Mammalian Genome

, Volume 17, Issue 6, pp 629–642 | Cite as

Prediction of cis-QTLs in a pair of inbred mouse strains with the use of expression and haplotype data from public databases

  • Richard A. Radcliffe
  • Michael J. Lee
  • Robert W. Williams
Article

Abstract

Cis-QTLs are important candidates for any other trait that maps to the same locus. In this article we have used publicly available databases and a small microarray data set to “map” cis-QTLs in the ILS and ISS inbred mouse strains without the need to generate microarray data from an ILSXISS segregating population. Expression data were obtained from brains of C57BL/6, DBA/2, ILS, and ISS. Cis-QTLs were mapped for the 760 transcripts found to be differentially expressed between the C57BL/6 and DBA/2 using expression data previously obtained from the BXD RIs. The 469 detected cis-QTLs were then examined for SNP haplotypes and expression patterns that could relate the ILS and ISS to the C57BL/6 and DBA/2. Of the 338 cis-QTL transcripts that had informative haplotypes, 189 were significantly different between the ILS and ISS with 184 showing segregation of haplotype with expression. These were considered to be probable cis-QTLs in the ILS and ISS. There were almost certainly additional ILS/ISS cis-QTLs among the other transcripts with informative haplotypes, but in the absence of an ILS/ISS expression difference, the level of confidence was reduced. Several of the putative ILS/ISS cis-QTLs are considered important candidate genes because they are linked to ILS/ISS behavioral QTLs. A potential ascertainment bias related to strain-dependent target sequences was observed suggesting that as much as 35% of the cis-QTLs were hybridization artifacts. Nonetheless, the results suggest that this approach is an economical and widely applicable method for mapping cis-QTLs in a strain pair of interest.

