Directed acyclic graph kernels for structural RNA analysis

BackgroundRecent discoveries of a large variety of important roles for non-coding RNAs (ncRNAs) have been reported by numerous researchers. In order to analyze ncRNAs by kernel methods including support vector machines, we propose stem kernels as an extension of string kernels for measuring the similarities between two RNA sequences from the viewpoint of secondary structures. However, applying stem kernels directly to large data sets of ncRNAs is impractical due to their computational complexity.ResultsWe have developed a new technique based on directed acyclic graphs (DAGs) derived from base-pairing probability matrices of RNA sequences that significantly increases the computation speed of stem kernels. Furthermore, we propose profile-profile stem kernels for multiple alignments of RNA sequences which utilize base-pairing probability matrices for multiple alignments instead of those for individual sequences. Our kernels outperformed the existing methods with respect to the detection of known ncRNAs and kernel hierarchical clustering.ConclusionStem kernels can be utilized as a reliable similarity measure of structural RNAs, and can be used in various kernel-based applications.

[1]  Peter S. Pacheco.  Parallel programming with MPI , 1996 .

[2]  James W. Brown.  The ribonuclease P database , 1997, Nucleic Acids Res..

[3]  Sean R. Eddy,et al.  A memory-efficient dynamic programming algorithm for optimal alignment of a sequence to an RNA secondary structure , 2002, BMC Bioinformatics.

[4]  Serafim Batzoglou,et al.  CONTRAfold: RNA secondary structure prediction without physics-based models , 2006, ISMB.

[5]  Peter F Stadler,et al.  Fast and reliable prediction of noncoding RNAs , 2005, Proc. Natl. Acad. Sci. USA.

[6]  Kiyoshi Asai,et al.  Marginalized kernels for RNA sequence data analysis. , 2002, Genome informatics. International Conference on Genome Informatics.

[7]  Robert P. W. Duin,et al.  Support Vector Data Description , 2004, Machine Learning.

[8]  Christian Zwieb,et al.  SRPDB: Signal Recognition Particle Database , 2003, Nucleic Acids Res..

[9]  S. Eddy.  Non–coding RNA genes and the modern RNA world , 2001, Nature Reviews Genetics.

[10]  Bjarne Knudsen,et al.  RNA secondary structure prediction using stochastic context-free grammars and evolutionary history , 1999, Bioinform..

[11]  Ian Holmes,et al.  Stem Stem Stem Stem Loop Loop Loop LoopLoop Loop Loop Loop Loop Loop Loop , 2005 .

[12]  Sean R. Eddy,et al.  Efficient pairwise RNA structure prediction and alignment using sequence alignment constraints , 2006, BMC Bioinformatics.

[13]  I. Hofacker,et al.  Consensus folding of aligned sequences as a new measure for the detection of functional RNAs by comparative genomics. , 2004, Journal of molecular biology.

[14]  David Haussler,et al.  Convolution kernels on discrete structures , 1999 .

[15]  Sean R. Eddy,et al.  Rfam: annotating non-coding RNAs in complete genomes , 2004, Nucleic Acids Res..

[16]  Tatsuya Akutsu,et al.  Protein homology detection using string alignment kernels , 2004, Bioinform..

[17]  Timothy R. Hughes,et al.  Considerations in the identification of functional RNA structural elements in genomic alignments , 2007, BMC Bioinformatics.

[18]  R. C. Underwood,et al.  Stochastic context-free grammars for tRNA modeling. , 1994, Nucleic acids research.

[19]  Baoyan Bai,et al.  Organization of the Caenorhabditis elegans small non-coding transcriptome: genomic features, biogenesis, and expression. , 2005, Genome research.

[20]  Christian Zwieb,et al.  SRPDB (Signal Recognition Particle Database) , 2001, Nucleic Acids Res..

[21]  D. Sankoff.  Simultaneous Solution of the RNA Folding, Alignment and Protosequence Problems , 1985 .

[22]  Rolf Backofen,et al.  Inferring Noncoding RNA Families and Classes by Means of Genome-Scale Structure-Based Clustering , 2007, PLoS Comput. Biol..

[23]  Bernhard Schölkopf,et al.  Kernel Methods in Computational Biology , 2005 .

[24]  Yasubumi Sakakibara,et al.  RNA secondary structural alignment with conditional random fields , 2005, ECCB/JBI.

[25]  Kiyoshi Asai,et al.  Robust prediction of consensus secondary structures using averaged base pairing probability matrices , 2007, Bioinform..

[26]  Sean R. Eddy,et al.  RSEARCH: Finding homologs of single structured RNA sequences , 2003, BMC Bioinformatics.

[27]  Chih-Jen Lin,et al.  Working Set Selection Using Second Order Information for Training Support Vector Machines , 2005, J. Mach. Learn. Res..

[28]  J. McCaskill.  The equilibrium partition function and base pair binding probabilities for RNA secondary structure , 1990, Biopolymers.

[29]  Peter F. Stadler,et al.  SnoReport: computational identification of snoRNAs with unknown targets , 2008, Bioinform..

[30]  Elena Rivas,et al.  Noncoding RNA gene detection using comparative sequence analysis , 2001, BMC Bioinformatics.

[31]  Kiyoshi Asai,et al.  Stem Kernels for RNA Sequence Analyses , 2007, BIRD.

[32]  Peter F. Stadler,et al.  Hairpins in a Haystack: recognizing microRNA precursors in comparative genomics data , 2006, ISMB.

[33]  D. Searls,et al.  Robots in invertebrate neuroscience , 2002, Nature.

[34]  Yasubumi Sakakibara,et al.  Pair hidden Markov models on tree structures , 2003, ISMB.

[35]  P. Stadler,et al.  Secondary structure prediction for aligned RNA sequences. , 2002, Journal of molecular biology.

[36]  R. Durbin,et al.  RNA sequence analysis using covariance models. , 1994, Nucleic acids research.

[37]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[38]  David Haussler,et al.  Identification and Classification of Conserved RNA Secondary Structures in the Human Genome , 2006, PLoS Comput. Biol..

[39]  Jonathan P. Bollback,et al.  Exploring genomic dark matter: a critical assessment of the performance of homology search methods on noncoding RNA. , 2006, Genome research.

[40]  Ivo L. Hofacker,et al.  Vienna RNA secondary structure server , 2003, Nucleic Acids Res..