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PMID: 21357752 Published · ppublish English Journal Article

RNAcode: robust discrimination of coding and noncoding regions in comparative sequence data.

RNA (New York, N.Y.) ·Vol. 17 ·No. 4 ·2011-04-00 ·Pages 578-94

Washietl S, Findeiss S, Müller SA, Kalkhof S, von Bergen M, Hofacker IL, Stadler PF, Goldman N

Abstract

With the availability of genome-wide transcription data and massive comparative sequencing, the discrimination of coding from noncoding RNAs and the assessment of coding potential in evolutionarily conserved regions arose as a core analysis task. Here we present RNAcode, a program to detect coding regions in multiple sequence alignments that is optimized for emerging applications not covered by current protein gene-finding software. Our algorithm combines information from nucleotide substitution and gap patterns in a unified framework and also deals with real-life issues such as alignment and sequencing errors. It uses an explicit statistical model with no machine learning component and can therefore be applied "out of the box," without any training, to data from all domains of life. We describe the RNAcode method and apply it in combination with mass spectrometry experiments to predict and confirm seven novel short peptides in Escherichia coli and to analyze the coding potential of RNAs previously annotated as "noncoding." RNAcode is open source software and available for all major platforms at http://wash.github.com/rnacode.

MeSH Terms
Algorithms Animals Base Pairing Drosophila melanogaster/genetics Escherichia coli/genetics Genetic Code Mass Spectrometry Molecular Sequence Annotation Molecular Sequence Data Open Reading Frames Peptides/genetics RNA, Messenger/genetics RNA, Untranslated/genetics Sequence Alignment/methods Sequence Analysis, RNA/methods Software
Chemicals
Peptides RNA, Messenger RNA, Untranslated
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Washietl Stefan
EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB101SD, United Kingdom. wash@mit.edu
Findeiss Sven
Müller Stephan A
Kalkhof Stefan
von Bergen Martin
Hofacker Ivo L
Stadler Peter F
Goldman Nick
References (66)
66 references, click to expand
  1. Noncoding RNA gene detection using comparative sequence analysis.
    BMC Bioinformatics. 2001;2:8 PMID: 11801179
  2. Using multiple alignments to improve gene prediction.
    J Comput Biol. 2006 Mar;13(2):379-93 PMID: 16597247
  3. Dating of the human-ape splitting by a molecular clock of mitochondrial DNA.
    J Mol Evol. 1985;22(2):160-74 PMID: 3934395
  4. Tricine-SDS-PAGE.
    Nat Protoc. 2006;1(1):16-22 PMID: 17406207
  5. FlyBase : a database for the Drosophila research community.
    Methods Mol Biol. 2008;420:45-59 PMID: 18641940
  6. The transcription unit architecture of the Escherichia coli genome.
    Nat Biotechnol. 2009 Nov;27(11):1043-9 PMID: 19881496
  7. The Universal Protein Resource (UniProt) in 2010.
    Nucleic Acids Res. 2010 Jan;38(Database issue):D142-8 PMID: 19843607
  8. A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood.
    Syst Biol. 2003 Oct;52(5):696-704 PMID: 14530136
  9. Assessing the impact of secondary structure and solvent accessibility on protein evolution.
    Genetics. 1998 May;149(1):445-58 PMID: 9584116
  10. Computational identification of protein coding potential of conserved sequence tags through cross-species evolutionary analysis.
    Nucleic Acids Res. 2003 Aug 1;31(15):4639-45 PMID: 12888525
  11. Amino acid substitution matrices from protein blocks.
    Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10915-9 PMID: 1438297
  12. Method to correlate tandem mass spectra of modified peptides to amino acid sequences in the protein database.
    Anal Chem. 1995 Apr 15;67(8):1426-36 PMID: 7741214
  13. Structured RNAs in the ENCODE selected regions of the human genome.
    Genome Res. 2007 Jun;17(6):852-64 PMID: 17568003
