Sequence Analyses to Study the Evolutionary History and Cis-Regulatory Elements of Hedgehog Genes

  • Ferenc Müller
  • Anne-Gaelle Borycki
Part of the Methods Inmolecular Biology™ book series (MIMB, volume 397)


Sequence analysis and comparative genomics are powerful tools to gain knowledge on multiple aspects of gene and protein regulation and function. These have been widely used to understand the evolutionary history and the biochemistry of Hedgehog (Hh) proteins, and the molecular control of Hedgehog gene expression. Here, we report on some of the methods available to retrieve protein and genomic sequences. We describe how protein sequence comparison can produce information on the evolutionary history of Hh proteins. Moreover, we describe the use of genomic sequence analysis including phylogenetic footprinting and transcription factor-binding site search tools, techniques that allow for the characterization of cis-regulatory elements of developmental genes such as the Hedgehog genes.

Key Words

Hedgehog sequence analysis evolution cis-regulatory element bioinformatics 


  1. 1.
    Bejerano, G., Pheasant, M., Makunin, I., et al. (2004) Ultraconserved elements in the human genome. Science 304, 1321–1325.PubMedCrossRefGoogle Scholar
  2. 2.
    Dermitzakis, E. T. and Clark, A. G. (2002) Evolution of transcription factor binding sites in Mammalian gene regulatory regions: conservation and turnover. Mol. Biol. Evol. 19, 1114–1121.PubMedGoogle Scholar
  3. 3.
    Frazer, K. A., Sheehan, J. B., Stokowski, R. P., et al. (2001) Evolutionarily conserved sequences on human chromosome 21. Genome Res. 11, 1651–1659.PubMedCrossRefGoogle Scholar
  4. 4.
    Hillier, L. W., Miller, W., Birney, E., (2004) Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432, 695–716.CrossRefGoogle Scholar
  5. 5.
    Mural, R. J., Adams, M. D., Myers, E. W., et al. (2002) A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome. Science 296, 1661–1671.PubMedCrossRefGoogle Scholar
  6. 6.
    Rubin, G. M., Yandell, M. D., Wortman, J. R., et al. (2000) Comparative genomics of the eukaryotes. Science 287, 2204–2215.PubMedCrossRefGoogle Scholar
  7. 7.
    Waterston, R. H., Lindblad-Toh, K., Birney, E., Rogers, J., et al. (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562.PubMedCrossRefGoogle Scholar
  8. 8.
    Echelard, Y., Epstein, D. J., St-Jacques, B., et al. (1993) Sonic Hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430.PubMedCrossRefGoogle Scholar
  9. 9.
    Johnson, R. L., Laufer, E., Riddle, R. D., and Tabin, C. (1994) Ectopic expression of Sonic Hedgehog alters dorsal-ventral patterning of somites. Cell 79, 1165–1173.PubMedCrossRefGoogle Scholar
  10. 10.
    Krauss, S., Concordet, J. P., and Ingham, P. W. (1993) A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell 75, 1431–1444.PubMedCrossRefGoogle Scholar
  11. 11.
    Ruiz I Altaba, A., Jessell, T. M., and Roelink, H. (1995) Restrictions to floor plate induction by Hedgehog and winged-helix genes in the neural tube of frog embryos. Mol. Cell. Neurosci. 6, 106–121.PubMedCrossRefGoogle Scholar
  12. 12.
    Shimeld, S. M. (1999) The evolution of the Hedgehog gene family in chordates: insights from amphioxus hedgehog. Dev. Genes Evol. 209, 40–47.PubMedCrossRefGoogle Scholar
  13. 13.
    Tsukurov, O., Boehmer, A., Flynn, J., et al. (1994) A complex bilateral polysyndactyly disease locus maps to chromosome 7q36. Nat. Genet. 6, 282–286.PubMedCrossRefGoogle Scholar
  14. 14.
    Lettice, L. A., Horikoshi, T., Heaney, S. J., et al. (2002). Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc. Natl Acad. Sci. USA 99, 7548–7553.PubMedCrossRefGoogle Scholar
  15. 15.
