Mammalian Genome

, Volume 17, Issue 12, pp 1193–1204

Further studies on using multiple-cross mapping (MCM) to map quantitative trait loci

  • Barry Malmanger
  • Maureen Lawler
  • Shannon Coulombe
  • Rochelle Murray
  • Staci Cooper
  • Yekaterina Polyakov
  • John Belknap
  • Robert Hitzemann
Article

Abstract

We have completed whole-genome scans for quantitative trait loci (QTLs) associated with acute ethanol-induced activation in the six F2 intercrosses that can be formed from the C57BL/6J (B6), DBA/2J (D2) , BALB/cJ (C), and LP/J (LP) inbred strains. The goal was to test the hypothesis that given the relatively simple structure of the laboratory mouse genome, the same QTLs will be detected in multiple crosses which in turn will provide support for the strategy of multiple-cross mapping (MCM). QTLs with LOD scores greater than 4 were detected on Chrs 1, 2, 3, 8, 9, 13, 14, and 16. Only for the QTL on distal Chr 1 was there convincing evidence that the same or at least a very similar QTL was detected in multiple crosses. We also mapped the Chr 2 QTL directly in heterogeneous stock (HS) animals derived from the four inbred strains. At G19 the QTL was mapped to an approximately 3-Mbp interval and this interval was associated with a haplotype block with a largely biallelic structure: B6-L:C-D2. We conclude that mapping in HS animals not only provides significantly greater QTL resolution, at least in some cases it provides significantly more information about the QTL haplotype structure.

