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Nucleic Acids Research, 2002, Vol. 30, No. 14 3214-3224
© 2002 Oxford University Press

Statistical significance of clusters of motifs represented by position specific scoring matrices in nucleotide sequences

Martin C. Frith1, John L. Spouge4, Ulla Hansen1,3 and Zhiping Weng*,1,2

1 Bioinformatics Program and 2 Department of Biomedical Engineering, Boston University, 44 Cummington Street, 3 Department of Biology, Boston University, 5 Cummington Street, Boston MA 02215, USA and 4 National Center for Biotechnology Information, National Library of Medicine, Building 38A, Room 8N805, Bethesda, MD 20894, USA

*To whom correspondence should be addressed at: Bioinformatics Program, Boston University, 44 Cummington Street, Boston, MA 02215, USA. Tel: +1 617 353 3509; Fax: +1 617 353 6766; Email: zhiping{at}bu.edu

The human genome encodes the transcriptional control of its genes in clusters of cis-elements that constitute enhancers, silencers and promoter signals. The sequence motifs of individual cis- elements are usually too short and degenerate for confident detection. In most cases, the requirements for organization of cis-elements within these clusters are poorly understood. Therefore, we have developed a general method to detect local concentrations of cis-element motifs, using predetermined matrix representations of the cis-elements, and calculate the statistical significance of these motif clusters. The statistical significance calculation is highly accurate not only for idealized, pseudorandom DNA, but also for real human DNA. We use our method ‘cluster of motifs E-value tool’ (COMET) to make novel predictions concerning the regulation of genes by transcription factors associated with muscle. COMET performs comparably with two alternative state-of-the-art techniques, which are more complex and lack E-value calculations. Our statistical method enables us to clarify the major bottleneck in the hard problem of detecting cis-regulatory regions, which is that many known enhancers do not contain very significant clusters of the motif types that we search for. Thus, discovery of additional signals that belong to these regulatory regions will be the key to future progress.


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