    Kumar, S., Balczarek, K. A., and Lai, Z. C. (1996) Evolution of the Hedgehog gene family. Genetics 142, 965–972.PubMedGoogle Scholar
  16. 16.
    Zardoya, R., Abouheif, E., and Meyer, A. (1996) Evolutionary analyses of Hedgehog and Hoxd-10 genes in fish species closely related to the zebrafish. Proc. Natl Acad. Sci. USA 93, 13,036–13,041.PubMedCrossRefGoogle Scholar
  17. 17.
    Avaron, F., Hoffman, L., Guay, D., and Akimenko, M. A. (2006) Characterization of two new zebrafish members of the Hedgehog family: atypical expression of a zebrafish indian hedgehog gene in skeletal elements of both endochondral and dermal origins. Dev. Dyn. 235, 478–489.PubMedCrossRefGoogle Scholar
  18. 18.
    Thompson, J. D., Higgins, D. G., and Gibson, T. J. (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680.PubMedCrossRefGoogle Scholar
  19. 19.
    Thompson, J. D., Gibson, T. J., Plewniak, F., Jeanmougin, F., and Higgins, D. G. (1997) The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 25, 4876–4882.PubMedCrossRefGoogle Scholar
  20. 20.
    Notredame, C., Higgins, D. G., and Heringa, J. (2000) T-Coffee: A novel method for fast and accurate multiple sequence alignment. J. Mol. Biol. 302, 205–217.PubMedCrossRefGoogle Scholar
  21. 21.
    Katoh, K., Misawa, K., Kuma, K., and Miyata, T. (2002) MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res. 30, 3059–3066.PubMedCrossRefGoogle Scholar
  22. 22.
    Edgar, R. C. (2004) MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics 5, 113.PubMedCrossRefGoogle Scholar
  23. 23.
    Felsenstein, J. (1988) Phylogenies from molecular sequences: inference and reliability. Annu. Rev. Genet 22, 521–565.PubMedCrossRefGoogle Scholar
  24. 24.
    Saitou, N. and Nei, M. (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol. Biol. Evol. 4, 406–425.PubMedGoogle Scholar
  25. 25.
    Zardoya, R., Abouheif, E., and Meyer, A. (1996) Evolution and orthology of Hedgehog genes. Trends Genet. 12, 496–497.PubMedCrossRefGoogle Scholar
  26. 26.
    Felsenstein, J. (1985) Confidence limits on phylogenies: An approach using the bootstrap. Evolution 39, 783–791.CrossRefGoogle Scholar
  27. 27.
    Conway Morris, S. (1993) The fossil record and the early evolution of the Metazoa. Nature 361, 219–225.CrossRefGoogle Scholar
  28. 28.
    Dehal, P., Satou, Y., Campbell, R.K., et al. (2002) The draft genome of Ciona intestinalis: insights into chordate and vertebrate origins. Science 298, 2157–2167.PubMedCrossRefGoogle Scholar
  29. 29.
    Takatori, N., Satou, Y., and Satoh, N. (2002) Expression of Hedgehog genes in Ciona intestinalis embryos. Mech. Dev. 116, 235–238.PubMedCrossRefGoogle Scholar
  30. 30.
    Aspock, G., Kagoshima, H., Niklaus, G., and Burglin, T. R. (1999) Caenorhabditis elegans has scores of Hedgehog-related genes: sequence and expression analysis. Genome Res. 9, 909–923.PubMedCrossRefGoogle Scholar
  31. 31.
    Hedges, S. B. (2002). The origin and evolution of model organisms. Nat. Rev. Genet. 3, 838–849.PubMedCrossRefGoogle Scholar
  32. 32.
    Blair, J. E., Ikeo, K., Gojobori, T., and Hedges, S. B. (2002) The evolutionary position of nematodes. BMC Evol. Biol. 2, 7.PubMedCrossRefGoogle Scholar
  33. 33.