References

  1. Aitman TJ, Glazier AM, Wallace CA, Cooper LD, et al. (1999) Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nat Genet 21, 76–83CrossRefPubMedGoogle Scholar
  2. Bachmanov AA, Reed DR, Li X, Li S, et al. (2002) Voluntary ethanol consumption by mice: genome-wide analysis of quantitative trait loci and their interactions in a C57BL/ByJ x 129P3/J F2 intercross. Genome Res 12, 1257–1268CrossRefPubMedGoogle Scholar
  3. Beck JA, Lloyd S, Hafezparst M, Lennon-Pierce M, et al. (2000) Genealogies of mouse inbred strains. Nat Genet 24, 23–25CrossRefPubMedGoogle Scholar
  4. Belknap JK, Atkins AL (2001) The replicability of QTLs for murine alcohol preference drinking behavior across eight independent studies. Mamm Genome 12, 893–899CrossRefPubMedGoogle Scholar
  5. Belknap JK, Hitzemann R, Crabbe JC, Phillips T, et al. (2001) QTL analysis and genome wide mutagenesis in mice: complementary genetic approaches to the dissection of complex traits. Behav Genet 31, 5–15CrossRefPubMedGoogle Scholar
  6. Bonhomme F (1986) Evolutionary relationships in the genus Mus. Curr Top Microbiol Immunol 127, 19–34PubMedGoogle Scholar
  7. Broman KW, Wu H, Sen S, Churchill GA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 1, 889–90CrossRefGoogle Scholar
  8. Carter TA, Del Rio JA, Greenhall JA, Latronica ML, et al. (2001) Chipping away at comples behavior: Transcriptome/phenotype correlations in the mouse brain. Physiol Behav 73, 849–857CrossRefPubMedGoogle Scholar
  9. Cervino AC, Guoya L, Edwards S, Zhu J, et al. (2005) Integrating QTL and highh density SNP analyses in mice to indentify Insig2 as a susceptibility gene for plasma cholesterol levels. Genomics 86, 505–517CrossRefPubMedGoogle Scholar
  10. 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, 233–242CrossRefPubMedGoogle Scholar
  11. Collison M, Glazier AM, Graham D, Morton J, et al. (2000) Cd36 and molecular mechanisms of insulin resistance in the stroke-prone spontaneously hypertensive rat. Diabetes 49, 2222–2226PubMedGoogle Scholar
  12. Darvasi A (1998) Experimental strategies for the genetic dissection of complex traits in animal models. Nat Genet 18, 19–24CrossRefPubMedGoogle Scholar
  13. Demarest K, McCaughran J, Mahjubi E, Cipp L, et al. (1999) Identification of an acute ethanol response quantitative trait locus on mouse chromosome 2. J Neurosci 19, 549–561PubMedGoogle Scholar
  14. Demarest K, Koyner J, McCaughran J, Cipp L, Hitzemann R (2001) Further characterization and high-resolution mapping of quantitative trait loci for ethanol-induced locomotor activity. Behav Genet 31, 79–91CrossRefPubMedGoogle Scholar
  15. Dietrich W, Katz H, Lincoln SE, Shin H, et al. (1992) A genetic map of the mouse suitable for typing intraspecific crosses. Genetics 131, 423–447PubMedGoogle Scholar
  16. Dietrich WF, Miller JC, Steen RG, et al. (1994) A genetic map of the mouse with 4,006 simple sequence polymorphisms. Nat Genet 7, 220–245CrossRefPubMedGoogle Scholar
  17. Dietrich WF, Miller J, Steen R, et al (1996) A comprehensive genetic map of the mouse genome. Nature 380, 149–152CrossRefPubMedGoogle Scholar
  18. Flint J (2003) Analysis of quantitative trait loci that influence animal behavior. J Neurobiol 54, 46–77CrossRefPubMedGoogle Scholar
  19. Flint J, Mott R (2001) Finding the molecular basis of quantitative traits: Successes and pitfalls. Nat Rev Genet 2, 437–445CrossRefPubMedGoogle Scholar
  20. Flint J, Corley R, DeFries JC, Fulker DW, et al. (1995) A simple genetic basis for a complex psychological trait in laboratory mice. Science 269, 1432–1435CrossRefPubMedGoogle Scholar
  21. Frankel WN, Valenzuela A, Lutz CM, Johnson EW, et al. (1995) New seizure frequency QTL and the complex genetics of epilepsy in EL mice. Mamm Genome 6, 830–838CrossRefPubMedGoogle Scholar
  22. Geschwind DH (2000) Mice, microarrays, and the genetic diversity of the brain. Proc Natl Acad Sci USA 97(20), 10676–10678CrossRefPubMedGoogle Scholar
  23. Gershenfeld HK, Neumann PE, Mathis C, Crawley JN, et al. (1997) Mapping quantitative trait loci for open-field behavior in mice. Behav Genet 27(3), 201–210CrossRefPubMedGoogle Scholar
  24. Gill K, Boyle A, Lake K, Desaulniers N (2000) Alcohol-induced locomotor activation in C57BL/6J, A/J and AXB/BXA recombinant inbred mice: strains distribution patterns and quantitative trait loci analysis. Psychopharmacology 150, 412–421CrossRefPubMedGoogle Scholar
  25. Grupe A, Germer S. Usuka J, Usuka J, et al. (2001) In silico mapping of complex disease-related traits in mice. Science 292, 1915–1918CrossRefPubMedGoogle Scholar
  26. Hitzemann R, Demarest K, Koyner J, Cipp L, et al. (2000) Effects of genetic cross on the detection of quantitative trait loci and a novel approach to mapping QTLs. Pharmacol Biochem Behav 67, 767–772CrossRefPubMedGoogle Scholar
  27. Hitzemann R, Malmanger B, Cooper S, Coulombe S, et al. (2002) Multiple cross mapping (MCM) markedly improves the localization of a QTL for ethanol-induced activation. Genes Brain Behav 1, 214–222CrossRefPubMedGoogle Scholar
