Home LiteratureArticle Details
PMID: 16024819 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.

Genome research ·Vol. 15 ·No. 8 ·2005-08-00 ·Pages 1034-50

Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, Clawson H, Spieth J, Hillier LW, Richards S, Weinstock GM, Wilson RK, Gibbs RA, Kent WJ, Miller W, Haussler D

Abstract

We have conducted a comprehensive search for conserved elements in vertebrate genomes, using genome-wide multiple alignments of five vertebrate species (human, mouse, rat, chicken, and Fugu rubripes). Parallel searches have been performed with multiple alignments of four insect species (three species of Drosophila and Anopheles gambiae), two species of Caenorhabditis, and seven species of Saccharomyces. Conserved elements were identified with a computer program called phastCons, which is based on a two-state phylogenetic hidden Markov model (phylo-HMM). PhastCons works by fitting a phylo-HMM to the data by maximum likelihood, subject to constraints designed to calibrate the model across species groups, and then predicting conserved elements based on this model. The predicted elements cover roughly 3%-8% of the human genome (depending on the details of the calibration procedure) and substantially higher fractions of the more compact Drosophila melanogaster (37%-53%), Caenorhabditis elegans (18%-37%), and Saccharaomyces cerevisiae (47%-68%) genomes. From yeasts to vertebrates, in order of increasing genome size and general biological complexity, increasing fractions of conserved bases are found to lie outside of the exons of known protein-coding genes. In all groups, the most highly conserved elements (HCEs), by log-odds score, are hundreds or thousands of bases long. These elements share certain properties with ultraconserved elements, but they tend to be longer and less perfectly conserved, and they overlap genes of somewhat different functional categories. In vertebrates, HCEs are associated with the 3' UTRs of regulatory genes, stable gene deserts, and megabase-sized regions rich in moderately conserved noncoding sequences. Noncoding HCEs also show strong statistical evidence of an enrichment for RNA secondary structure.

MeSH Terms
3' Untranslated Regions Animals Base Pairing/genetics Base Sequence Caenorhabditis elegans/genetics Conserved Sequence DNA, Intergenic Evolution, Molecular Genome Humans Insecta/genetics Molecular Sequence Data Saccharomyces/genetics Vertebrates/genetics Yeasts/genetics
Chemicals
3' Untranslated Regions DNA, Intergenic
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Siepel Adam
Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, California 95064, USA. acs@soe.ucsc.edu
Bejerano Gill
Pedersen Jakob S
Hinrichs Angie S
Hou Minmei
Rosenbloom Kate
Clawson Hiram
Spieth John
Hillier Ladeana W
Richards Stephen
Weinstock George M
Wilson Richard K
Gibbs Richard A
Kent W James
Miller Webb
Haussler David
References (91)
91 references, click to expand
  1. Phylogenetic shadowing of primate sequences to find functional regions of the human genome.
    Science. 2003 Feb 28;299(5611):1391-4 PMID: 12610304
  2. Widespread occurrence of antisense transcription in the human genome.
    Nat Biotechnol. 2003 Apr;21(4):379-86 PMID: 12640466
  3. LAGAN and Multi-LAGAN: efficient tools for large-scale multiple alignment of genomic DNA.
    Genome Res. 2003 Apr;13(4):721-31 PMID: 12654723
  4. Sequencing and comparison of yeast species to identify genes and regulatory elements.
    Nature. 2003 May 15;423(6937):241-54 PMID: 12748633
  5. Intronic sequences flanking alternatively spliced exons are conserved between human and mouse.
    Genome Res. 2003 Jul;13(7):1631-7 PMID: 12840041
  6. Nervous system targets of RNA editing identified by comparative genomics.
    Science. 2003 Aug 8;301(5634):832-6 PMID: 12907802
  7. Comparative analyses of multi-species sequences from targeted genomic regions.
    Nature. 2003 Aug 14;424(6950):788-93 PMID: 12917688
  8. Evolution's cauldron: duplication, deletion, and rearrangement in the mouse and human genomes.
    Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11484-9 PMID: 14500911
  9. Mechanisms of alternative pre-messenger RNA splicing.
    Annu Rev Biochem. 2003;72:291-336 PMID: 12626338
  10. Transposable elements in mammals promote regulatory variation and diversification of genes with specialized functions.
