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...st entropy Smin and use this value as an additional descriptor, Table 1. 2.3 SVM implementation For classification we used a support vector machine as implemented in the libsvm package, version 2.8, (=-=Chang & Lin, 2001-=-). Descriptor vectors were scaled linearly to the interval 1‚ þ 1Š before training using the binary version of svm-scale which is included in the libsvm package. The SVM was then trained using a rad...

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... development of efficient automatic tools for their further classification and annotation. With the exception of a small number of evolutionarily very well conserved RNAs (in particular rRNAs, tRNAs (=-=Lowe & Eddy, 1997-=-), the U5 snRNA (Collins et al., 2004), RNAse P and MRP (Piccinelli et al., 2005)), most ncRNAs are not only hard to discover de novo in large genomes, but they are also surprisingly hard to recognize...

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... steps from the input alignment. For each window, consensus sequence and consensus structure are computed using the RNAalifold algorithm (Hofacker et al., 2002) implemented in the Vienna RNA Package (=-=Hofacker et al., 1994-=-; Hofacker, 2003). The automaton in Fig. 1 is then used to analyze the consensus secondary structure, which is obtained in ‘dotparenthesis’ notation 4 . Alignment windows whose consensus structure doe...

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...005b) have been published recently. The screen of vertebrate genomes (Washietl et al., 2005a) was based on the top 5% conserved multiz alignments (Blanchette et al., 2004) as determined by phastcons (=-=Siepel et al., 2005-=-). For nematodes and urochordates, alignments were constructed using clustalw based on initial blast hits, see (Missal et al., 2005, 2006) for details. In all three cases, only non-repetitive non-prot...

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... the mature miRNAs, approximately 22 nt in length, are cut out from one side of the precursor stem structure. For reviews on the discovery and function of miRNAs we refer to the literature, see e.g. (=-=Ambros, 2004-=-; Kidner & Martienssen, 2005). At present, several hundred distinct miRNA families are known in metazoan animals (Griffiths-Jones et al., 2005; Hertel et al., 2006), and a few dozens have been describ...

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...lignment. For each window, consensus sequence and consensus structure are computed using the RNAalifold algorithm (Hofacker et al., 2002) implemented in the Vienna RNA Package (Hofacker et al., 1994; =-=Hofacker, 2003-=-). The automaton in Fig. 1 is then used to analyze the consensus secondary structure, which is obtained in ‘dotparenthesis’ notation 4 . Alignment windows whose consensus structure does not contain a ...

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...he discovery and function of miRNAs we refer to the literature, see e.g. (Ambros, 2004; Kidner & Martienssen, 2005). At present, several hundred distinct miRNA families are known in metazoan animals (=-=Griffiths-Jones et al., 2005-=-; Hertel et al., 2006), and a few dozens have been described in plants (Griffiths-Jones et al., 2005; Zhang et al., 2005; Axtell & Bartel, 2005). In contrast to other major RNA classes, in particular ...

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...ining data are almost never known at all. Even for the most benign case, microRNA precursors, there is only a few hundred independent known examples, namely the miRNA families listed in the mir-base (=-=Griffiths-Jones, 2004-=-; Griffiths-Jones et al., 2005; Hertel et al., 2006). Over-training is thus a serious problem. As a consequence, it is necessary to restrict oneself to a small set of descriptors. This constraint, how...

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...d patterns in phylogenetic footprints located in the 3 0 UTRs of mRNAs. These motifs constitute putative microRNA target sites and are used to guide the search for corresponding pre-miRNA candidates (=-=Xie et al., 2005-=-). Advances in computational RNomics have most recently made it feasible to perform genome-wide surveys for non-coding RNAs that are not a priori restricted to particular RNA classes. Programs such as...

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...oth thermodynamic stabilization of the secondary structure relative to a randomized control and structural conservation as measured by the relative folding energy of an alignment consensus consensus (=-=Hofacker et al., 2002-=-). A support vector machine (SVM) is then employed to classify the multiple sequence alignment as ‘‘structured RNA’’. Both RNAz and Evofold have been applied to surveying the human genome providing ev...

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...ys of metazoan genomes using RNAz (Washietl et al., 2005b) have been published recently. The screen of vertebrate genomes (Washietl et al., 2005a) was based on the top 5% conserved multiz alignments (=-=Blanchette et al., 2004-=-) as determined by phastcons (Siepel et al., 2005). For nematodes and urochordates, alignments were constructed using clustalw based on initial blast hits, see (Missal et al., 2005, 2006) for details....

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...nces in computational RNomics have most recently made it feasible to perform genome-wide surveys for non-coding RNAs that are not a priori restricted to particular RNA classes. Programs such as qrna (=-=Rivas & Eddy, 2001-=-), EvoFold (Pedersen et al., 2006), and RNAz (Washietl et al., 2005b) attempt to discover evolutionarily conserved RNA secondary structures in given multiple sequence alignments. Two distinct approach...