    Tagle, D. A., Koop, B. F., Goodman, M., Slightom, J. L., Hess, D. L., and Jones, R. T. (1988) Embryonic epsilon and gamma globin genes of a prosimian primate (Galago crassicaudatus). Nucleotide and amino acid sequences, developmental regulation and phylogenetic footprints. J. Mol. Biol. 203, 439–455.PubMedCrossRefGoogle Scholar
  34. 34.
    Dermitzakis, E. T., Reymond, A., Lyle, R., Scamuffa, N., et al. (2002) Numerous potentially functional but non-genic conserved sequences on human chromosome 21. Nature 420, 578–582.PubMedCrossRefGoogle Scholar
  35. 35.
    Wasserman, W. W. and Sandelin, A. (2004) Applied bioinformatics for the identification of regulatory elements. Nat. Rev. Genet. 5, 276–287.PubMedCrossRefGoogle Scholar
  36. 36.
    Muller, F., Blader, P., and Strahle, U. (2002). Search for enhancers: teleost models in comparative genomic and transgenic analysis of cis regulatory elements. Bioessays 24, 564–572.PubMedCrossRefGoogle Scholar
  37. 37.
    Nardone, J., Lee, D. U., Ansel, K. M., and Rao, A. (2004) Bioinformatics for the ‘bench biologist’: how to find regulatory regions in genomic DNA. Nat. Immunol. 5, 768–774PubMedCrossRefGoogle Scholar
  38. 38.
    Boffelli, D., Nobrega, M. A., and Rubin, E. M. (2004). Comparative genomics at the vertebrate extremes. Nat. Rev. Genet. 5, 456–465.PubMedCrossRefGoogle Scholar
  39. 39.
    Lemos, B., Yunes, J. A., Vargas, F. R., Moreira, M. A., Cardoso, A. A., and Seuanez, H. N. (2004) Phylogenetic footprinting reveals extensive conservation of Sonic Hedgehog (SHH) regulatory elements. Genomics 84, 511–523.PubMedCrossRefGoogle Scholar
  40. 40.
    Woolfe, A., Goodson, M., Goode, D. K., et al. (2004) Highly conserved noncoding sequences are associated with vertebrate development. PLoS Biol. 3, e7.PubMedCrossRefGoogle Scholar
  41. 41.
    Goode, D. K., Snell, P., Smith, S. F., Cooke, J. E., and Elgar, G. (2005) Highly conserved regulatory elements around the SHH gene may contribute to the maintenance of conserved synteny across human chromosome 7q36.3. Genomics 86, 172–181.PubMedCrossRefGoogle Scholar
  42. 42.
    Jeong, Y. and Epstein, D. J. (2003) Distinct regulators of Shh transcription in the floor plate and notochord indicate separate origins for these tissues in the mouse node. Development 130, 3891–3902.PubMedCrossRefGoogle Scholar
  43. 43.
    Schwartz, S., Kent, W. J., Smit, A., et al. (2003) Human-mouse alignments with BLASTZ. Genome Res. 13, 103–107.PubMedCrossRefGoogle Scholar
  44. 44.
    Brudno, M., Do, C. B., Cooper, G. M., et al. (2003) LAGAN and Multi-LAGAN: efficient tools for large-scale multiple alignment of genomic DNA. Genome Res. 13, 721–731.PubMedCrossRefGoogle Scholar
  45. 45.
    Pollard, D. A., Bergman, C. M., Stoye, J., Celniker, S. E., and Eisen, M. B. (2004) Benchmarking tools for the alignment of functional noncoding DNA. BMC Bioinformatics 5, 6.PubMedCrossRefGoogle Scholar
  46. 46.
    Schwartz, S., Zhang, Z., Frazer, K. A., et al. (2000) PipMaker—a web server for aligning two genomic DNA sequences. Genome Res. 10, 577–586.PubMedCrossRefGoogle Scholar
  47. 47.
    Ovcharenko, I., Nobrega, M. A., Loots, G. G., and Stubbs, L. (2004) ECR Browser: a tool for visualizing and accessing data from comparisons of multiple vertebrate genomes. Nucleic Acids Res. 32(Web Server issue), W280–W286.PubMedCrossRefGoogle Scholar
  48. 48.
