Conservation and evolution of cis-regulatory regions

The task of identifying transcription factor binding sites from gene expression is limited by the diversity of physiological perturbations or tissue samples.  Also, in more complex genomes of mammals, such binding sites may occur very far away from the gene itself.  An alternative approach for identifying functional regulatory elements is to infer them from non-coding DNA-sequence conservation between closely related species.  In this, so called, phylogenetic footprinting, functional binding sites are inferred from blocks of conserved sequences within global alignments of regulatory regions.  However, global alignments are problematic when the positions of regulatory elements within functionally conserved promoter regions have been shuffled, for example through genomic reduction and rearrangements.  We are developing non-alignment based comparative genomic strategies for identifying transcriptional and post-transcriptional regulatory elements in the genomes of flies, worms, and mammals.  We have found these methods to be extremely powerful at identifying known elements using only pairs of genomes.  We are currently using such methods to extract higher-order cis-regulatory modules composed of specific configuration of multiple transcription factor binding sites.  The large number of sequenced genomes allows us to study the evolutionary dynamics of these regulatory elements both within and between species.

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