Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

A genomic view of alternative splicing

Nature Genetics volume 30, pages 13–19 (2002)Cite this article

Abstract

Recent genome-wide analyses of alternative splicing indicate that 40–60% of human genes have alternative splice forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Here we review these recent results from bioinformatics studies, assess their reliability and consider the impact of alternative splicing on biological functions. Although the 'big picture' of alternative splicing that is emerging from genomics is exciting, there are many challenges. High-throughput experimental verification of alternative splice forms, functional characterization, and regulation of alternative splicing are key directions for research. We recommend a community-based effort to discover and characterize alternative splice forms comprehensively throughout the human genome.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Computational identification of alternative splicing.
Figure 2: Types of alternative splicing and possible effects on protein.
Figure 3: Experimental analysis of alternative splicing.
Figure 4: Cooperative roles for bioinformatics and experimentation in an alternative splicing annotation project (ASAP).

Similar content being viewed by others

References

  1. Pennisi, E. Human genome project: and the gene number is...? Science 288, 1146–1147 (2000).

    Article  CAS  Google Scholar 

  2. Adams, M.D. et al. The genome sequence of Drosophila melanogaster. Science 287, 2185–2195 (2000).

    Article  Google Scholar 

  3. The C. elegans Sequencing Consortium. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282, 2012–2018 (1998).

  4. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

  5. Venter, J.C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    Article  CAS  Google Scholar 

  6. Sambrook, J. Adenovirus amazes at Cold Spring Harbor. Nature 268, 101–104 (1977).

    Article  CAS  Google Scholar 

  7. Gilbert, W. Why genes in pieces? Nature 271, 501 (1978).

    Article  CAS  Google Scholar 

  8. Early, P. et al. Two mRNAs can be produced from a single immunoglobulin m gene by alternative RNA processing pathways. Cell 20, 313–319 (1980).

    Article  CAS  Google Scholar 

  9. Rosenfeld, M.G. et al. Calcitonin mRNA polymorphism: peptide switching associated with alternative RNA splicing events. Proc. Natl Acad. Sci. USA 79, 1717–1721 (1982).

    Article  CAS  Google Scholar 

  10. Sharp, P.A. Split genes and RNA splicing. Cell 77, 805–815 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Boise, L.H. et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74, 597–608 (1993).

    Article  CAS  Google Scholar 

  13. Smith, C.W.J. & Valcarcel, J. Alternative pre-mRNA splicing: the logic of combinatorial control. Trends. Biochem. Sci. 25, 381–388 (2000).

    Article  CAS  Google Scholar 

  14. Mironov, A.A., Fickett, J.W. & Gelfand, M.S. Frequent alternative splicing of human genes. Genome Res. 9, 1288–1293 (1999).

    Article  CAS  Google Scholar 

  15. Croft, L. et al. ISIS, the intron information system, reveals the high frequency of alternative splicing in the human genome. Nature Genet. 24, 340–341 (2000).

    Article  CAS  Google Scholar 

  16. Brett, D. et al. EST comparison indicates 38% of human mRNAs contain possible alternative splice forms. FEBS Lett. 474, 83–86 (2000).

    Article  CAS  Google Scholar 

  17. Kan, Z., Rouchka, E.C., Gish, W.R. & States, D.J. Gene structure prediction and alternative splicing analysis using genomically aligned ESTs. Genome Res. 11, 889–900 (2001).

    Article  CAS  Google Scholar 

  18. 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  CAS  Google Scholar 

  19. Burset, M., Seledtsov, I.A. & Solovyev, V.V. Analysis of canonical and non-canonical splice sites in mammalian genomes. Nucleic Acids Res. 28, 4364–4375 (2000).

    Article  CAS  Google Scholar 

  20. Beaudoing, E., Freier, S., Wyatt, J.R., Claverie, J. & Gautheret, D. Patterns of variant polyadenylation signal usage in human genes. Genome Res. 10, 1001–1010 (2000).

    Article  CAS  Google Scholar 

  21. Graveley, B.R. Alternative splicing: increasing diversity in the proteomic world. Trends Genet. 17, 100–107 (2001).

    Article  CAS  Google Scholar 

  22. Wheeler, D.L. et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 28, 10–14 (2000).

    Article  CAS  Google Scholar 

  23. Burke, J., Wang, H., Hide, W. & Davison, D.B. Alternative gene form discovery and candidate gene selection from gene indexing projects. Genome Res. 8, 276–290 (1998).