    Mayor, C., Brudno, M., Schwartz, J. R., et al. (2000) VISTA: visualizing global DNA sequence alignments of arbitrary length. Bioinformatics 16, 1046–1047.PubMedCrossRefGoogle Scholar
  49. 49.
    Frazer, K. A., Pachter, L., Poliakov, A., Rubin, E. M., and Dubchak, I. (2004) VISTA: computational tools for comparative genomics. Nucleic Acids Res. 32(Web Server issue), W273–W279.PubMedCrossRefGoogle Scholar
  50. 50.
    Brudno, M., Steinkamp, R., and Morgenstern, B. (2004) The CHAOS/DIALIGN WWW server for multiple alignment of genomic sequences. Nucleic Acids Res. 32(Web Server issue), W41–W44.PubMedCrossRefGoogle Scholar
  51. 51.
    Morgenstern, B. (1999) DIALIGN 2: improvement of the segment-to-segment approach to multiple sequence alignment. Bioinformatics 15, 211–218.PubMedCrossRefGoogle Scholar
  52. 52.
    Ovcharenko, I., Boffelli, D., and Loots, G. G. (2004) eShadow: a tool for comparing closely related sequences. Genome Res. 14, 1191–1198.PubMedCrossRefGoogle Scholar
  53. 53.
    Cooper, G. M. and Sidow, A. (2003) Genomic regulatory regions: insights from comparative sequence analysis. Curr. Opin. Genet. Dev. 13, 604–610.PubMedCrossRefGoogle Scholar
  54. 54.
    Hardison, R. C. (2000) Conserved noncoding sequences are reliable guides to regulatory elements. Trends Genet. 16, 369–372.PubMedCrossRefGoogle Scholar
  55. 55.
    Oeltjen, J. C., Malley, T. M., Muzny, D. M., Miller, W., Gibbs, R. A., and Belmont, J. W. (1997) Large-scale comparative sequence analysis of the human and murine Bruton’s tyrosine kinase loci reveals conserved regulatory domains. Genome Res. 7, 315–329.PubMedGoogle Scholar
  56. 56.
    Brickner, A. G., Koop, B. F., Aronow, B. J., and Wiginton, D. A. (1999) Genomic sequence comparison of the human and mouse adenosine deaminase gene regions. Mamm Genome 10, 95–101.PubMedCrossRefGoogle Scholar
  57. 57.
    Lenhard, B., Sandelin, A., Mendoza, L., Engstrom, P., Jareborg, N., and Wasserman, W. W. (2003) Identification of conserved regulatory elements by comparative genome analysis. J. Biol. 2, 13.PubMedCrossRefGoogle Scholar
  58. 58.
    Suzuki, Y., Yamashita, R., Shirota, M., et al. (2004) Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions. Genome Res. 14, 1711–1718.PubMedCrossRefGoogle Scholar
  59. 59.
    Tautz, D. (2000) Evolution of transcriptional regulation. Curr. Opin. Genet. Dev. 10, 575–579.PubMedCrossRefGoogle Scholar
  60. 60.
    Thomas, J. W., Touchman, J. W., Blakesley, R. W., et al. (2003) Comparative analyses of multi-species sequences from targeted genomic regions. Nature 424, 788–793.PubMedCrossRefGoogle Scholar
  61. 61.
    Plessy, C., Dickmeis, T., Chalmel, F., and Strähle, U. (2005) Enhancer sequence conservation between vertebrates is favoured in developmental regulator genes. Trends Genet. 21, 207–210.PubMedCrossRefGoogle Scholar
  62. 62.
    Muller, F., Chang, B., Albert, S., Fischer, N., Tora, L., and Strahle, U. (1999) Intronic enhancers control expression of zebrafish sonic Hedgehog in floor plate and notochord. Development 126, 2103–2116.PubMedGoogle Scholar
  63. 63.
