c-REDUCE: Incorporating sequence conservation to detect motifs that correlate with expression

In this work, we describe a method for predicting motifs that combines the correlation-based strategy with phylogenetic footprinting, where motifs are identified by evaluating orthologous sequence regions from multiple species. Our method, c-REDUCE, can account for variability at a motif position inferred from evolutionary information. c-REDUCE has been tested on ChIP-chip data for yeast transcription factors and on gene expression data in Drosophila.Our results indicate that utilizing sequence conservation information in addition to correlation-based methods improves the identification of known motifs.An important problem in genome annotation is the identification and characterization of functional elements. These elements include transcription factor binding sites (TFBS), which are short, degenerate sequences that appear frequently in the genome. The interactions between transcription factors (TFs) and their respective binding sites are critical for regulating gene expression. To characterize binding sequences for a TF, computational methods search for sequence patterns or "motifs" that appear repeatedly in genomic regions of interest (for a recent review, see [1]).For many motif-finding methods, it is necessary to input upstream sequences from a set of genes (e.g., genes that have been identified as co-expressed from a microarray gene expression analysis), with the assumption that a common motif is shared by the sequences (e.g., [2,3]). However, upstream sequences of genes included in this set may not have an occurrence of the same motif, or genes that have the occurrence of the motif in their upstream sequence may not be identified in the co-expressed set. To address these weaknesses, correlation-based motif finding methods [4] have been developed that do not rely on a pre-determined set of genes either based on co-expression (e.g., [2,3]) or over-representation of motifs as in [5]. Using all genes from a single experiment, oligos in a specified length range are