    Article  CAS  Google Scholar 

  24. Shoemaker, D.D. et al. Experimental annotation of the human genome using microarray technology. Nature 409, 922–927 (2001).

    Article  CAS  Google Scholar 

  25. Hu, G.K. et al. Predicting splice variant from DNA chip expression data. Genome Res. 11, 1237–1245 (2001).

    Article  CAS  Google Scholar 

  26. Krawzczak, M., Reiss, J. & Cooper, D.N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum. Genet. 90, 41–54 (1992).

    Google Scholar 

  27. Liu, H.X., Cartegni, L., Zhang, M.Q. & Krainer, A.R. A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nature Genet. 27, 55–58 (2001).

    Article  CAS  Google Scholar 

  28. Stamm, S., Zhang, M.Q., Marr, T.G. & Helfman, D.M. A sequence compilation and comparison of exons that are alternatively spliced in neurons. Nucleic Acids Res. 22, 1515–1526 (1994).

    Article  CAS  Google Scholar 

  29. Kent, W.J. & Zahler, A.M. Conservation, regulation, synteny, and introns in a large-scale C. briggsae–C. elegans genomic alignment. Genome Res. 10, 1115–1125 (2000).

    Article  CAS  Google Scholar 

  30. Stamm, S. et al. An alternative-exon database and its statistical analysis. DNA Cell Biol. 19, 739–756 (2000).

    Article  CAS  Google Scholar 

  31. Brudno, M. et al. Computational analysis of candidate intron regulatory elements for tissue-specific alternative pre-mRNA splicing. Nucleic Acids Res. 29, 2338–2348 (2001).

    Article  CAS  Google Scholar 

  32. Modafferi, E.F. & Black, D.L. A complex intronic splicing enhancer from the c-src pre-mRNA activates inclusion of a heterologous exon. Mol. Cell. Biol. 17, 6537–6545 (1997).

    Article  CAS  Google Scholar 

  33. Huh, G.S. & Hynes, R.O. Regulation of alternative pre-mRNA splicing by a novel repeated hexanucleotide element. Genes Dev. 8, 1561–1574 (1994).

    Article  CAS  Google Scholar 

  34. Hedjran, F., Yeakley, J.M., Huh, G.S., Hynes, R.O. & Rosenfeld, M.G. Control of alternative pre-mRNA splicing by distributed pentameric repeats. Proc. Natl Acad. Sci. USA 94, 12343–12347 (1997).

    Article  CAS  Google Scholar 

  35. Kawamoto, S. Neuron-specific alternative splicing of nonmuscle myosin II heavy chain-B pre-mRNA requires a cis-acting intron sequence. J. Biol. Chem. 271, 17613–17616 (1996).

    CAS  Google Scholar 

  36. Dralyuk, I., Brudno, M., Gelfand, M.S., Zorn, M. & Dubchak, I. ASDB: database of alternatively spliced genes. Nucleic Acids Res. 28, 296–297 (2000).

    Article  CAS  Google Scholar 

  37. Ji, H. et al. AsMamDB: an alternative splice database of mammals. Nucleic Acids Res. 29, 260–263 (2001).

    Article  CAS  Google Scholar 

  38. Spingola, M., Grate, L., Haussler, D. & Ares, M.J. Genome-wide bioinformatic and molecular analysis of introns in Saccharomyces cervisiae. RNA 5, 221–234 (1999).

    Article  CAS  Google Scholar 

  39. Kent, W.J. & Zahler, A.M. The intronerator: exploring introns and alternative splicing in Caenorhabditis elegans. Nucleic Acids Res. 28, 91–93 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to D. Black, S. Galbraith and K. Ke for their critical comments and suggestions. C.L. was supported by a grant from the Department of Energy. B.M. was supported by National Science Foundation Integrative Graduate Education and Research Training award.

Author information

Authors and Affiliations

  1. Departments of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, 90095-1570, California, USA

    Barmak Modrek & Christopher Lee

Authors
  1. Barmak Modrek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Modrek, B., Lee, C. A genomic view of alternative splicing. Nat Genet 30, 13–19 (2002). https://doi.org/10.1038/ng0102-13

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0102-13

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing