A dominant theme in our group's research has been the development of computer algorithms to discover novel functional motifs in biological sequences. A natural application of this idea arises in the study of gene regulation.
One of the challenges currently facing biologists is to understand the varied and complex mechanisms that regulate gene expression. An important aspect of this challenge is the identification of binding sites for the factors involved in such regulation.
One approach to the problem of discovering such regulatory elements is to consider the regulatory regions of several (putatively) coregulated genes from a single genome. We have developed algorithms that search for statistically overrepresented motifs in this collection of regulatory regions, these motifs being good candidates for functional regulatory elements.
An orthogonal approach deduces regulatory elements by considering orthologous regulatory regions of a single gene from several species. This approach has been called "phylogenetic footprinting". The simple premise underlying phylogenetic footprinting is that selective pressure causes functional elements to evolve at a slower rate than nonfunctional sequences. This means that unusually well conserved sites among a set of orthologous regulatory regions are excellent candidates for functional regulatory elements. Given orthologous input sequences and the phylogenetic tree relating them, we have developed a practical algorithm that identifies the best conserved sites.
Adrienne X. Wang, Walter L. Ruzzo, and Martin Tompa, How Accurately Is ncRNA Aligned within Whole-Genome Multiple Alignments?. BMC Bioinformatics, vol. 8, no. 417, October 2007.
Amol Prakash and Martin Tompa, Measuring the Accuracy of Genome-Size Multiple Alignments. Genome Biology, vol. 8, issue 6, June 2007, R124.
Shane Neph and Martin Tompa, MicroFootPrinter: a Tool for Phylogenetic Footprinting in Prokaryotic Genomes. Nucleic Acids Research, vol. 34, July 2006, W366-W368.
Amol Prakash and Martin Tompa, Discovery of regulatory elements in vertebrates through comparative genomics. Nature Biotechnology, vol. 23, no. 10, October 2005, 1249 - 1256.
M. Tompa, N. Li, T. L. Bailey , G. M. Church , B. De Moor, E. Eskin, A. V. Favorov, M. C. Frith, Y. Fu, W. J. Kent, V. J. Makeev, A. A. Mironov, W. S. Noble, G. Pavesi, G. Pesole, M. Regnier, N. Simonis, S. Sinha, G. Thijs, J. van Helden, M. Vandenbogaert, Z. Weng, C. Workman, C. Ye, and Z. Zhu, Assessing Computational Tools for the Discovery of Transcription Factor Binding Sites. Nature Biotechnology, vol. 23, no. 1, January 2005, 137 - 144.
Maria Shnyreva, William M. Weaver, Mathieu Blanchette, Scott L. Taylor, Martin Tompa, David R. Fitzpatrick, and Christopher B. Wilson, Evolutionarily Conserved Sequence Elements that Positively Regulate IFN-γ Expression in T Cells. Proceedings of the National Academy of Science USA, vol. 101, no. 34, August 2004, 12622-12627.
H.-D. Park, K. M. Guinn, M. I. Harrell, R. Liao, M. I. Voskull, M. Tompa, G. K. Schoolnik, and D. R. Sherman, "Rv3133c/dosR is a Transcription Factor that Mediates the Hypoxic Response of Mycobacterium tuberculosis". Molecular Microbiology, vol. 48, issue 3, May 2003, 833-843.
Saurabh Sinha and Martin Tompa, "Discovery of Novel Transcription Factor Binding Sites by Statistical Overrepresentation". Nucleic Acids Research, vol. 30, no. 24, December 2002, 5549-5560.
Mathieu Blanchette and Martin Tompa, Discovery of Regulatory Elements by a Computational Method for Phylogenetic Footprinting. Genome Research, vol. 12, no. 5, May 2002, 739-748.