Skip to main content
SpringerLink
Log in
Book cover

Annual International Conference on Research in Computational Molecular Biology

RECOMB 2008: Research in Computational Molecular Biology pp 372–395Cite as

Bubbles: Alternative Splicing Events of Arbitrary Dimension in Splicing Graphs

  • Conference paper

Part of the book series: Lecture Notes in Computer Science ((LNBI,volume 4955))

Abstract

Eukaryotic splicing structures are known to involve a high degree of alternative forms derived from a premature transcript by alternative splicing (AS). With the advent of new sequencing technologies, evidence for new splice forms becomes more and more easily available—bit by bit revealing that the true splicing diversity of “AS events” often comprises more than two alternatives and therefore cannot be sufficiently described by pairwise comparisons as conducted in analyzes hitherto. Further challenges emerge from the richness of data (millions of transcripts) and artifacts introduced during the technical process of obtaining transcript sequences (noise)—especially when dealing with single-read sequences known as expressed sequence tags (ESTs). We describe a novel method to efficiently predict AS events in different resolutions (i.e., dimensions) from transcript annotations that allows for combination of fragmented EST data with full-length cDNAs and can cope with large datasets containing noise. Applying this method to estimate the real complexity of alternative splicing, we found in human thousands of novel AS events that either have been disregarded or mischaracterized in earlier works. In fact, the majority of exons that are observed as “mutually exclusive” in pairwise comparisons truly involve at least one other alternative splice form that disagrees with their mutual exclusion. We identified four major classes that contain such “optional” neighboring exons and show that they clearly differ from each other in characteristics, especially in the length distribution of the middle intron.

General Terms: Alternative Splicing, ESTs, New Sequencing Technologies, Algorithms, Graph Theory.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. The human sequencing consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001)

    Google Scholar 

  2. Smith, C.W., Valcarcel, J.: Alternative pre-mrna splicing: the logic of combinatorial control. Annu. Rev. Genet. 25, 381–388 (2000)

    Google Scholar 

  3. Lopez, A.J.: Alternative splicing of pre-mrna: developmental consequences and mechanisms of regulation. Annu. Rev. Genet. 32, 279–305 (1998)

    Article  Google Scholar 

  4. Kuyumcu-Martinez, N.M., Cooper, T.A.: Mis-regulation of alternative splicing causes pathogenesis in myotonic dystrophy. Prog. Mol. Subcell. Biol. 44, 133–159 (2006)

    Article  Google Scholar 

  5. Stamm, S., Riethoven, J.J., Le Texier, V., Gopalakrishnan, C., Kumanduri, V., Tang, Y., Barbosa-Morais, N.L., Thanaraj, T.A.: ASD: A bioinformatics resource on alternative splicing. Nucleic Acids Res. 34, D46–55 (2006)

    Article  Google Scholar 

  6. Le Texier, V., Riethoven, J.J., Kumanduri, V., Gopalakrishnan, C., Lopez, F., Gautheret, D., Thanaraj, T.A.: AltTrans: Transcript pattern variants annotated for both alternative splicing and alternative polyadenylation. BMC Bioinformatics 7, 169 (2006)

    Article  Google Scholar 

  7. Dralyuk, I., Brudno, M., Gelfand, M.S., Zorn, M., Dubchak, I.: ASDB: Database of alternatively spliced genes. BMC Bioinformatics 28, 296–297 (2000)

    Google Scholar 

  8. Holste, D., Huo, G., Tung, V., Burge, C.B.: HOLLYWOOD: a comparative relational database of alternative splicing. Nucleic Acids Res. 34, D56–62 (2006)

    Article  Google Scholar 

  9. Zhou, Y., Zhou, C., Ye, L., Dong, J., Xu, H., Cai, L., Zhang, L., Wei, L.: Database and analyses of known alternatively spliced genes in plants. Genomics 82, 584–595 (2003)

    Article  Google Scholar 

  10. Coward, E., Haas, S., Vingron, M.: SpliceNest: visualizing gene structure and alternative splicing based on EST clusters. Trends in Genetics 18, 53–55 (2002)

    Article  Google Scholar 

  11. Huang, Y.H., Chen, Y.T., Lai, J.J., Yang, S.T., Yang, U.C.: PALS dbç: Putative alternative splicing database. Nucleic Acids Res. 30, 186–190 (2002)

    Article  Google Scholar 

  12. Burset, M., Seledtsov, I.A., Solovyev, V.V.: SpliceDB: database of canonical and non-canonical mammalian splice sites. Nucleic Acids Res. 29, 255–259 (2001)