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.... Distribution of two closely related upstream motifs (A) and (B) reported for both C. elegans and C. briggsae (Ohler et al., 2004, Fig.2). We plot the fraction of RNAmicro candidates for which mast (=-=Bailey & Gribskov, 1998-=-) recovers at least one copy A or B within 2000 nt upstream of the miRNA candidate as a function of the mast E-value cutoff. For small cutoffs, the miRNA specific sequence elements are overrepresented...

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...have most recently made it feasible to perform genome-wide surveys for non-coding RNAs that are not a priori restricted to particular RNA classes. Programs such as qrna (Rivas & Eddy, 2001), EvoFold (=-=Pedersen et al., 2006-=-), and RNAz (Washietl et al., 2005b) attempt to discover evolutionarily conserved RNA secondary structures in given multiple sequence alignments. Two distinct approaches have been realized: EvoFold an...

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...machine (SVM) to identify microRNAs among these candidates (Sewer et al., 2005). A related technique is described by Xue et al. (2005). The program PalGrade scores hairpins in a somewhat similar way (=-=Bentwich et al., 2005-=-). A quite different 1 http://genes.mit.edu/mirscan/ 2 http://bioinfo.au.tsinghua.edu.cn/miralign 3 http://www.mirz.unibas.ch/cgi/pred_miRNA_genes.cgi Ó The Author 2006. Published by Oxford University...

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...t we have seen only a small fraction of the true miRNA repertoire to due to small expression levels and expression e201sJ.Hertel and P.F.Stadler patterns restricted to a few cell-lines (Ambros, 2004; =-=Bartel & Chen, 2004-=-; Mattick, 2004). ACKNOWLEDGEMENTS Financial support by the German DFG in the framework of the Bioinformatics Initiative (BIZ-6/1-2) and the SPP ‘Metazoan Deep Phylogeny’ is gratefully acknowledged. R...

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...nct miRNA families are known in metazoan animals (Griffiths-Jones et al., 2005; Hertel et al., 2006), and a few dozens have been described in plants (Griffiths-Jones et al., 2005; Zhang et al., 2005; =-=Axtell & Bartel, 2005-=-). In contrast to other major RNA classes, in particular tRNAs, there is no recognizable homology between different families, so that it is unclear whether they arose independently in evolution or whe...

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... genome of the species. Hence the number of alignment slices is much larger than the number of ‘RNAz hits’ reported in these studies. Redundancies arising from miRNAs that appear in more than one 206 =-=Grad et al 2003-=- other RNAs 3332 1 RNAmicro P > 0.5 P > 0.9 54 25 1 2 0 339 18 4 104 31 Ciona intestinalis (b) alignment slice have been removed. The Venn diagrams in Fig. 2 summarize our classification. It is reassu...

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...enes and are probably false positives. MicroRNAs have a tendency to appear in clusters, probably because they are frequently processed from a polycistronic transcript. This fact has been utilized by (=-=Altuvia et al., 2005-=-; Sewer Hairpins in a Haystack et al., 2005) to identify additional miRNAs in the vicinity of known ones. Using a rather conservative distance cutoff of <1000 nt between adjacent miRNAs, we found 143 ...

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...ation in related organisms, and the sequence conservation patterns of the 3 0 and 5 0 arms precursor hairpin. The programs miRscan 1 (Lim et al., 2003b), miRseeker (Lai et al., 2003), and miralign 2 (=-=Wang et al., 2005-=-) have lead to the discovery of a large number of novel microRNAs in nematodes (Lim et al., 2003b), insects (Lai et al., 2003;Wang et al., 2005) and vertebrates (Lim et al., 2003a). Grad et al., (2003...

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...ecting novel miRNAs. The simpler one uses sequence homology to experimentally known To whom correspondence should be addressed. miRNAs as well as the characteristic hairpin structure of the premiRNA (=-=Weber, 2005-=-; Legendre et al., 2005; Hertel et al., 2006; Dezulian et al., 2006). A specialized machine learning approach that is specifically designed to search for distant homologs of human miRNA families is de...

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...escriptors summarizes the thermodynamic properties of local sequence interval. MicroRNA precursors are known to be more stable than other RNAs with the same sequence composition (Bonnet et al., 2004; =-=Clote et al., 2005-=-). We thus use the average z of the energy z-scores z ðE hEirandomÞ/s ð1Þ where E is the folding energy of the given sequence. The mean hEi random and s of the distribution of randomized sequences is...

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...t al., 2005; Hertel et al., 2006; Dezulian et al., 2006). A specialized machine learning approach that is specifically designed to search for distant homologs of human miRNA families is described in (=-=Nam et al., 2005-=-). Clearly, this approach is not capable of finding miRNAs for which no family member is already known. Several approaches have focused on detecting novel miRNAs based on the secondary structure of th...

