Identification of conserved regulatory elements by comparative genome analysis

By Boris Lenhard, Albin Sandelin, L. Mendoza, Pär G. Engström, N. Jareborg, Wyeth W. Wasserman. Journal of Biology, 2003

304 citations recorded by the source corpus.

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 . 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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/64c16be8c0f23a5ca8ea3d502f7b414fe8d4630f

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Citations in the corpus

Genome-wide analysis of mammalian promoter architecture and evolution (2006, background): “Promoter evolution in mammalian genomes Phylogenetic footprintin”
Computational prediction of transcription-factor binding site locations (2003, background): “In a recently published study, Wasserman and colleagues [96] performed human-mouse sequence comparisons of 14 well-studied genes and searched for matches to TFBS PWMs within the conserved noncoding regions, using a range of PWM score thresholds.”
Understanding eukaryotic linear motifs and their role in cell signaling and regulation. (2008, background): “In that field, the best results have been achieved by predictive schemes that combine statistical models to represent the site (90) with phylogenetic footprinting (91).”
Applied bioinformatics for the identification of regulatory elements (2004, background): “The initial studies emphasized pairwise comparisons of sequences that are separated by 50–70 million years of evolution (for example, human–rodent”
JASPAR: an open-access database for eukaryotic transcription factor binding profiles (2004, background): “To meet this need, diverse researchers are dedicated to the creation of innovative new algorithms based on phylogenetic footprinting (3,4) and analysis of regulatory modules (5,6).”
An improved map of conserved regulatory sites for Saccharomyces cerevisiae (2006, background): “Mapping these sites is an important step in understanding transcriptional regulation, and can be significantly facilitated by integrating multiple data sources such as sequence, gene annotations, and phylogenetic conservation [1,2].”
oPOSSUM: identification of over-represented transcription factor binding sites in co-expressed genes (2005, background): “Other resources are available for detecting and visualizing binding sites within the conserved regions of human genes [Consite (11), rVISTA (38), dbTSS (39), CONREAL (40), CORG (41)], as well as for identifying statistically over-represented motifs in the promoters of related sequences [Clover (42),”
ConSite: web-based prediction of regulatory elements using cross-species comparison (2004, methodology): “Conversely, relatively long evolutionary distances, such as between human and ﬁsh, often render similarities in promoters all but undetectable with current methodology (11).”