  14. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.
    Nature. 2007 Jun 14;447(7146):799-816 PMID: 17571346
  15. Estimating synonymous and nonsynonymous substitution rates under realistic evolutionary models.
    Mol Biol Evol. 2000 Jan;17(1):32-43 PMID: 10666704
  16. CONTRAST: a discriminative, phylogeny-free approach to multiple informant de novo gene prediction.
    Genome Biol. 2007;8(12):R269 PMID: 18096039
  17. Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search.
    Anal Chem. 2002 Oct 15;74(20):5383-92 PMID: 12403597
  18. Identification of candidate structured RNAs in the marine organism 'Candidatus Pelagibacter ubique'.
    BMC Genomics. 2009 Jun 16;10:268 PMID: 19531245
  19. Gene prediction: compare and CONTRAST.
    Genome Biol. 2007;8(12):233 PMID: 18096089
  20. Methods in comparative genomics: genome correspondence, gene identification and regulatory motif discovery.
    J Comput Biol. 2004;11(2-3):319-55 PMID: 15285895
  21. Probability-based protein identification by searching sequence databases using mass spectrometry data.
    Electrophoresis. 1999 Dec;20(18):3551-67 PMID: 10612281
  22. Small peptide regulators of actin-based cell morphogenesis encoded by a polycistronic mRNA.
    Nat Cell Biol. 2007 Jun;9(6):660-5 PMID: 17486114
  23. Sequencing and comparison of yeast species to identify genes and regulatory elements.
    Nature. 2003 May 15;423(6937):241-54 PMID: 12748633
  24. The low molecular weight proteome of Halobacterium salinarum.
    J Proteome Res. 2007 Apr;6(4):1510-8 PMID: 17326674
  25. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.
    Genome Res. 2005 Aug;15(8):1034-50 PMID: 16024819
  26. Mass spectrometry-based proteomics.
    Nature. 2003 Mar 13;422(6928):198-207 PMID: 12634793
  27. Aligning multiple genomic sequences with the threaded blockset aligner.
    Genome Res. 2004 Apr;14(4):708-15 PMID: 15060014
  28. EMBOSS: the European Molecular Biology Open Software Suite.
    Trends Genet. 2000 Jun;16(6):276-7 PMID: 10827456
  29. Small membrane proteins found by comparative genomics and ribosome binding site models.
    Mol Microbiol. 2008 Dec;70(6):1487-501 PMID: 19121005
  30. The small untranslated RNA SR1 from the Bacillus subtilis genome is involved in the regulation of arginine catabolism.
    Mol Microbiol. 2006 Oct;62(2):520-36 PMID: 17020585
  31. Dinucleotide controlled null models for comparative RNA gene prediction.
    BMC Bioinformatics. 2008 May 27;9:248 PMID: 18505553
  32. Implication of CcpN in the regulation of a novel untranslated RNA (SR1) in Bacillus subtilis.
    Mol Microbiol. 2005 Oct;58(1):189-206 PMID: 16164558
  33. CRITICA: coding region identification tool invoking comparative analysis.
    Mol Biol Evol. 1999 Apr;16(4):512-24 PMID: 10331277
  34. Discrimination of non-protein-coding transcripts from protein-coding mRNA.
    RNA Biol. 2006 Jan-Mar;3(1):40-8 PMID: 17114936
  35. The transcriptional landscape of the mammalian genome.
    Science. 2005 Sep 2;309(5740):1559-63 PMID: 16141072
  36. Staphylococcus aureus RNAIII coordinately represses the synthesis of virulence factors and the transcription regulator Rot by an antisense mechanism.
    Genes Dev. 2007 Jun 1;21(11):1353-66 PMID: 17545468
  37. ETOPE: Evolutionary test of predicted exons.
    Nucleic Acids Res. 2003 Jul 1;31(13):3564-7 PMID: 12824366
  38. Detection and identification of low-mass peptides and proteins from solvent suspensions of Escherichia coli by high performance liquid chromatography fractionation and matrix-assisted laser desorption/ionization mass spectrometry.
    Rapid Commun Mass Spectrom. 1999;13(1):73-8 PMID: 9921691
  39. RNAz 2.0: improved noncoding RNA detection.
    Pac Symp Biocomput. 2010;:69-79 PMID: 19908359
  40. Low-molecular-weight human serum proteome using ultrafiltration, isoelectric focusing, and mass spectrometry.
    Electrophoresis. 2004 May;25(9):1299-306 PMID: 15174052
