Evaluation of phylogenetic footprint discovery for predicting bacterial cis-regulatory elements and revealing their evolution.
BACKGROUND
The detection of conserved motifs in promoters of orthologous genes (phylogenetic footprints) has become a common strategy to predict cis-acting regulatory elements. Several software tools are routinely used to raise hypotheses about regulation. However, these tools are generally used as black boxes, with default parameters. A systematic evaluation of optimal parameters for a footprint discovery strategy can bring a sizeable improvement to the predictions.


RESULTS
We evaluate the performances of a footprint discovery approach based on the detection of over-represented spaced motifs. This method is particularly suitable for (but not restricted to) Bacteria, since such motifs are typically bound by factors containing a Helix-Turn-Helix domain. We evaluated footprint discovery in 368 Escherichia coli K12 genes with annotated sites, under 40 different combinations of parameters (taxonomical level, background model, organism-specific filtering, operon inference). Motifs are assessed both at the levels of correctness and significance. We further report a detailed analysis of 181 bacterial orthologs of the LexA repressor. Distinct motifs are detected at various taxonomical levels, including the 7 previously characterized taxon-specific motifs. In addition, we highlight a significantly stronger conservation of half-motifs in Actinobacteria, relative to Firmicutes, suggesting an intermediate state in specificity switching between the two Gram-positive phyla, and thereby revealing the on-going evolution of LexA auto-regulation.


CONCLUSIONS
The footprint discovery method proposed here shows excellent results with E. coli and can readily be extended to predict cis-acting regulatory signals and propose testable hypotheses in bacterial genomes for which nothing is known about regulation.
Janky
Rekin's
R
Laboratoire de Bioinformatique des Génomes et des Réseaux, Université Libre de Bruxelles (ULB), Campus Plaine, CP 263, Boulevard du Triomphe, 1050 Bruxelles, Belgium. rekins@scmbb.ulb.ac.be
van Helden
Jacques
J
D039903:Actinobacteria / Q000235:genetics; D000465:Algorithms; D020816:Amino Acid Motifs / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D017124:Conserved Sequence; D018983:DNA Footprinting / Q000379:methods*; D048168:Escherichia coli K12 / Q000235:genetics; D019143:Evolution, Molecular; D016680:Genome, Bacterial; D016936:Gram-Positive Endospore-Forming Bacteria; D010802:Phylogeny; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D012697:Serine Endopeptidases / Q000235:genetics; D012984:Software; D000099160:LexA Repressor Protein
D001426:Bacterial Proteins; D012697:Serine Endopeptidases; D000099160:LexA Repressor Protein