Research

PhyloScan: identification of transcription factor binding sites using cross-species evidence

C Steven Carmack¹ , Lee Ann McCue^1,2 , Lee A Newberg^1,3 and Charles E Lawrence^1,4

¹  The Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA

²  Pacific Northwest National Laboratory, Richland, WA 99352, USA

³  Departrnent of Computer Science, Rensselaer Polytechnic Institute, Troy, NY 12180, USA

⁴  Division of Applied Mathematics, Brown University, Providence, RI 02912, USA

author email corresponding author email

Algorithms for Molecular Biology 2007, 2:1doi:10.1186/1748-7188-2-1

Published:	23 January 2007

Abstract

Background

When transcription factor binding sites are known for a particular transcription factor, it is possible to construct a motif model that can be used to scan sequences for additional sites. However, few statistically significant sites are revealed when a transcription factor binding site motif model is used to scan a genome-scale database.

Methods

We have developed a scanning algorithm, PhyloScan, which combines evidence from matching sites found in orthologous data from several related species with evidence from multiple sites within an intergenic region, to better detect regulons. The orthologous sequence data may be multiply aligned, unaligned, or a combination of aligned and unaligned. In aligned data, PhyloScan statistically accounts for the phylogenetic dependence of the species contributing data to the alignment and, in unaligned data, the evidence for sites is combined assuming phylogenetic independence of the species. The statistical significance of the gene predictions is calculated directly, without employing training sets.

Results

In a test of our methodology on synthetic data modeled on seven Enterobacteriales, four Vibrionales, and three Pasteurellales species, PhyloScan produces better sensitivity and specificity than MONKEY, an advanced scanning approach that also searches a genome for transcription factor binding sites using phylogenetic information. The application of the algorithm to real sequence data from seven Enterobacteriales species identifies novel Crp and PurR transcription factor binding sites, thus providing several new potential sites for these transcription factors. These sites enable targeted experimental validation and thus further delineation of the Crp and PurR regulons in E. coli.

Conclusion

Better sensitivity and specificity can be achieved through a combination of (1) using mixed alignable and non-alignable sequence data and (2) combining evidence from multiple sites within an intergenic region.