Alternative Splicing Database EC Project

Introduction

Humans have fewer genes than previously anticipated. Since humans contain not many more genes than for example fruit flies, they have to use other mechanisms to create their large transcriptome and proteome. Alternative splicing in the processing of pre-mRNA is such a mechanism. ASD aims to analyse this mechanism on a genome-wide scale by creating a database that contains all alternatively spliced exons from human, and other model species. Disease causing mutations seem to induce aberrations in the process of splicing and its regulation. The ASD consortium will develop a DNA microarray (chip) that contains cDNAs of all the splicing regulatory proteins and their isoforms, as well as a chip that contains a number of disease relevant genes. We will concentrate on three models of disease (breast cancer, FTDP-17, male infertility) in which a connection between mis-splicing and a pathological state has been observed. Finally, these chips will be developed as demonstrative kits to detect predisposition for and diagnosis of such diseases.

Products

Work package overview
(click to enlarge)

• a human curated database of alternative spliced genes and their properties¹⁾
• a computer generated database of alternatively spliced genes and their properties²⁾
• the integration of the above and newly found knowledge in a user-friendly interface and research workbench for both bioinformaticists and biologists
• DNA chips that are based on the data in the above databases
• the DNA chips will be used to test against predisposition for and diagnoses of human diseases

Current Status

Members of the ASD Consortium

Funding

The ASD consortium is extremely grateful to the EU for funding ASD under its Fifth Framework Programme (FP5) - "Quality of Life and living resources" (QoL) section. The EU proposal number for ASD is QLRT-2001-02062.

Services

Publications resulting from this project

• Thanaraj, T.A., Stamm, S., Clark, F., Riethoven, J.J., Le-Texier, V. and Muilu, J. (2004) ASD: the Alternative Splicing Database. Nucleic Acids Res 32: D64-D69.
• Thanaraj, T.A., Cochet, O. and Stamm, S. (2003) Misregulation of alternative splicing as a novel target for drug intervention. Pharm. Visions, 2, 4-6.
• Tang, Y., Novoyatleva , T., Benderska, N., Kishore, S., Thanaraj, T.A. and Stamm, S. (2004) Analysis of alternative splicing in vivo using minigenes. In Westhof, Bindereif, Schön and Hartmann (eds.), Handbook of RNA Biochemistry. Wiley-VCH.
• Boue S, Letunic I, Bork P. Alternative splicing and evolution. Bioessays. 2003 Nov;25(11):1031-4
• Thanaraj, T.A., Clark, F. and Muilu, J. (2003) Conservation of human alternative splice events in mouse. Nucleic Acids Res, 31, 2544-52.
• Wang, J., Gao, Q.-S., Wang, Y., Lafyatis, R., Stamm, S. and Andreadis, A. (2004) Tau Exon 10, Whose Missplicing Causes Frontotemporal Dementia, is Regulated by an Intricate Interplay of Cis Elements and Trans Factors. J.Neurochem., in press.
• Chava Perry, Ella H. Sklan and Hermona Soreq (2004) CREB regulates AChE-R-induced proliferation of human glioblastoma cells. Neoplasia, in press
• Stoilov, P., Daoud, R., Nayler, O. and Stamm, S. (2004) Human tra2-beta1 autoregulates its protein concentration by binding to novel exonic enhancers of its exon 2. Hum Mol Genet, in press.

References

• "Categorisation and characterization of transcript-confirmed constitutively and alternatively spliced introns and exons from human", Clark, F. and T. A. Thanaraj. Human Molecular Genetics 11:451-464 (2002).
• "Pre-mRNA splicing modulations in senescence", Meshorer, E. and H. Soreq. Aging Cell 1:10-16 (2002). [link]
• "Signals and their transduction pathways regulating alternative splicing: a new dimension of the human genome", Stamm, S. Hum. Mol. Genet., 11, 2409-2416 (2002).
• "Prediction and statistical analysis of alternatively spliced exons", Thanaraj, T.A. & S. Stamm. Progress in Molecular and Subcellular Biology: Vol. 31., 1-31. (2002).
• "GC-AG alternative intron isoforms with weak donor sites show enhanced consensus at acceptor exon positions", Thanaraj, T.A., and F. Clark. Nucleic Acids Research, 29:2581-2593 (2001).
• "Htra2-beta1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2)", Hofmann, Y., C.L. Lorson, S. Stamm, E.J. Androphy, and B. Wirth. Proc. Natl.Acad. Sci. USA, 97:9618-9623 (2000).
• "An alternative exon database and its statistical analysis", Stamm, S., J. Zhu, K. Nakai, P. Stoilov, O. Stoss, and M.Q. Zhang. DNA and Cell Biol., 19: 739-756 (2000).

Project Contacts