Supplementary material

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References

  1. Alberts R, Terpstra P, Bystrykh LV, de Haan G, Jansen RC (2005) A statistical multiprobe model for analyzing cis and trans genes in genetical genomics experiments with short-oligonucleotide arrays. Genetics 171:1437–1439PubMedCrossRefGoogle Scholar
  2. Andersson L, Georges M (2004) Domestic-animal genomics: deciphering the genetics of complex traits. Nat Rev Genet 5:202–212PubMedCrossRefGoogle Scholar
  3. Beck JA, Lloyd S, Hafezparast M, Lennon-Pierce M, Eppig JT, et al. (2000) Genealogies of mouse inbred strains. Nature Genet 24: 23–25PubMedCrossRefGoogle Scholar
  4. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing J R Stat Soc B 57: 289–300Google Scholar
  5. Bennett B, Beeson M, Gordon L, Carosone-Link P, Johnson TE (2002a) Genetic dissection of quantitative trait loci specifying sedative/hypnotic sensitivity to ethanol: mapping with interval-specific congenic recombinant lines. Alcohol Clin Exp Res 26:1615–1624CrossRefGoogle Scholar
  6. Bennett B, Beeson M, Gordon L, Johnson TE (2002b) Reciprocal congenics defining individual quantitative trait Loci for sedative/hypnotic sensitivity to ethanol. Alcohol Clin Exp Res 26:149–157CrossRefGoogle Scholar
  7. Brem RB, Yvert G, Clinton R, Kruglyak L (2002) Genetic dissection of transcriptional regulation in budding yeast. Science 296:752–755PubMedCrossRefGoogle Scholar
  8. Chesler EJ, Williams RW (2004) Brain gene expression: genomics and genetics. Int Rev Neurobiol 60:59–95PubMedCrossRefGoogle Scholar
  9. Chesler EJ, Wang J, Lu L, Qu Y, Manly KF, et al. (2003) Genetic correlates of gene expression in recombinant inbred strains: a relational model system to explore neurobehavioral phenotypes. Neuroinformatics 1:343–357PubMedCrossRefGoogle Scholar
  10. Chesler EJ, Lu L, Wang J, Williams RW, Manly KF (2004) WebQTL: rapid exploratory analysis of gene expression and genetic networks for brain and behavior. Nat Neurosci 7:485–486PubMedCrossRefGoogle 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. Darvasi A (1998) Experimental strategies for the genetic dissection of complex traits in animal models. Nat Genet 18:19–24PubMedCrossRefGoogle Scholar
  13. Doss S, Schadt EE, Drake TA, Lusis AJ (2005) Cis-acting expression quantitative trait loci in mice. Genome Res 15:681–691PubMedCrossRefGoogle Scholar
  14. Ehringer MA, Thompson J, Conroy O, Xu Y, Yang F, et al. (2001) High-throughput sequence identification of gene coding variants within alcohol-related QTL. Mamm Genome 12:657–663PubMedCrossRefGoogle Scholar
  15. Erwin VG, Gehle VM, Davidson K, Radcliffe RA (2001) Confirmation of correlations and common quantitative trait loci between neurotensin receptor density and hypnotic sensitivity to ethanol. Alcohol Clin Exp Res 25:1699–1707PubMedCrossRefGoogle Scholar
  16. Flint J, Valdar W, Shifman S, Mott R (2005) Strategies for mapping and cloning quantitative trait genes in rodents. Nat Rev Genet 6:271–286PubMedCrossRefGoogle Scholar
  17. Glazier AM, Nadeau JH, Aitman TJ (2002) Finding genes that underlie complex traits. Science 298:2345–2349PubMedCrossRefGoogle Scholar
  18. Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L, et al. (2002) Serotonin1A receptor acts during development to establish normal anxiety-like behavior in the adult. Nature 416:396–400PubMedCrossRefGoogle Scholar
  19. Haley CS, Knott SA (1992) A simple regression method for mapping quantitative trait loci in line crosses using flanking markers. Heredity 69:315–324PubMedGoogle Scholar
  20. Hamilton BA (2002) Variations in abundance: genome-wide responses to genetic variation and vice versa. Genome Biol 3, reviews 1029.1–1029.3CrossRefGoogle Scholar
  21. Hitzemann R, Belknap JK, McWeeney S (2005) Regional differences in the regulation of gene expression as detected by microarrays: relevance to the detection of genes associated with alcohol-related traits. Alcohol Clin Exp Res (Suppl) 29:5Google Scholar
  22. Hoff PR, Young WG, Bloom FE, Belichenko PV, Celio MR (2000) Comparative cytoarchitectonic atlas of the C57BL/6 and 129/Sv Mouse Brains (Amsterdam: Elsevier)Google Scholar
  23. Hubner N, Wallace CA, Zimdahl H, Petretto E, Schulz H, et al. (2005) Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat Genet 37:243–253PubMedCrossRefGoogle Scholar
  24. Jansen RC, Nap JP (2001) Genetical genomics: the added value from segregation. Trends Genet 17:388–391PubMedCrossRefGoogle Scholar