    Article  Google Scholar 

  13. Ji, H., Zhou, Q., Wen, F., Xia, H., Lu, X., Li, Y.: AsMamDB: An alternative splice database of mammals. Nucleic Acids Res. 29, 260–263 (2001)

    Article  Google Scholar 

  14. Modrek, B., Resch, A., Grasso, C., Lee, C.: Genome-wide analysis of alternative splicing using human expressed sequence data. Nucleic Acids Res. 29, 2850–2859 (2001)

    Article  Google Scholar 

  15. Huang, H.D., Horng, J.T., Lee, C.C., Liu, B.J.: Prosplicer: A database of putative alternative splicing information derived from protein, mrna and expressed sequence tag sequence data. Genome Biol. 4, R29 (2003)

    Article  Google Scholar 

  16. Bhasi, A., Pandey, R.V., Utharasamy, S.P., Senapathy, P.: ASD: a bioinformatics resource on alternative splicing. Boinformatics 23, 1815–1823 (2007)

    Article  Google Scholar 

  17. Nagasaki, H., Arita, M., Nishizawa, T., Suwa, M., Gotoh, O.: Species-specific variation of alternative splicing and transcriptional initiation in six eukaryotes. Gene 364, 53–62 (2005)

    Article  Google Scholar 

  18. Kim, E., Magen, A., Ast, G.: Different levels of alternative splicing among eukaryotes. Nucleic Acids Res. 35, 125–131 (2007)

    Article  Google Scholar 

  19. Yandell, M., Mungall, C.J., Smith, C., Prochnik, S., Kaminker, J., Hartzell, G., Lewis, G.M., Rubin, S.: Large-scale trends in the evolution of gene structures within 11 animal genomes. PLoS Comput. Biol., vol. 2, p. 15 (2006)

    Google Scholar 

  20. Grasso, C., Modrek, B., Xing, Y., Lee, C.: Genome-wide detection of alternative splicing in expressed sequences using partial order multiple sequence alignment graphs. In: Pac. Symp. Biocomput., pp. 29–41 (2004)

    Google Scholar 

  21. Zavolan, M., van Nimwegen, E.: The types and prevalence of alternative splice forms. Curr. Opin. Struct. Biol. 16, 1–6 (2006)

    Article  Google Scholar 

  22. Florea, L., Hartzell, G., Zhang, Z., Rubin, G.M., Miller, W.: A computer program for aligning a cDNA sequence with a genomic DNA sequence. Genome Res. 8, 967–974 (1998)

    Google Scholar 

  23. Kent, W.J.: BLAT - the blast-like alignment tool. Genome Res. 12, 656–664 (2002)

    Article  MathSciNet  Google Scholar 

  24. Bonizzoni, P., Rizzi, R., Pesole, G.: ASPIC: a novel method to predict the exon-intron structure of a gene that is optimally compatible to a set of transcript sequences. BMC Bioinformatics 6, 244 (2005)

    Article  Google Scholar 

  25. Pruitt, K.D., Tatusova, T., Maglott, D.R.: NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 35, D61–D65 (2007)

    Article  Google Scholar 

  26. Benson, D.A., Karsch-Mizrachi, I., Lipman, D.J., Ostell, J., Wheeler, D.L.: GenBank. Nucleic Acids Res. 35, D21–D25 (2007)

    Article  Google Scholar 

  27. Weber, A.P., Weber, K.L., Carr, K., C.,, Wilkerson, O.J.B.: Sampling the arabidopsis transcriptome with massively parallel pyrosequencing. Plant Physiol. 144, 32–42 (2007)

    Article  Google Scholar 

  28. Ruan, Y., Ooi, H.S., Choo, S.W., Chiu, K.P., Zhao, X.D., Srinivasan, K.G., Yao, F., Choo, C.Y., Liu, J., Ariyaratne, P., Bin, W.G.W., Kuznetsov, V.A., Shahab, A., Sung, W.-K., Bourque, G., Palanisamy, N., Wei, C.-L.: Fusion transcripts and transcribed retrotransposed loci discovered through comprehensive transcriptome analysis using paired-end ditags (pets). Genome Res. 17, 828–838 (2007)

    Article  Google Scholar 

  29. Sugnet, C.W., Kent, W.J., Ares, M., Haussler, D.: Transcriptome and genome conservation of alternative splicing events in humans and mice. In: Pac. Symp. Biocomput., pp. 66–77 (2004)

