CSMET: Comparative Genomic Motif Detection via Multi-Resolution Phylogenetic Shadowing

@article{citeulike:2872502, abstract = {Functional turnover of transcription factor binding sites (TFBSs), such as whole-motif loss or gain, are common events during genome evolution. Conventional probabilistic phylogenetic shadowing methods model the evolution of genomes only at nucleotide level, and lack the ability to capture the evolutionary dynamics of functional turnover of aligned sequence entities. As a result, comparative genomic search of non-conserved motifs across evolutionarily related taxa remains a difficult challenge, especially in higher eukaryotes, where the cis-regulatory regions containing motifs can be long and divergent; existing methods rely heavily on specialized pattern-driven heuristic search or sampling algorithms, which can be difficult to generalize and hard to interpret based on phylogenetic principles. We propose a new method: Conditional Shadowing via Multi-resolution Evolutionary Trees, or CSMET, which uses a context-dependent probabilistic graphical model that allows aligned sites from different taxa in a multiple alignment to be modeled by either a background or an appropriate motif phylogeny conditioning on the functional specifications of each taxon. The functional specifications themselves are the output of a phylogeny which models the evolution not of individual nucleotides, but of the overall functionality (e.g., functional retention or loss) of the aligned sequence segments over lineages. Combining this method with a hidden Markov model that autocorrelates evolutionary rates on successive sites in the genome, CSMET offers a principled way to take into consideration lineage-specific evolution of TFBSs during motif detection, and a readily computable analytical form of the posterior distribution of motifs under TFBS turnover. On both simulated and real Drosophila cis-regulatory modules, CSMET outperforms other state-of-the-art comparative genomic motif finders.}, author = {Ray, Pradipta and Shringarpure, Suyash and Kolar, Mladen and Xing, Eric P. }, citeulike-article-id = {2872502}, doi = {10.1371/journal.pcbi.1000090}, journal = {PLoS Comput Biol}, keywords = {comparative, detection, footprinting, genomics, motif, phylogenetic}, month = {June}, number = {6}, pages = {e1000090+}, posted-at = {2008-06-14 14:43:13}, priority = {5}, publisher = {Public Library of Science}, title = {CSMET: Comparative Genomic Motif Detection via Multi-Resolution Phylogenetic Shadowing}, url = {http://dx.doi.org/10.1371/journal.pcbi.1000090}, volume = {4}, year = {2008} }

TY - JOUR ID - citeulike:2872502 L3 - citeulike-article-id:2872502 TI - CSMET: Comparative Genomic Motif Detection via Multi-Resolution Phylogenetic Shadowing JF - PLoS Comput Biol VL - 4 IS - 6 SP - e1000090 PB - Public Library of Science N2 - Functional turnover of transcription factor binding sites (TFBSs), such as whole-motif loss or gain, are common events during genome evolution. Conventional probabilistic phylogenetic shadowing methods model the evolution of genomes only at nucleotide level, and lack the ability to capture the evolutionary dynamics of functional turnover of aligned sequence entities. As a result, comparative genomic search of non-conserved motifs across evolutionarily related taxa remains a difficult challenge, especially in higher eukaryotes, where the cis-regulatory regions containing motifs can be long and divergent; existing methods rely heavily on specialized pattern-driven heuristic search or sampling algorithms, which can be difficult to generalize and hard to interpret based on phylogenetic principles. We propose a new method: Conditional Shadowing via Multi-resolution Evolutionary Trees, or CSMET, which uses a context-dependent probabilistic graphical model that allows aligned sites from different taxa in a multiple alignment to be modeled by either a background or an appropriate motif phylogeny conditioning on the functional specifications of each taxon. The functional specifications themselves are the output of a phylogeny which models the evolution not of individual nucleotides, but of the overall functionality (e.g., functional retention or loss) of the aligned sequence segments over lineages. Combining this method with a hidden Markov model that autocorrelates evolutionary rates on successive sites in the genome, CSMET offers a principled way to take into consideration lineage-specific evolution of TFBSs during motif detection, and a readily computable analytical form of the posterior distribution of motifs under TFBS turnover. On both simulated and real Drosophila cis-regulatory modules, CSMET outperforms other state-of-the-art comparative genomic motif finders. KW - comparative KW - detection KW - footprinting KW - genomics KW - motif KW - phylogenetic AU - Ray, Pradipta AU - Shringarpure, Suyash AU - Kolar, Mladen AU - Xing, Eric PY - 2008/06/06/ UR - http://dx.doi.org/10.1371/journal.pcbi.1000090 ER -