  28. Hitzemann R, Malmanger B, Reed C, Lawler M, et al. (2003) A strategy for the integration of QTL, gene expression and sequence analyses. Mamm Genome 11, 733–747CrossRefGoogle Scholar
  29. Hitzemann R, Reed C, Malmanger B, Lawler M, et al. (2004) On the integration of alcohol related quantitative trait loci and gene expression analyses. Alcohol Clin Exp Res 28, 1437–1438CrossRefPubMedGoogle Scholar
  30. Karp CL, Grupe A, Schadt E, Ewart SL, et al. (2000) Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol 1, 221–226CrossRefPubMedGoogle Scholar
  31. Khatkar MS, Thomson PC, Tammen I, Raadsma HW (2004) Quantitative trait loci mapping in dairy cattle: review and meta analysis. Genet Select Evol 26, 163–190CrossRefGoogle Scholar
  32. Koyner J, Demarest K, McCaughran J, Cipp L, et al. (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 Gene. 30(3), 159–170CrossRefGoogle Scholar
  33. Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11, 241–247CrossRefPubMedGoogle Scholar
  34. Li R, Lyons MA, Wittenburg H, Paigen B, Churchill GA (2005) Combining data from multiple inbred line crosses improves the power and resolution of qunatitative trait loci mapping. Genetics 169, 1699–1709CrossRefPubMedGoogle Scholar
  35. Lockhart DJ, Barlow C (2001) Expressing what’s on your mind: DNA arrays and the brain. Nat Rev Neurosci 2, 63–68CrossRefPubMedGoogle Scholar
  36. Mackay TF (2001) The genetic architecture of quantitative traits. Annu Rev Genet 35, 303–339CrossRefPubMedGoogle Scholar
  37. Markel PD, DeFries JC, Johnson TE (1995) Ethanol-induced anesthesia in inbred strains of long-sleep and short-sleep mice: a genetic analysis of repeated measures using censored data. Behav Gen 25(1), 67–73CrossRefGoogle Scholar
  38. Mott R, Talbot CJ, Turri MG, Collins AC, Flint J (2000) A method for fine mapping quantitative trait loci in outbred animal stocks. Proc Natl Acad Sci U S A 97, 12649–12654CrossRefPubMedGoogle Scholar
  39. Park YG, Clifford R, Buettow KH, Hunter KW (2003) Multiple cross and inbred strain haplotype mapping of complex trait candidate genes. Genome Res 13, 118–121CrossRefPubMedGoogle Scholar
  40. Patel NV, Hitzemann RJ (1999) Detection and mapping of quantitative trait loci for haloperidol-induced catalepsy in a C57BL/6J x DBA/2J F2 intercross. Behav Genet 29(5), 303–310CrossRefPubMedGoogle Scholar
  41. Phillips TJ, Huson M, Gwiazdon C, Burkhart-Kasch S, Shen EH (1995) Effects of acute and repeated ethanol exposures on the locomotor activity of BXD recombinant inbred mice. Alcohol Clin Exp Res 19, 1–10CrossRefGoogle Scholar
  42. Rasmussen E, Cipp L, Hitzemann R (1999) Identification of quantitative trait loci for haloperidol-induced catalepsy on mouse chromosome 14. J Pharmacol Exp Ther 290(3), 1337–1346PubMedGoogle Scholar
  43. Sandberg R, Yasuda R, Pankratz DG, Carter TA, et al. (2000) Regional and strain-specific gene expression mapping in the adult mouse brain. Proc Natl Acad Sci U S A 97, 11038–11043CrossRefPubMedGoogle Scholar
  44. Silver L (1995) Mouse Genetics (Oxford: Oxford University Press)Google Scholar
  45. Solberg LC, Valdar W, Gauguier D, Nunez G, et al. (2006) A protocol for high-throughput phenotyping, suitable for quantitative trait analysis in mice. Mamm Genome 17, 129–146CrossRefPubMedGoogle Scholar
  46. Talbot CJ, Radcliffe RA, Fullerton J, Hitzemann R, Wehner JM, et al. (2003) Fine scale mapping of a genetic locus for conditioned fear. Mamm Genome 14(4), 223–230CrossRefPubMedGoogle Scholar
  47. Wade CM, Kulbokas EJ 3rd, Kirby AW, Zody MC, Mullikin JC, et al. (2002) The mosaic structure of variation in the laboratory mouse genome. Nature 420(6915), 547–548CrossRefGoogle Scholar
  48. Wayne ML, McIntyre LM (2002) Combining mapping and arraying: An approach to candidate gene identification. Proc Nat Acad Sci U S A 99(23), 14903–14906CrossRefGoogle Scholar
  49. Wiltshire T, Pletcher MT, Batalov S, Barnes SW, et al. (2003) Genome-wide single nucleotide polymorphism anlaysis defines halplotype patterns in mouse. Proc Natl Acad Sci U S A 100, 3380–3385CrossRefPubMedGoogle Scholar
  50. Yalcin B, Fullerton J, Miller S, Keays DA, et al. (2004) Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice. Proc Natl Acad Sci U S A 101(26), 9734–9739CrossRefPubMedGoogle Scholar
  51. Yi N, Xu S (2002) Linkage analysis of quantitative trait loci in multiple line crosses. Genetica 114, 217–230CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Barry Malmanger
    • 1
    • 2
  • Maureen Lawler
    • 1
    • 2
  • Shannon Coulombe
    • 1
    • 2
  • Rochelle Murray
    • 1
    • 2
  • Staci Cooper
    • 1
    • 2
  • Yekaterina Polyakov
    • 1
    • 2
  • John Belknap
    • 1
    • 2
  • Robert Hitzemann
    • 1
    • 2
    • 3
  1. 1.Department of Behavioral NeuroscienceOregon Health & Science UniversityPortlandUSA
  2. 2.Research Service, Veterans Affairs Medical CenterPortlandUSA
  3. 3.Department of Behavioral Neuroscience, L-470Oregon Health & Science UniversityPortlandUSA

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