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Mapping Association between Long-Range Cis-Regulatory Regions and Their Target Genes Using Comparative Genomics

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Comparative Genomics (RECOMB-CG 2010)

Part of the book series: Lecture Notes in Computer Science ((LNBI,volume 6398))

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Abstract

In chordates, long-range cis-regulatory regions are involved in the control of transcription initiation (either as repressors or enhancers). They can be located as far as 1 Mb from the transcription start site of the target gene and can regulate more than one gene. Therefore, proper characterization of functional interactions between long-range cis-regulatory regions and their target genes remains problematic. We present a novel method to predict such interactions based on the analysis of rearrangements between the human and 16 other vertebrate genomes. Our method is based on the assumption that genome rearrangements that would disrupt the functional interaction between a cis-regulatory region and its target gene are likely to be deleterious. Therefore, conservation of synteny through evolution would be an indication of a functional interaction. We use our algorithm to classify a set of 1,406,084 putative associations from the human genome. This genome-wide map of interactions has many potential applications, including the selection of candidate regions prior to in vivo experimental characterization, a better characterization of regulatory regions involved in position effect diseases, and an improved understanding of the mechanisms and importance of long-range regulation.

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References

  1. Leipoldt, M., Erdel, M., Bien-Willner, G.A., et al.: Two novel translocation breakpoints upstream of sox9 define borders of the proximal and distal breakpoint cluster region in campomelic dysplasia. Clin. Genet. 71, 67–75 (2007)

    Article  CAS  PubMed  Google Scholar 

  2. Lettice, L.A., Heaney, S.J.H., Purdie, L.A., Li, L., de Beer, P., et al.: 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 (2003)

    Article  CAS  PubMed  Google Scholar 

  3. Blanchette, M., Kent, W., Riemer, C., Elnitski, L., Smit, A., et al.: Aligning multiple genomic sequences with the threaded blockset aligner. Genome Res. 14, 708–715 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Paten, B., Herrero, J., Beal, K., Fitzgerald, S., Birney, E.: Enredo and pecan: genome-wide mammalian consistency-based multiple alignment with paralogs. Genome Res. 18, 1814–1828 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Siepel, A., Bejerano, G., Pedersen, J., Hinrichs, A., Hou, M., et al.: Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034–1050 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pennacchio, L.A., Ahituv, N., Moses, A., Prabhakar, S., et al.: In vivo enhancer analysis of human conserved non-coding sequences. Nature 444, 499–502 (2006)

    Article  CAS  PubMed  Google Scholar 

  7. Pevzner, P., Tesler, G.: Human and mouse genomic sequences reveal extensive breakpoint reuse in mammalian evolution. Proc. Natl. Acad. Sci. USA 100, 7672–7677 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Peng, Q., Pevzner, P.A., Tesler, G.: The fragile breakage versus random breakage models of chromosome evolution. PLoS Comput. Biol. 2, e14 (2006)

    Google Scholar 

  9. Nadeau, J.H., Taylor, B.: A Lengths of chromosomal segments conserved since divergence of man and mouse. Proc. Natl. Acad. Sci. USA 81, 814–818 (1984)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mongin, E., Dewar, K., Blanchette, M.: Long-range regulation is a major driving force in maintaining genome integrity. BMC Evol. Biol. 9, 203 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  11. Larkin, D.M., Pape, G., Donthu, R., Auvil, L., Welge, M., et al.: Breakpoint regions and homologous synteny blocks in chromosomes have different evolutionary histories. Genome Res. 19, 770–777 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Flint, J., Tufarelli, C., Peden, J., Clark, K., Daniels, R.J., et al.: Comparative genome analysis delimits a chromosomal domain and identifies key regulatory elements in the alpha globin cluster. Hum. Mol. Genet. 10, 371–382 (2001)

    Article  CAS  PubMed  Google Scholar 

  13. Ahituv, N., Prabhakar, S., Poulin, F., Rubin, E.M., Couronne, O.: Mapping cis-regulatory domains in the human genome using multi-species conservation of synteny. Hum. Mol. Genet. 14, 3057–3063 (2005)

    Article  CAS  PubMed  Google Scholar 

  14. Sun, H., Skogerbø, G., Wang, Z., Liu, W., Li, Y.: Structural relationships between highly conserved elements and genes in vertebrate genomes. PLoS ONE 3, e3727 (2008)

    Google Scholar 

  15. Vavouri, T., McEwen, G.K., Woolfe, A., Gilks, W.R., Elgar, G.: Defining a genomic radius for long-range enhancer action: duplicated conserved non-coding elements hold the key. Trends Genet. 22, 5–10 (2006)

    Article  CAS  PubMed  Google Scholar 

  16. Dong, X., Fredman, D., Lenhard, B.: Synorth: exploring the evolution of synteny and long-range regulatory interactions in vertebrate genomes. Genome Biology 10, R86 (2009)

    Google Scholar 

  17. Hubbard, T.J.P., Aken, B.L., Ayling, S., Ballester, B., Beal, K., et al.: Ensembl. Nucleic Acids Res. 37, D690–D697 (2009)

    Google Scholar 

  18. Miller, W., Rosenbloom, K., Hardison, R.C., Hou, M., Taylor, J., et al.: 28-way vertebrate alignment and conservation track in the ucsc genome browser. Genome Res. 17, 1797–1808 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kent, W.J., Sugnet, C.W., Furey, T.S., Roskin, K.M., Pringle, T.H., et al.: The human genome browser at ucsc. Genome Res. 12, 996–1006 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fitch, W.M., Margoliash, E.: Construction of phylogenetic trees. Science 155, 279–284 (1967)

    Article  CAS  PubMed  Google Scholar 

  21. Al-Shahrour, F., Carbonell, J., Minguez, P., Goetz, S., Conesa, A., et al.: Babelomics: advanced functional profiling of transcriptomics, proteomics and genomics experiments. Nucleic Acids Res. 36, 341–346 (2008)

    Article  Google Scholar 

  22. Howard, M.L., Davidson, E.H.: cis-regulatory control circuits in development. Dev. Biol. 271, 109–118 (2004)

    Article  CAS  PubMed  Google Scholar 

  23. Ovcharenko, I., Loots, G.G., Nobrega, M.A., Hardison, R.C., Miller, W., et al.: Evolution and functional classification of vertebrate gene deserts. Genome Res. 15, 137–145 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bernstein, B.E., Kamal, M., Lindblad-Toh, K., Bekiranov, S., Bailey, D.K., et al.: Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181 (2005)

    Article  CAS  PubMed  Google Scholar 

  25. Mikkelsen, T.S., Ku, M., Jaffe, D.B., Issac, B., Lieberman, E., et al.: Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Mongin, E., Dewar, K., Blanchette, M. (2010). Mapping Association between Long-Range Cis-Regulatory Regions and Their Target Genes Using Comparative Genomics. In: Tannier, E. (eds) Comparative Genomics. RECOMB-CG 2010. Lecture Notes in Computer Science(), vol 6398. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-16181-0_18

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  • DOI: https://doi.org/10.1007/978-3-642-16181-0_18

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-16180-3

  • Online ISBN: 978-3-642-16181-0

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