  25. Kerns RT, Ravindranathan A, Hassan S, Cage MP, York T, et al. (2005) Ethanol-responsive brain region expression networks: implications for behavioral responses to acute ethanol in DBA/2J versus C57BL/6J mice. J Neurosci 25:2255–2266PubMedCrossRefGoogle Scholar
  26. Korstanje R, Paigen B (2002) From QTL to gene: the harvest begins. Nat Genet 31:235–236PubMedCrossRefGoogle Scholar
  27. Lander ES, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247PubMedCrossRefGoogle Scholar
  28. Mackay TF (2001) The genetic architecture of quantitative traits. Ann Rev Genet 35:303–339PubMedCrossRefGoogle Scholar
  29. Mackay TF (2004) The genetic architecture of quantitative traits: lessons from Drosophila. Curr Opin Genet Dev 14:253–257PubMedCrossRefGoogle Scholar
  30. MacLaren EJ, Sikela JM (2005) Cerebellar gene expression profiling and eQTL analysis in inbred mouse strains selected for ethanol sensitivity. Alcohol Clin Exp Res 29:1568–1579PubMedCrossRefGoogle Scholar
  31. Manly KF, Wang J, Williams RW (2005) Weighting by heritability for detection of quantitative trait loci with microarray estimates of gene expression. Genome Biol 6:R27PubMedCrossRefGoogle Scholar
  32. Markel PD, Fulker DW, Bennett B, Corley RP, DeFries JC, et al. (1996) Quantitative trait loci for ethanol sensitivity in the LS × SS recombinant inbred strains: interval mapping. Behav Genet 26:447–458PubMedCrossRefGoogle Scholar
  33. Markel PD, Bennett B, Beeson M, Gordon L, Johnson TE (1997) Confirmation of quantitative trait loci for ethanol sensitivity in long-sleep and short-sleep mice. Genome Res 7:92–99PubMedGoogle Scholar
  34. McClearn GE, Tarantino LM, Hofer SM, Jones B, Plomin R (1998) Developmental loss of effect of a Chromosome 15 QTL on alcohol acceptance. Mamm Genome 9:991–994PubMedCrossRefGoogle Scholar
  35. Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, et al. (2004) Genetic analysis of genome-wide variation in human gene expression. Nature 430:743–747PubMedCrossRefGoogle Scholar
  36. Peirce JL, Lu L, Gu J, Silver LM, Williams RW (2004) A new set of BXD recombinant inbred lines from advanced intercross populations in mice. BMC Genet 5:7PubMedCrossRefGoogle Scholar
  37. Radcliffe RA, Bohl ML, Lowe MV, Cykowski CS, Wehner JM (2000) Mapping of quantitative trait loci for hypnotic sensitivity to ethanol in crosses derived from the C57BL/6 and DBA/2 mouse strains. Alcohol Clin Exp Res 24: 1335–1342PubMedCrossRefGoogle Scholar
  38. 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 19:367–373PubMedCrossRefGoogle Scholar
  39. Sandberg R, Yasuda R, Pankratz DG, Carter TA, Del Rio JA, et al. (2000) Regional and strain-specific gene expression mapping in the adult mouse brain. Proc Nat Acad Sci U S A 97:11038–11043PubMedCrossRefGoogle Scholar
  40. 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
  41. Silver LM (1995) Mouse Genetics: Concepts and Applications (New York, NY: Oxford University Press), pp 207–227Google Scholar
  42. Taylor BA, Wnek C, Kotlus BS, Roemer N, MacTaggart T, et al. (1999) Genotyping new BXD recombinant inbred mouse strains and comparison of BXD and consensus maps. Mamm Genome 10:335–348PubMedCrossRefGoogle Scholar
  43. Wang J, Williams RW, Manly KF (2003) WebQTL: web-based complex trait analysis. Neuroinformatics 1:299–308PubMedCrossRefGoogle Scholar
  44. Xu Y, Ehringer M, Yang F, Sikela JM (2001) Comparison of global brain gene expression profiles between inbred long-sleep and inbred short-sleep mice by high-density gene array hybridization. Alcohol Clin Exp Res 25:810–818PubMedCrossRefGoogle Scholar
  45. Yalcin B, Fullerton J, Miller S, Keays DA, Brady S, et al. (2004) Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice. Proc Nat Acad Sci USA 101:9734–9739PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Richard A. Radcliffe
    • 1
    • 2
    • 4
  • Michael J. Lee
    • 1
  • Robert W. Williams
    • 3
  1. 1.Department of Pharmaceutical SciencesUniversity of Colorado at Denver and Health Sciences CenterDenverUSA
  2. 2.Institute for Behavioral GeneticsUniversity of ColoradoBoulderUSA
  3. 3.Department of Anatomy and NeurobiologyUniversity of Tennessee Health Science CenterMemphisUSA
  4. 4.Department of Pharmaceutical SciencesUniversity of Colorado at Denver and Health Sciences CenterDenverUSA

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