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...discovered by (Lagos-Quintanta et al., 2002) (in total, we found 54 candidates in multiple tight clusters between positions 100M and 101M of the hg17 assembly) and the paralogs of the mir-17 cluster (=-=Tanzer & Stadler, 2004-=-). In C. elegans we find 30 clusters with 131 members, in C. intestinalis there are 5 clusters with 10 members. Note that these are conservative estimates since in some cases, such as the C. elegans m...

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... this case, secondary structure is used in a later filtering step. Genomic context also can give additional information: Mirscan-II, for example, takes conservation of surrounding genes into account (=-=Ohler et al., 2004-=-). Altuvia et al., (2005) utilize the propensity of miRNAs to appear in genomic clusters (often in the form of polycistronic transcripts) as an additional selection criterion. MicroRNA detection witho...

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...miRNAs. The simpler one uses sequence homology to experimentally known To whom correspondence should be addressed. miRNAs as well as the characteristic hairpin structure of the premiRNA (Weber, 2005; =-=Legendre et al., 2005-=-; Hertel et al., 2006; Dezulian et al., 2006). A specialized machine learning approach that is specifically designed to search for distant homologs of human miRNA families is described in (Nam et al.,...

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...ly conserved secondary structure (Washietl et al., 2005b; Pedersen et al., 2006) and detected tens of thousands of putative structured RNAs. Further RNAz surveys have been conducted for urochordates (=-=Missal et al., 2005-=-), nematodes (Missal et al., 2006), and yeasts (Steigele et al., 2006). These surveys produced extensive lists of candidates for functional RNAs without using (or providing) information on membership ...

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...(Washietl et al., 2005b; Pedersen et al., 2006) and detected tens of thousands of putative structured RNAs. Further RNAz surveys have been conducted for urochordates (Missal et al., 2005), nematodes (=-=Missal et al., 2006-=-), and yeasts (Steigele et al., 2006). These surveys produced extensive lists of candidates for functional RNAs without using (or providing) information on membership in a particular class of RNAs. Th...

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...RNAs, approximately 22 nt in length, are cut out from one side of the precursor stem structure. For reviews on the discovery and function of miRNAs we refer to the literature, see e.g. (Ambros, 2004; =-=Kidner & Martienssen, 2005-=-). At present, several hundred distinct miRNA families are known in metazoan animals (Griffiths-Jones et al., 2005; Hertel et al., 2006), and a few dozens have been described in plants (Griffiths-Jone...

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...7 candidates (20%) are located in introns (of which 36 are known microRNAs). This is in agreement with a recent study reporting that intronic microRNAs are much more frequent than previously thought (=-=Ying & Lin, 2006-=-). The remaining 88 sequences map to exons of known genes and are probably false positives. MicroRNAs have a tendency to appear in clusters, probably because they are frequently processed from a polyc...

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...gy to experimentally known To whom correspondence should be addressed. miRNAs as well as the characteristic hairpin structure of the premiRNA (Weber, 2005; Legendre et al., 2005; Hertel et al., 2006; =-=Dezulian et al., 2006-=-). A specialized machine learning approach that is specifically designed to search for distant homologs of human miRNA families is described in (Nam et al., 2005). Clearly, this approach is not capabl...

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... and annotation. With the exception of a small number of evolutionarily very well conserved RNAs (in particular rRNAs, tRNAs (Lowe & Eddy, 1997), the U5 snRNA (Collins et al., 2004), RNAse P and MRP (=-=Piccinelli et al., 2005-=-)), most ncRNAs are not only hard to discover de novo in large genomes, but they are also surprisingly hard to recognize if presented without annotation. Indeed, given an alignment not more than a few...

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...c tools for their further classification and annotation. With the exception of a small number of evolutionarily very well conserved RNAs (in particular rRNAs, tRNAs (Lowe & Eddy, 1997), the U5 snRNA (=-=Collins et al., 2004-=-), RNAse P and MRP (Piccinelli et al., 2005)), most ncRNAs are not only hard to discover de novo in large genomes, but they are also surprisingly hard to recognize if presented without annotation. Ind...

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...iRNAs we refer to the literature, see e.g. (Ambros, 2004; Kidner & Martienssen, 2005). At present, several hundred distinct miRNA families are known in metazoan animals (Griffiths-Jones et al., 2005; =-=Hertel et al., 2006-=-), and a few dozens have been described in plants (Griffiths-Jones et al., 2005; Zhang et al., 2005; Axtell & Bartel, 2005). In contrast to other major RNA classes, in particular tRNAs, there is no re...

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...et al., 2006) and detected tens of thousands of putative structured RNAs. Further RNAz surveys have been conducted for urochordates (Missal et al., 2005), nematodes (Missal et al., 2006), and yeasts (=-=Steigele et al., 2006-=-). These surveys produced extensive lists of candidates for functional RNAs without using (or providing) information on membership in a particular class of RNAs. The large number of putative ncRNAs (f...