    Google Scholar 

  30. Heber, S., Alekseyev, M., Sing-Hoi, S., Pevzner, P.: Splicng graphs and EST assembly problem. Bioinformatics 18, 181–188 (2002)

    Google Scholar 

  31. Gusfield, D., Bansal, V.: A fundamental decomposition theorem for phylogenetic networks and incompatible characters. In: Miyano, S., Mesirov, J., Kasif, S., Istrail, S., Pevzner, P.A., Waterman, M. (eds.) RECOMB 2005. LNCS (LNBI), vol. 3500, pp. 217–232. Springer, Heidelberg (2005)

    Google Scholar 

  32. Gusfield, D., Eddhu, S., Langley, C.: Optimal, efficient reconstruction of phylogenetic networks with constrained recombination. J. Bioinformatics and Computational Biology 2, 173–213 (2004)

    Article  Google Scholar 

  33. University of California Santa Cruz (UCSC) Genome Browser, http://genome.ucsc.edu

  34. Boguski, M.S., Lowe, T.M., Tolstoshev, C.M.: dbEST–database for ”expressed sequence tags. Nat. Genet. 4, 332–333 (1993)

    Article  Google Scholar 

  35. Human Genome Sequencing Consortium, http://genome.ucsc.edu/goldenPath/labs.html

  36. Mouse Genome Sequencing Consortium, http://www.ensembl.org/Mus_musculus/credits.html

  37. R Development Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria (2007) ISBN 3-900051-07-0

    Google Scholar 

  38. Smith, C.W., Nadal-Ginard, B.: Mutually exclusive splicing of alpha-tropomyosin exons enforced by an unusual lariat branch point location: implications for constitutive splicing. Cell 56, 749–758 (1989)

    Article  Google Scholar 

  39. Zhuang, Y., Leung, H., Weiner, A.M.: The natural 5’ splice site of simian virus 40 large t antigen can be improved by increasing the base complementarity to u1 rna. Mol. Cell Biol. 7, 3018–3020 (1987)

    Google Scholar 

  40. Kuo, H.C., Nasim, F.H., Grabowski, P.J.: Control of alternative splicing by the differential binding of u1 small nuclear ribonucleoprotein particle. Science 251, 1045–1050 (1991)

    Article  Google Scholar 

  41. Mullen, M.P., Smith, C.W.J., Patton, J.G., Nadal-Girnard, B.: α-tropomyosin mutually exclusive exon selection: competition between branchpoint/polypyrimidine tracts determines default exon choice. Genes Dev. 5, 642–655 (1991)

    Article  Google Scholar 

  42. Fu, X.Y., Ge, H., Manley, J.L.: In vitro splicing of mutually exclusive exons from the chicken β-tropomyosin gene: role of the branch point location and very long pyrimidine stretch. EMBO J. 7, 809–817 (1988)

    Google Scholar 

  43. Noble, J.C., Pan, Z.Q., Prives, C., Manley, J.L.: Splicing of sv40 early pre-mrna to large t and small t mrnas utilizes different patterns of lariat branch sites. Cell 27, 227–236 (1987)

    Article  Google Scholar 

  44. Noble, J.C., Prives, C., Manley, J.L.: Alternative splicing of sv40 early pre-mrna is determined by branch site selection. Genes Dev. 2, 1460–1475 (1988)

    Article  Google Scholar 

  45. Gattoni, R., Schmitt, P., Stevenin, J.: In vitro splicing of adenovirus e1a transcripts: characterization of novel reactions and of multiple branch points abnormally far from the 3’ splice site. Nucleic Acids Res. 16, 2389–2409 (1988)

    Article  Google Scholar 

  46. Helfman, D.M., Ricci, W.M.: Branch point selection in alternative splicing of tropomyosin pre-mrnas. Nucleic Acids Res. 17, 5633–5650 (1989)

    Article  Google Scholar 

  47. Goux-Pelletan, M., Libri, D., d’Aubenton-Carafa, Y., Fiszman, M., Brody, E., Marie, J.: In vitro splicing of mutually exclusive exons from the chicken β-tropomyosin gene: role of the branch point location and very long pyrimidine stretch. EMBO J. 9, 241–249 (1990)

    Google Scholar 

  48. Helfman, D.M., Roscigno, R.F., Mulligan, G.J., Finn, L.A., Weber, K.S.: Identification of two distinct intron elements involved in alternative splicing of the β-tropomyosin pre-mRNA. Genes Dev. 4, 98–110 (1990)