    Epstein, D. J., McMahon, A. P., and Joyner, A. L. (1999) Regionalization of Sonic Hedgehog transcription along the anteroposterior axis of the mouse central nervous system is regulated by Hnf3-dependent and-independent mechanisms. Development 126, 281–292.PubMedGoogle Scholar
  64. 64.
    Goode, D. K., Snell, P. K., and Elgar, G. K. (2003) Comparative analysis of vertebrate Shh genes identifies novel conserved non-coding sequence. Mamm Genome 14, 192–201.PubMedCrossRefGoogle Scholar
  65. 65.
    Adams, M. D. (2005) Conserved sequences and the evolution of gene regulatory signals. Curr. Opin. Genet. Dev. 15, 628–633.PubMedCrossRefGoogle Scholar
  66. 66.
    Osborne, C. S., Chakalova, L., Brown, K. E., et al. (2004) Active genes dynamically colocalize to shared sites of ongoing transcription. Nat. Genet. Google Scholar
  67. 67.
    Force, A., Lynch, M., Pickett, F. B., Amores, A., Yan, Y. L., and Postlethwait, J. (1999) Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151, 1531–1545.PubMedGoogle Scholar
  68. 68.
    Vavouri, T., McEwen, G. K., Woolfe, A., Gilks, W. R., and Elgar, G. (2006) Defining a genomic radius for long-range enhancer action: duplicated conserved non-coding elements hold the key. Trends Genet. 22, 5–10.PubMedCrossRefGoogle Scholar
  69. 69.
    Lettice, L. A., Heaney, S. J., Purdie, L. A., et al. (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum. Mol. Genet. 12, 1725–1735.PubMedCrossRefGoogle Scholar
  70. 70.
    Sagai, T., Hosoya, M., Mizushina, Y., Tamura, M., and Shiroishi, T. (2005) Elimination of a long-range cis-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb. Development 132, 797–803.PubMedCrossRefGoogle Scholar
  71. 71.
    Mackenzie, A., Miller, K. A., and Collinson, J. M. (2004) Is there a functional link between gene interdigitation and multi-species conservation of synteny blocks? Bioessays 26, 1217–1224.PubMedCrossRefGoogle Scholar
  72. 72.
    Flint, J., Tufarelli, C., Peden, J., et al. (2001) Comparative genome analysis delimits a chromosomal domain and identifies key regulatory elements in the alpha globin cluster. Hum. Mol. Genet. 10, 371–382.PubMedCrossRefGoogle Scholar
  73. 73.
    Halling-Brown, M., Sansom, C., Moss, D. S., Elgar, G., and Edwards, Y. J. (2004) A Fugu-Human Genome Synteny Viewer: web software for graphical display and annotation reports of synteny between Fugu genomic sequence and human genes. Nucleic Acids Res. 32, 2618–2622.PubMedCrossRefGoogle Scholar
  74. 74.
    Butler, J. E. and Kadonaga, J. T. (2002) The RNA polymerase II core promoter: a key component in the regulation of gene expression. Genes Dev. 16, 2583–2592.PubMedCrossRefGoogle Scholar
  75. 75.
    Hashimoto, S., Suzuki, Y., Kasai, Y., et al. (2004) 5′-end SAGE for the analysis of transcriptional start sites. Nat. Biotechnol. 22, 1146–1149.PubMedCrossRefGoogle Scholar
  76. 76.
    Kawaji, H., Kasukawa, T., Fukuda, S., et al. (2006) CAGE Basic/Analysis Databases: the CAGE resource for comprehensive promoter analysis. Nucleic Acids Res. 34 (Database issue), D632–D636.PubMedCrossRefGoogle Scholar
  77. 77.
    FitzGerald, P. C., Shlyakhtenko, A., Mir, A. A., and Vinson, C. (2004) Clustering of DNA sequences in human promoters. Genome Res. 14, 1562–1574.PubMedCrossRefGoogle Scholar
  78. 78.
    Kadonaga, J. T. (2002) The DPE, a core promoter element for transcription by RNA polymerase II. Exp. Mol. Med. 34, 259–264.PubMedGoogle Scholar
  79. 79.