    Trends Genet. 2003 Oct;19(10):530-6 PMID: 14550626
  11. Mobile elements inserted in the distant past have taken on important functions.
    Gene. 1997 Dec 31;205(1-2):177-82 PMID: 9461392
  12. RNA secondary structure prediction using stochastic context-free grammars and evolutionary history.
    Bioinformatics. 1999 Jun;15(6):446-54 PMID: 10383470
  13. Comparison of five methods for finding conserved sequences in multiple alignments of gene regulatory regions.
    Nucleic Acids Res. 1999 Oct 1;27(19):3899-910 PMID: 10481030
  14. Pattern of selective constraint in C. elegans and C. briggsae genomes.
    Genet Res. 1999 Aug;74(1):23-30 PMID: 10505405
  15. Human MicroRNA targets.
    PLoS Biol. 2004 Nov;2(11):e363 PMID: 15502875
  16. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution.
    Nature. 2004 Dec 9;432(7018):695-716 PMID: 15592404
  17. Improvements to GALA and dbERGE II: databases featuring genomic sequence alignment, annotation and experimental results.
    Nucleic Acids Res. 2005 Jan 1;33(Database issue):D466-70 PMID: 15608239
  18. WormBase: a multi-species resource for nematode biology and genomics.
    Nucleic Acids Res. 2004 Jan 1;32(Database issue):D411-7 PMID: 14681445
  19. MicroRNA targets in Drosophila.
    Genome Biol. 2003;5(1):R1 PMID: 14709173
  20. Analysis of multiple genomic sequence alignments: a web resource, online tools, and lessons learned from analysis of mammalian SCL loci.
    Genome Res. 2004 Feb;14(2):313-8 PMID: 14718377
  21. Scanning human gene deserts for long-range enhancers.
    Science. 2003 Oct 17;302(5644):413 PMID: 14563999
  22. Noncoding RNA gene detection using comparative sequence analysis.
    BMC Bioinformatics. 2001;2:8 PMID: 11801179
  23. Mutation rate variation in the mammalian genome.
    Curr Opin Genet Dev. 2003 Dec;13(6):562-8 PMID: 14638315
  24. Identification and characterization of multi-species conserved sequences.
    Genome Res. 2003 Dec;13(12):2507-18 PMID: 14656959
  25. Evolutionary conservation of a 2-kb intronic sequence flanking a tissue-specific alternative exon in the PTBP2 gene.
    Genomics. 2004 Jan;83(1):76-84 PMID: 14667811
  26. Characterization of the pufferfish Otx2 cis-regulators reveals evolutionarily conserved genetic mechanisms for vertebrate head specification.
    Development. 2004 Jan;131(1):57-71 PMID: 14645121
  27. Saccharomyces Genome Database (SGD) provides tools to identify and analyze sequences from Saccharomyces cerevisiae and related sequences from other organisms.
    Nucleic Acids Res. 2004 Jan 1;32(Database issue):D311-4 PMID: 14681421
  28. MAVID: constrained ancestral alignment of multiple sequences.
    Genome Res. 2004 Apr;14(4):693-9 PMID: 15060012
  29. Aligning multiple genomic sequences with the threaded blockset aligner.
    Genome Res. 2004 Apr;14(4):708-15 PMID: 15060014
  30. In search of antisense.
    Trends Biochem Sci. 2004 Feb;29(2):88-94 PMID: 15102435
  31. MicroRNA-directed cleavage of HOXB8 mRNA.
    Science. 2004 Apr 23;304(5670):594-6 PMID: 15105502
  32. Ultraconserved elements in the human genome.
    Science. 2004 May 28;304(5675):1321-5 PMID: 15131266
  33. Into the heart of darkness: large-scale clustering of human non-coding DNA.
    Bioinformatics. 2004 Aug 4;20 Suppl 1:i40-8 PMID: 15262779
  34. Efficient identification of regulatory sequences in the chicken genome by a powerful combination of embryo electroporation and genome comparison.
    Mech Dev. 2004 Sep;121(9):1145-58 PMID: 15296978
  35. The share of human genomic DNA under selection estimated from human-mouse genomic alignments.
    Cold Spring Harb Symp Quant Biol. 2003;68:245-54 PMID: 15338624
  36. A comparative method for finding and folding RNA secondary structures within protein-coding regions.
    Nucleic Acids Res. 2004;32(16):4925-36 PMID: 15448187
  37. Bayesian Markov chain Monte Carlo sequence analysis reveals varying neutral substitution patterns in mammalian evolution.
    Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):13994-4001 PMID: 15292512
  38. Evidence for turnover of functional noncoding DNA in mammalian genome evolution.
    Genomics. 2004 Nov;84(5):806-13 PMID: 15475259
  39. Megabase deletions of gene deserts result in viable mice.
    Nature. 2004 Oct 21;431(7011):988-93 PMID: 15496924
  40. The ENCODE (ENCyclopedia Of DNA Elements) Project.
    Science. 2004 Oct 22;306(5696):636-40 PMID: 15499007
  41. Mutation rates differ among regions of the mammalian genome.
    Nature. 1989 Jan 19;337(6204):283-5 PMID: 2911369
  42. Strong conservation of non-coding sequences during vertebrates evolution: potential involvement in post-transcriptional regulation of gene expression.
    Nucleic Acids Res. 1993 May 25;21(10):2315-22 PMID: 8506129
  43. A space-time process model for the evolution of DNA sequences.
    Genetics. 1995 Feb;139(2):993-1005 PMID: 7713447
  44. A Hidden Markov Model approach to variation among sites in rate of evolution.
    Mol Biol Evol. 1996 Jan;13(1):93-104 PMID: 8583911
  45. Control of messenger RNA stability in higher eukaryotes.
    Trends Genet. 1996 May;12(5):171-5 PMID: 8984731
  46. Making (anti)sense of non-coding sequence conservation.
    Nucleic Acids Res. 1997 Sep 15;25(18):3580-3 PMID: 9278476
  47. Long human-mouse sequence alignments reveal novel regulatory elements: a reason to sequence the mouse genome.
    Genome Res. 1997 Oct;7(10):959-66 PMID: 9331366
  48. Transcriptome and genome conservation of alternative splicing events in humans and mice.
    Pac Symp Biocomput. 2004;:66-77 PMID: 14992493
  49. Noncoding sequences conserved in a limited number of mammals in the SIM2 interval are frequently functional.
    Genome Res. 2004 Mar;14(3):367-72 PMID: 14962988
  50. zPicture: dynamic alignment and visualization tool for analyzing conservation profiles.
    Genome Res. 2004 Mar;14(3):472-7 PMID: 14993211
  51. Phylogenetic estimation of context-dependent substitution rates by maximum likelihood.
    Mol Biol Evol. 2004 Mar;21(3):468-88 PMID: 14660683
  52. The genome sequence of Caenorhabditis briggsae: a platform for comparative genomics.
    PLoS Biol. 2003 Nov;1(2):E45 PMID: 14624247
  53. Genome sequence of the Brown Norway rat yields insights into mammalian evolution.
    Nature. 2004 Apr 1;428(6982):493-521 PMID: 15057822
  54. Characterization of evolutionary rates and constraints in three Mammalian genomes.
    Genome Res. 2004 Apr;14(4):539-48 PMID: 15059994
  55. Highly conserved non-coding sequences are associated with vertebrate development.
    PLoS Biol. 2005 Jan;3(1):e7 PMID: 15630479
  56. Mulan: multiple-sequence local alignment and visualization for studying function and evolution.
    Genome Res. 2005 Jan;15(1):184-94 PMID: 15590941
  57. Evolution and functional classification of vertebrate gene deserts.
    Genome Res. 2005 Jan;15(1):137-45 PMID: 15590943
  58. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.
    Cell. 2005 Jan 14;120(1):15-20 PMID: 15652477
  59. Naturally occurring antisense: transcriptional leakage or real overlap?
    Genome Res. 2005 Mar;15(3):364-8 PMID: 15710751
  60. Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals.
    Nature. 2005 Mar 17;434(7031):338-45 PMID: 15735639
  61. Generation and annotation of the DNA sequences of human chromosomes 2 and 4.
    Nature. 2005 Apr 7;434(7034):724-31 PMID: 15815621
  62. Combinatorial microRNA target predictions.
    Nat Genet. 2005 May;37(5):495-500 PMID: 15806104
  63. Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution.
    Science. 2005 May 20;308(5725):1149-54 PMID: 15790807
  64. Ultraconserved elements in insect genomes: a highly conserved intronic sequence implicated in the control of homothorax mRNA splicing.
    Genome Res. 2005 Jun;15(6):800-8 PMID: 15899965
  65. Evaluation of regulatory potential and conservation scores for detecting cis-regulatory modules in aligned mammalian genome sequences.
    Genome Res. 2005 Aug;15(8):1051-60 PMID: 16024817
  66. Analysis of complex disease association and linkage studies using the University of California Santa Cruz Genome Browser.