    Article  Google Scholar 

  49. Reed, R., Maniatis, T.: The role of the mammalian branchpoint sequence in pre-mrna splicing. Genes Dev. 2, 1268–1276 (1988)

    Article  Google Scholar 

  50. Zhuang, Y.A., Goldstein, A.M., Weiner, A.M.: Uacuaac is the preferred branch site for mammalian mrna splicing. Proc. Natl. Acad. Sci. USA 86, 2752–2756 (1989)

    Article  Google Scholar 

  51. Libri, D., Goux-Pelletan, M., Brody, E., Fiszman, M.Y.: Exon as well as intron sequences are cis-regulating elements for the mutually exclusive alternative splicing of the β tropomyosin gene. Mol. Cell Biol. 10, 5036–5046 (1990)

    Google Scholar 

  52. Reed, R., Maniatis, T.: A role for exon sequences and splice-site proximity in splice-site selection. Cell 46, 681–690 (1986)

    Article  Google Scholar 

  53. Mardon, H.J., Sebastio, G., Baralle, F.E.: A role for exon sequences in alternative splicing of the human fibronectin gene. Nucleic Acids Res. 15, 7725–7733 (1987)

    Article  Google Scholar 

  54. Somasekhar, M.B., Mertz, J.E.: Exon mutations that affect the choice of splice sites used in processing the sv40 late transcripts. Nucleic Acids Res. 13, 5591–5609 (1985)

    Article  Google Scholar 

  55. Helfman, D.M., Ricci, W.M., Finn, L.A.: Alternative splicing of tropomyosin pre-mrnas in vitro and in vivo. Genes Dev. 2, 1627–1638 (1988)

    Article  Google Scholar 

  56. Cooper, T.A., Ordahl, C.P.: Nucleotide substitutions within the cardiac troponin t alternative exon disrupt pre-mrna alternative splicing. Nucleic Acids Res. 17, 7905–7921 (1989)

    Article  Google Scholar 

  57. Hampson, R.K., La Follette, L., Rottman, F.M.: Alternative processing of bovine growth hormone mRNA is influenced by downstream exon sequences. Mol. Cell Biol. 9, 1604–1610 (1989)

    Google Scholar 

  58. Streuli, M., Saito, H.: Regulation of tissue-specific alternative splicing: exon-specific cis-elements govern the splicing of leukocyte common antigen pre-mRNA. EMBO J. 8, 787–796 (1989)

    Google Scholar 

  59. Black, D.L.: Does steric interference between splice sites block the splicing of a short c-src neuron-specific exon in non-neuronal cells? Genes Dev. 5, 389–402 (1991)

    Article  Google Scholar 

  60. Libri, D., Piseri, A., Fiszman, M.Y.: Exon as well as intron sequences are cis-regulating elements for the mutually exclusive alternative splicing of the β tropomyosin gene. Science 252, 1842–1845 (1991)

    Article  Google Scholar 

  61. Ge, H., Manley, J.L.: A protein factor, asf, controls cell-specific alternative splicing of sv40 early pre-mrna in vitro. cell 13, 25–34 (1990)

    Article  Google Scholar 

  62. Krainer, A.R., Conway, G.C., Kozak, D.: The essential pre-mrna splicing factor sf2 influences 5’ splice site selection by activating proximal sites. Cell 13, 35–42 (1990)

    Article  Google Scholar 

  63. Foissac, S., Sammeth, M.: Astalavista: dynamic and flexible analysis of alternative splicing events in custom gene datasets. Nucleic Acids Res. 35, W297–W299 (2007)

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Genome Bioinformatics Lab, Center for Genomic Regulation, E-08003, Barcelona,  

    Michael Sammeth & Roderic Guigó

  2. Algorithms, Bioinformatics, Complexity and Formal Methods Research Group, Technical University of Catalonia, E-08034, Barcelona,  

    Gabriel Valiente

Authors
  1. Michael Sammeth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriel Valiente
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roderic Guigó
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Martin Vingron Limsoon Wong

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Sammeth, M., Valiente, G., Guigó, R. (2008). Bubbles: Alternative Splicing Events of Arbitrary Dimension in Splicing Graphs. In: Vingron, M., Wong, L. (eds) Research in Computational Molecular Biology. RECOMB 2008. Lecture Notes in Computer Science(), vol 4955. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-78839-3_32

Download citation

  • DOI: https://doi.org/10.1007/978-3-540-78839-3_32

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-78838-6

  • Online ISBN: 978-3-540-78839-3

  • eBook Packages: Computer ScienceComputer Science (R0)

Publish with us

Policies and ethics

Search

Navigation