaughran J Jr, Cipp L, Hitzemann R (2000) Identification and time dependence of quantitative trait loci for basal locomotor activity in the BXD recombinant inbred series and a B6D2 F2 intercross. Behav Genet 30:159–170CrossRefPubMedGoogle Scholar
  42. Laarakker MC, Ohl F, van Lith HA (2008) Chromosomal assignment of quantitative trait loci influencing modified hole board behavior in laboratory mice using consomic strains, with special reference to anxiety-related behavior and mouse chromosome 19. Behav Genet 38:159–184CrossRefPubMedGoogle Scholar
  43. Lalonde R, Strazielle C (2007) Spontaneous and induced mouse mutations with cerebellar dysfunctions: behavior and neurochemistry. Brain Res 1140:51–74CrossRefPubMedGoogle Scholar
  44. Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247CrossRefPubMedGoogle Scholar
  45. Lavebratt C, Sjoholm LK, Partonen T, Schalling M, Forsell Y (2010) PER2 variation is associated with depression vulnerability. Am J Med Genet B Neuropsychiatr Genet 153B:570–581PubMedGoogle Scholar
  46. McClearn GE (1959) The genetics of mouse behavior in novel situations. J Comp Physiol Psychol 52:62–67CrossRefPubMedGoogle Scholar
  47. Mozhui K, Ciobanu DC, Schikorski T, Wang X, Lu L et al (2008) Dissection of a QTL hotspot on mouse distal chromosome 1 that modulates neurobehavioral phenotypes and gene expression. PLoS Genet 4:e1000260CrossRefPubMedGoogle Scholar
  48. Nettleton D, Doerge RW (2000) Accounting for variability in the use of permutation testing to detect quantitative trait loci. Biometrics 56:52–58CrossRefPubMedGoogle Scholar
  49. Ponder CA, Kliethermes CL, Drew MR, Muller J, Das K et al (2007) Selection for contextual fear conditioning affects anxiety-like behaviors and gene expression. Genes Brain Behav 6:736–749CrossRefPubMedGoogle Scholar
  50. Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33CrossRefPubMedGoogle Scholar
  51. Rieseberg LH, Archer MA, Wayne RK (1999) Transgressive segregation, adaptation and speciation. Heredity 83(Pt 4):363–372CrossRefPubMedGoogle Scholar
  52. Russell E (1978) Genetic origins and some research uses of C57BL/6, DBA/2 and B6D2F1 mice. In: Gibson D, Adelman R, Finch C (eds) Development of the rodent as a model system of aging. USPHS-DHEW Publ (NIH), Washington, DC, pp 79–161Google Scholar
  53. Sen S, Churchill GA (2001) A statistical framework for quantitative trait mapping. Genetics 159:371–387PubMedGoogle Scholar
  54. Singer JB, Hill AE, Nadeau JH, Lander ES (2005) Mapping quantitative trait loci for anxiety in chromosome substitution strains of mice. Genetics 169:855–862CrossRefPubMedGoogle Scholar
  55. Smith R, Sheppard K, DiPetrillo K, Churchill G (2009) Quantitative trait locus analysis using J/qtl. Methods Mol Biol 573:175–188CrossRefPubMedGoogle Scholar
  56. Solberg LC, Valdar W, Gauguier D, Nunez G, Taylor A et al (2006) A protocol for high-throughput phenotyping, suitable for quantitative trait analysis in mice. Mamm Genome 17:129–146CrossRefPubMedGoogle Scholar
  57. Su Z, Ishimori N, Chen Y, Leiter EH, Churchill GA et al (2009) Four additional mouse crosses improve the lipid QTL landscape and identify Lipg as a QTL gene. J Lipid Res 50:2083–2094CrossRefGoogle Scholar
  58. Sugiyama F, Churchill GA, Higgins DC, Johns C, Makaritsis KP et al (2001) Concordance of murine quantitative trait loci for salt-induced hypertension with rat and human loci. Genomics 71:70–77CrossRefPubMedGoogle Scholar
  59. Sugiyama F, Churchill GA, Li R, Libby LJ, Carver T et al (2002) QTL associated with blood pressure, heart rate, and heart weight in CBA/CaJ and BALB/cJ mice. Physiol Genomics 10:5–12PubMedGoogle Scholar
  60. Szatkiewicz JP, Beane GL, Ding Y, Hutchins L, Pardo-Manuel de Villena F et al (2008) An imputed genotype resource for the laboratory mouse. Mamm Genome 19(3):199–208CrossRefPubMedGoogle Scholar
  61. Turri MG, Talbot CJ, Radcliffe RA, Wehner JM, Flint J (1999) High-resolution mapping of quantitative trait loci for emotionality in selected strains of mice. Mamm Genome 10:1098–1101CrossRefPubMedGoogle Scholar
  62. Turri MG, Henderson ND, DeFries JC, Flint J (2001) Quantitative trait locus mapping in laboratory mice derived from a replicated selection experiment for open-field activity. Genetics 158:1217–1226PubMedGoogle Scholar
  63. Turri MG, DeFries JC, Henderson ND, Flint J (2004) Multivariate analysis of quantitative trait loci influencing variation in anxiety-related behavior in laboratory mice. Mamm Genome 15:69–76CrossRefPubMedGoogle Scholar
  64. Utge SJ, Soronen P, Loukola A, Kronholm E, Ollila HM et al (2010) Systematic analysis of circadian genes in a population-based sample reveals association of TIMELESS with depression and sleep disturbance. PLoS One 5:e9259CrossRefPubMedGoogle Scholar
  65. van Abeelen JH (1977) Rearing responses and locomotor activity in mice: single-locus control. Behav Biol 19:401–404CrossRefPubMedGoogle Scholar
  66. Williams RT, Lim JE, Harr B, Wing C, Walters R et al (2009) A common and unstable copy number variant is associated with differences in Glo1 expression and anxiety-like behavior. PLoS One 4:e4649CrossRefPubMedGoogle Scholar
  67. Wiltshire T, Pletcher MT, Batalov S, Barnes SW, Tarantino LM et al (2003) Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse. Proc Natl Acad Sci USA 100:3380–3385CrossRefPubMedGoogle Scholar
  68. Yalcin B, Willis-Owen SA, Fullerton J, Meesaq A, Deacon RM et al (2004) Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice. Nat Genet 36:1197–1202CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Amy F. Eisener-Dorman
    • 1
  • Laura Grabowski-Boase
    • 2
  • Brian M. Steffy
    • 3
  • Tim Wiltshire
    • 3
  • Lisa M. Tarantino
    • 1
    Email author
  1. 1.Department of PsychiatryUniversity of North CarolinaChapel HillUSA
  2. 2.Genomics Institute of the Novartis Research FoundationSan DiegoUSA
  3. 3.Institute of Pharmacogenomics and Individualized Therapy, Division of Pharmacotherapy and Experimental TherapeuticsUniversity of North CarolinaChapel HillUSA

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