    Kitazawa, S., Kitazawa, R., Tamada, H., and Maeda, S. (1998) Promoter structure of human sonic Hedgehog gene. Biochim. Biophys. Acta 1443, 358–363.PubMedGoogle Scholar
  80. 80.
    Chang, B. E., Blader, P., Fischer, N., Ingham, P. W., and Strahle, U. (1997) Axial (HNF3beta) and retinoic acid receptors are regulators of the zebrafish sonic Hedgehog promoter. EMBO J. 16, 3955–3964.PubMedCrossRefGoogle Scholar
  81. 81.
    Suzuki, Y., Yamashita, R., Sugano, S., and Nakai, K. (2004) DBTSS, DataBase of Transcriptional Start Sites: progress report 2004. Nucleic Acids Res. 32(Database issue), D78–D81.PubMedCrossRefGoogle Scholar
  82. 82.
    Wingender, E., Dietze, P., Karas, H., and Knuppel, R. (1996) TRANSFAC: a database on transcription factors and their DNA binding sites. Nucleic Acids Res. 24, 238–241.PubMedCrossRefGoogle Scholar
  83. 83.
    Sandelin, A., Alkema, W., Engstrom, P., Wasserman, W. W., and Lenhard, B. (2004) JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res. 32(Database issue), D91–D94.PubMedCrossRefGoogle Scholar
  84. 84.
    Arnone, M. I. and Davidson, E. H. (1997) The hardwiring of development: organization and function of genomic regulatory systems. Development 124, 1851–1864.PubMedGoogle Scholar
  85. 85.
    Markstein, M., Markstein, P., Markstein, V., and Levine, M. S. (2002) Genomewide analysis of clustered Dorsal binding sites identifies putative target genes in the Drosophila embryo. Proc. Natl Acad. Sci. USA 99, 763–768.PubMedCrossRefGoogle Scholar
  86. 86.
    Stathopoulos, A., Van Drenth, M., Erives, A., Markstein, M., and Levine, M. (2002) Whole-genome analysis of dorsal-ventral patterning in the Drosophila embryo. Cell 111, 687–701.PubMedCrossRefGoogle Scholar
  87. 87.
    Rebeiz, M., Reeves, N. L., and Posakony, J. W. (2002) SCORE: a computational approach to the identification of cis-regulatory modules and target genes in whole-genome sequence data. Site clustering over random expectation. Proc. Natl Acad. Sci. USA 99, 9888–9893.PubMedCrossRefGoogle Scholar
  88. 88.
    Berman, B. P., Nibu, Y., Pfeiffer, B. D., et al. (2002) Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome. Proc. Natl Acad. Sci. USA 99, 757–762.PubMedCrossRefGoogle Scholar
  89. 89.
    Halfon, M. S., Grad, Y., Church, G. M., and Michelson, A. M. (2002) Computation-based discovery of related transcriptional regulatory modules and motifs using an experimentally validated combinatorial model. Genome Res. 12, 1019–1028.PubMedGoogle Scholar
  90. 90.
    Erives, A. and Levine, M. (2004). Coordinate enhancers share common organizational features in the Drosophila genome. Proc. Natl Acad. Sci. USA 101, 3851–3856.PubMedCrossRefGoogle Scholar
  91. 91.
    Markstein, M., Zinzen, R., Markstein, P., et al. (2004) A regulatory code for neurogenic gene expression in the Drosophila embryo. Development 131, 2387–2394.PubMedCrossRefGoogle Scholar
  92. 92.
    Berman, B. P., Pfeiffer, B. D., Laverty, T. R., et al. (2004) Computational identification of developmental enhancers: conservation and function of transcription factor binding-site clusters in Drosophila melanogaster and Drosophila pseudoobscura. Genome Biol. 5, R61.PubMedCrossRefGoogle Scholar
  93. 93.
