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Open Access Highly Accessed Research article

Identification of conserved regulatory elements by comparative genome analysis

Boris Lenhard1, Albin Sandelin1, Luis Mendoza12, Pär Engström1, Niclas Jareborg13 and Wyeth W Wasserman14*

Author affiliations

1 Center for Genomics and Bioinformatics, Karolinska Institutet, 171 77 Stockholm, Sweden

2 Current address: Serono Research and Development, CH-1121 Geneva 20, Switzerland

3 Current address: AstraZeneca Research and Development, S-151 85 Södertälje, Sweden

4 Current address: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada

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Citation and License

Journal of Biology 2003, 2:13  doi:10.1186/1475-4924-2-13

Published: 22 May 2003

Abstract

Background

For genes that have been successfully delineated within the human genome sequence, most regulatory sequences remain to be elucidated. The annotation and interpretation process requires additional data resources and significant improvements in computational methods for the detection of regulatory regions. One approach of growing popularity is based on the preferential conservation of functional sequences over the course of evolution by selective pressure, termed 'phylogenetic footprinting'. Mutations are more likely to be disruptive if they appear in functional sites, resulting in a measurable difference in evolution rates between functional and non-functional genomic segments.

Results

We have devised a flexible suite of methods for the identification and visualization of conserved transcription-factor-binding sites. The system reports those putative transcription-factor-binding sites that are both situated in conserved regions and located as pairs of sites in equivalent positions in alignments between two orthologous sequences. An underlying collection of metazoan transcription-factor-binding profiles was assembled to facilitate the study. This approach results in a significant improvement in the detection of transcription-factor-binding sites because of an increased signal-to-noise ratio, as demonstrated with two sets of promoter sequences. The method is implemented as a graphical web application, ConSite, which is at the disposal of the scientific community at http://www.phylofoot.org/ webcite.

Conclusions

Phylogenetic footprinting dramatically improves the predictive selectivity of bioinformatic approaches to the analysis of promoter sequences. ConSite delivers unparalleled performance using a novel database of high-quality binding models for metazoan transcription factors. With a dynamic interface, this bioinformatics tool provides broad access to promoter analysis with phylogenetic footprinting.