    Circ Cardiovasc Genet. 2009 Apr;2(2):199-204 PMID: 20031585
  67. Cuticle collagen genes. Expression in Caenorhabditis elegans.
    Trends Genet. 2000 Jan;16(1):21-7 PMID: 10637627
  68. A phylogenetic analysis reveals an unusual sequence conservation within introns involved in RNA editing.
    RNA. 2000 Feb;6(2):257-69 PMID: 10688364
  69. Comparative genomics of the eukaryotes.
    Science. 2000 Mar 24;287(5461):2204-15 PMID: 10731134
  70. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons.
    Science. 2000 Apr 7;288(5463):136-40 PMID: 10753117
  71. PipMaker--a web server for aligning two genomic DNA sequences.
    Genome Res. 2000 Apr;10(4):577-86 PMID: 10779500
  72. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
    Nat Genet. 2000 May;25(1):25-9 PMID: 10802651
  73. VISTA : visualizing global DNA sequence alignments of arbitrary length.
    Bioinformatics. 2000 Nov;16(11):1046-7 PMID: 11159318
  74. Selective constraint in intergenic regions of human and mouse genomes.
    Trends Genet. 2001 Jul;17(7):373-6 PMID: 11418197
  75. The search for meaning in noncoding DNA.
    Genome Res. 2001 Aug;11(8):1319-20 PMID: 11483570
  76. Analysis of conserved noncoding DNA in Drosophila reveals similar constraints in intergenic and intronic sequences.
    Genome Res. 2001 Aug;11(8):1335-45 PMID: 11483574
  77. Evolutionarily conserved sequences on human chromosome 21.
    Genome Res. 2001 Oct;11(10):1651-9 PMID: 11591642
  78. Regulatory functions of 3'UTRs.
    Biochem Biophys Res Commun. 2001 Oct 26;288(2):291-5 PMID: 11606041
  79. Untranslated regions of mRNAs.
    Genome Biol. 2002;3(3):REVIEWS0004 PMID: 11897027
  80. BLAT--the BLAST-like alignment tool.
    Genome Res. 2002 Apr;12(4):656-64 PMID: 11932250
  81. Computational discovery of sense-antisense transcription in the human and mouse genomes.
    Genome Biol. 2002 Aug 22;3(9):RESEARCH0044 PMID: 12225583
  82. Initial sequencing and comparative analysis of the mouse genome.
    Nature. 2002 Dec 5;420(6915):520-62 PMID: 12466850
  83. Numerous potentially functional but non-genic conserved sequences on human chromosome 21.
    Nature. 2002 Dec 5;420(6915):578-82 PMID: 12466853
  84. NCBI Reference Sequence project: update and current status.
    Nucleic Acids Res. 2003 Jan 1;31(1):34-7 PMID: 12519942
  85. The UCSC Genome Browser Database.
    Nucleic Acids Res. 2003 Jan 1;31(1):51-4 PMID: 12519945
  86. The FlyBase database of the Drosophila genome projects and community literature.
    Nucleic Acids Res. 2003 Jan 1;31(1):172-5 PMID: 12519974
  87. Rfam: an RNA family database.
    Nucleic Acids Res. 2003 Jan 1;31(1):439-41 PMID: 12520045
  88. Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution.
    Genome Res. 2003 Jan;13(1):13-26 PMID: 12529302
  89. Human-mouse alignments with BLASTZ.
    Genome Res. 2003 Jan;13(1):103-7 PMID: 12529312
  90. Assessing the impact of comparative genomic sequence data on the functional annotation of the Drosophila genome.
    Genome Biol. 2002;3(12):RESEARCH0086 PMID: 12537575
  91. Origin of a substantial fraction of human regulatory sequences from transposable elements.
    Trends Genet. 2003 Feb;19(2):68-72 PMID: 12547512
Article Info
Journal
Genome research
Abbr.
Genome Res
ISSN
1088-9051
DOI
10.1101/gr.3715005
Email
acs@soe.ucsc.edu
Published
2005-08-00
Epub
2005-00-15
Pages
1034-50
Language
English
Region
United States
NLM ID
9518021
PMCID
PMC1182216
Subset
IM
Grants
NHGRI NIH HHS · P41 HG002371 · United States
NHGRI NIH HHS · R01 HG002238 · United States
NHGRI NIH HHS · IP41HG02371 · United States
NHGRI NIH HHS · HG02238 · United States
External Links
PubMed source DOI: 10.1101/gr.3715005 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2