  41. Transcriptome analysis of Escherichia coli using high-density oligonucleotide probe arrays.
    Nucleic Acids Res. 2002 Sep 1;30(17):3732-8 PMID: 12202758
  42. Distinguishing protein-coding and noncoding genes in the human genome.
    Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19428-33 PMID: 18040051
  43. Steady progress and recent breakthroughs in the accuracy of automated genome annotation.
    Nat Rev Genet. 2008 Jan;9(1):62-73 PMID: 18087260
  44. The UCSC Archaeal Genome Browser.
    Nucleic Acids Res. 2006 Jan 1;34(Database issue):D407-10 PMID: 16381898
  45. TANDEM: matching proteins with tandem mass spectra.
    Bioinformatics. 2004 Jun 12;20(9):1466-7 PMID: 14976030
  46. Optimization of parameters for coverage of low molecular weight proteins.
    Anal Bioanal Chem. 2010 Dec;398(7-8):2867-81 PMID: 20803007
  47. Molecular biology. Hiding in plain sight.
    Science. 2010 Jul 16;329(5989):284-5 PMID: 20647453
  48. Genome-wide discovery and verification of novel structured RNAs in Plasmodium falciparum.
    Genome Res. 2008 Feb;18(2):281-92 PMID: 18096748
  49. A statistical model for identifying proteins by tandem mass spectrometry.
    Anal Chem. 2003 Sep 1;75(17):4646-58 PMID: 14632076
  50. A high-resolution map of transcription in the yeast genome.
    Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5320-5 PMID: 16569694
  51. Fast and reliable prediction of noncoding RNAs.
    Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2454-9 PMID: 15665081
  52. EGASP: the human ENCODE Genome Annotation Assessment Project.
    Genome Biol. 2006;7 Suppl 1:S2.1-31 PMID: 16925836
  53. Differentiating protein-coding and noncoding RNA: challenges and ambiguities.
    PLoS Comput Biol. 2008 Nov;4(11):e1000176 PMID: 19043537
  54. Seq-Gen: an application for the Monte Carlo simulation of DNA sequence evolution along phylogenetic trees.
    Comput Appl Biosci. 1997 Jun;13(3):235-8 PMID: 9183526
  55. The UCSC Genome Browser Database: update 2009.
    Nucleic Acids Res. 2009 Jan;37(Database issue):D755-61 PMID: 18996895
  56. Rfam: updates to the RNA families database.
    Nucleic Acids Res. 2009 Jan;37(Database issue):D136-40 PMID: 18953034
  57. Performance and scalability of discriminative metrics for comparative gene identification in 12 Drosophila genomes.
    PLoS Comput Biol. 2008 Apr 18;4(4):e1000067 PMID: 18421375
  58. Peptides encoded by short ORFs control development and define a new eukaryotic gene family.
    PLoS Biol. 2007 May;5(5):e106 PMID: 17439302
  59. Finding the genes in genomic DNA.
    Curr Opin Struct Biol. 1998 Jun;8(3):346-54 PMID: 9666331
  60. In vitro analysis of the interaction between the small RNA SR1 and its primary target ahrC mRNA.
    Nucleic Acids Res. 2007;35(13):4331-46 PMID: 17576690
  61. Small peptides switch the transcriptional activity of Shavenbaby during Drosophila embryogenesis.
    Science. 2010 Jul 16;329(5989):336-9 PMID: 20647469
  62. Metatranscriptomics reveals unique microbial small RNAs in the ocean's water column.
    Nature. 2009 May 14;459(7244):266-9 PMID: 19444216
  63. Variation in evolutionary processes at different codon positions.
    Mol Biol Evol. 2007 Feb;24(2):513-21 PMID: 17119011
  64. Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures.
    Nature. 2007 Nov 8;450(7167):219-32 PMID: 17994088
  65. A dual-function sRNA from B. subtilis: SR1 acts as a peptide encoding mRNA on the gapA operon.
    Mol Microbiol. 2010 May;76(4):990-1009 PMID: 20444087
  66. nGASP--the nematode genome annotation assessment project.
    BMC Bioinformatics. 2008 Dec 19;9:549 PMID: 19099578
Article Info
Journal
RNA (New York, N.Y.)
Abbr.
RNA
ISSN
1469-9001
DOI
10.1261/rna.2536111
Email
wash@mit.edu
Published
2011-04-00
Epub
2011-00-28
Pages
578-94
Language
English
Region
United States
NLM ID
9509184
PMCID
PMC3062170
Subset
IM
External Links
PubMed source DOI: 10.1261/rna.2536111 PMC Full Text View journal details
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