Identification of conserved regulatory elements by comparative genome analysis.
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/.


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.
Lenhard
Boris
B
Center for Genomics and Bioinformatics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Sandelin
Albin
A
Center for Genomics and Bioinformatics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Mendoza
Luis
L
Center for Genomics and Bioinformatics, Karolinska Institutet, 171 77 Stockholm, Sweden.|Current address: Serono Research and Development, CH-1121 Geneva 20, Switzerland.
Engström
Pär
P
Center for Genomics and Bioinformatics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Jareborg
Niclas
N
Center for Genomics and Bioinformatics, Karolinska Institutet, 171 77 Stockholm, Sweden.|Current address: AstraZeneca Research and Development, S-151 85 Södertälje, Sweden.
Wasserman
Wyeth W
WW
Center for Genomics and Bioinformatics, Karolinska Institutet, 171 77 Stockholm, Sweden.|Current address: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
D000465:Algorithms; D001665:Binding Sites / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D003196:Computer Graphics; D017124:Conserved Sequence / Q000235:genetics*; D018983:DNA Footprinting / Q000379:methods; D005809:Genes, Regulator / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D008957:Models, Genetic; D010802:Phylogeny; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D014157:Transcription Factors / Q000235:genetics
D014157:Transcription Factors