    Rajewsky, N., Vergassola, M., Gaul, U., and Siggia, E. D. (2002) Computational detection of genomic cis-regulatory modules applied to body patterning in the early Drosophila embryo. BMC Bioinformatics 3, 30.PubMedCrossRefGoogle Scholar
  94. 94.
    Schroeder, M. D., Pearce, M., Fak, J., et al. (2004) Transcriptional control in the segmentation gene network of Drosophila. PLoS Biol. 2, E271.PubMedCrossRefGoogle Scholar
  95. 95.
    Sinha, S., van Nimwegen, E., and Siggia, E. D. (2003) A probabilistic method to detect regulatory modules. Bioinformatics 19(Suppl 1), i292–i301.PubMedCrossRefGoogle Scholar
  96. 96.
    Sinha, S., Schroeder, M. D., Unnerstall, U., Gaul, U., and Siggia, E. D. (2004) Cross-species comparison significantly improves genome-wide prediction of cis-regulatory modules in Drosophila. BMC Bioinformatics 5, 129.PubMedCrossRefGoogle Scholar
  97. 97.
    Bigelow, H. R., Wenick, A. S., Wong, A., and Hobert, O. (2004) CisOrtho: a program pipeline for genome-wide identification of transcription factor target genes using phylogenetic footprinting. BMC Bioinformatics 5, 27.PubMedCrossRefGoogle Scholar
  98. 98.
    Senger, K., Armstrong, G. W., Rowell, W. J., Kwan, J. M., Markstein, M., and Levine, M. (2004) Immunity regulatory DNAs share common organizational features in Drosophila. Mol. Cell. 13, 19–32.PubMedCrossRefGoogle Scholar
  99. 99.
    Jegga, A. G., Sherwood, S. P., Carman, J. W., et al. (2002) Detection and visualization of compositionally similar cis-regulatory element clusters in orthologous and coordinately controlled genes. Genome Res. 12, 1408–1417.PubMedCrossRefGoogle Scholar
  100. 100.
    Loots, G. G. and Ovcharenko, I. (2004) rVISTA 2.0: evolutionary analysis of transcription factor binding sites. Nucleic Acids Res. 32 (Web Server issue), W217–W221.PubMedCrossRefGoogle Scholar
  101. 101.
    Loots, G. G., Ovcharenko, I., Pachter, L., Dubchak, I., and Rubin, E. M. (2002) rVista for comparative sequence-based discovery of functional transcription factor binding sites. Genome Res. 12, 832–839.PubMedGoogle Scholar
  102. 102.
    Berezikov, E., Guryev, V., Plasterk, R. H., and Cuppen, E. (2004) CONREAL: conserved regulatory elements anchored alignment algorithm for identification of transcription factor binding sites by phylogenetic footprinting. Genome Res. 14, 170–178.PubMedCrossRefGoogle Scholar
  103. 103.
    Wang, T. and Stormo, G. D. (2003) Combining phylogenetic data with co-regulated genes to identify regulatory motifs. Bioinformatics 19, 2369–2380.PubMedCrossRefGoogle Scholar
  104. 104.
    Liu, Y., Liu, X. S., Wei, L., Altman, R. B., and Batzoglou, S. (2004) Eukaryotic regulatory element conservation analysis and identification using comparative genomics. Genome Res. 14, 451–458.PubMedCrossRefGoogle Scholar
  105. 105.
    Blanchette, M. and Tompa, M. (2002) Discovery of regulatory elements by a computational method for phylogenetic footprinting. Genome Res. 12, 739–748.PubMedCrossRefGoogle Scholar
  106. 106.
    Kent, W. J. and Zahler, A. M. (2000) Conservation, regulation, synteny, and introns in a large-scale C. briggsae-C. elegans genomic alignment. Genome Res. 10, 1115–1125.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2007

Authors and Affiliations

  • Ferenc Müller
    • 1
  • Anne-Gaelle Borycki
    • 2
  1. 1.Institute of Toxicology and Genetics, ForschungszentrumKarlsruheGermany
  2. 2.Department of Biomedical ScienceUniversity of Sheffield, Centre for Developmental GeneticsSheffieldUK

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