CoChat
Sign Up
Cited by 72Genomics and Phylogenetic StudiesGenomics and Chromatin DynamicsChromosomal and Genetic Variations

Computational methods to detect conserved non-genic elements in phylogenetically isolated genomes: application to zebrafish

Open access
Hiller, Michael, Agarwal, Saatvik, Notwell, James H., Parikh, Ravi, Guturu, Harendra, Wenger, Aaron M., Bejerano, Gill·2013·Nucleic Acids Research
DOI 10.1093/nar/gkt557PMC PMC3753653
Open this paper in CoChat — free account

Abstract

Many important model organisms for biomedical and evolutionary research have sequenced genomes, but occupy a phylogenetically isolated position, evolutionarily distant from other sequenced genomes. This phylogenetic isolation is exemplified for zebrafish, a vertebrate model for cis-regulation, development and human disease, whose evolutionary distance to all other currently sequenced fish exceeds the distance between human and chicken. Such large distances make it difficult to align genomes and use them for comparative analysis beyond gene-focused questions. In particular, detecting conserved non-genic elements (CNEs) as promising cis-regulatory elements with biological importance is challenging. Here, we develop a general comparative genomics framework to align isolated genomes and to comprehensively detect CNEs. Our approach integrates highly sensitive and quality-controlled local alignments and uses alignment transitivity and ancestral reconstruction to bridge large evolutionary distances. We apply our framework to zebrafish and demonstrate substantially improved CNE detection and quality compared with previous sets. Our zebrafish CNE set comprises 54 533 CNEs, of which 11 792 (22%) are conserved to human or mouse. Our zebrafish CNEs (http://zebrafish.stanford.edu) are highly enriched in known enhancers and extend existing experimental (ChIP-Seq) sets. The same framework can now be applied to the isolated genomes of frog, amphioxus, Caenorhabditis elegans and many others.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/nar/gkt557

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Placental mammals are separated by an evolutionary distance of ~0.5 or fewer substitutions per neutral site.

    “Since placental mammals are separated by an evolutionary distance of ~0.5 or fewer substitutions per neutral site61”

    From A genomics approach reveals insights into the importance of gene losses for mammalian adaptations (2018) · cites this paper as [61]

    The Introduction’s Figure 1 caption identifies human and mouse as a comparatively close pair and describes evolutionary distances in neutral substitutions per site. The Discussion likewise uses the human–mouse distance as a benchmark, but the available text gives neither a value of ~0.5 nor an upper bound for placental mammals generally. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 58

  1. [1]Stark A Lin MF Kheradpour P Pedersen JS Parts L Carlson JW Crosby MA Rasmussen MD Roy S Deoras AN Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures Nature 2007 450 219 232 17994088 PMC2474711
  2. [2]Lindblad-Toh K Garber M Zuk O Lin MF Parker BJ Washietl S Kheradpour P Ernst J Jordan G Mauceli E A high-resolution map of human evolutionary constraint using 29 mammals Nature 2011 478 476 482 21993624 PMC3207357
  3. [3]Waterston RH Lindblad-Toh K Birney E Rogers J Abril JF Agarwal P Agarwala R Ainscough R Alexandersson M An P Initial sequencing and comparative analysis of the mouse genome Nature 2002 420 520 562 12466850
  4. [4]Hillier LW Miller W Birney E Warren W Hardison RC Ponting CP Bork P Burt DW Groenen MA Delany ME Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution Nature 2004 432 695 716 15592404
  5. [6]Birney E Stamatoyannopoulos JA Dutta A Guigo R Gingeras TR Margulies EH Weng Z Snyder M Dermitzakis ET Thurman RE Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project Nature 2007 447 799 816 17571346 PMC2212820
  6. [7]Woolfe A Goodson M Goode DK Snell P McEwen GK Vavouri T Smith SF North P Callaway H Kelly K Highly conserved non-coding sequences are associated with vertebrate development PLoS Biol. 2005 3 e7 15630479 PMC526512
  7. [9]Visel A Prabhakar S Akiyama JA Shoukry M Lewis KD Holt A Plajzer-Frick I Afzal V Rubin EM Pennacchio LA Ultraconservation identifies a small subset of extremely constrained developmental enhancers Nat. Genet. 2008 40 158 160 18176564 PMC2647775
  8. [10]Shin JT Priest JR Ovcharenko I Ronco A Moore RK Burns CG MacRae CA Human-zebrafish non-coding conserved elements act in vivo to regulate transcription Nucleic Acids Res. 2005 33 5437 5445 16179648 PMC1236720
  9. [11]Navratilova P Fredman D Hawkins TA Turner K Lenhard B Becker TS Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes Dev. Biol. 2009 327 526 540 19073165
  10. [12]Bejerano G Pheasant M Makunin I Stephen S Kent WJ Mattick JS Haussler D Ultraconserved elements in the human genome Science 2004 304 1321 1325 15131266
  11. [13]Sandelin A Bailey P Bruce S Engstrom PG Klos JM Wasserman WW Ericson J Lenhard B Arrays of ultraconserved non-coding regions span the loci of key developmental genes in vertebrate genomes BMC Genomics 2004 5 99 15613238 PMC544600
  12. [14]Vavouri T Walter K Gilks WR Lehner B Elgar G Parallel evolution of conserved non-coding elements that target a common set of developmental regulatory genes from worms to humans Genome Biol. 2007 8 R15 17274809 PMC1852409
  13. [15]Ragvin A Moro E Fredman D Navratilova P Drivenes O Engstrom PG Alonso ME de la Calle Mustienes E Gomez Skarmeta JL Tavares MJ Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3 Proc. Natl Acad. Sci. USA 2010 107 775 780 20080751 PMC2818943
  14. [16]Wasserman NF Aneas I Nobrega MA An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer Genome Res. 2010 20 1191 1197 20627891 PMC2928497
  15. [18]Kleinjan DA Lettice LA Long-range gene control and genetic disease Adv. Genet. 2008 61 339 388 18282513
  16. [19]Miller W Makova KD Nekrutenko A Hardison RC Comparative genomics Annu. Rev. Genomics Hum. Genet. 2004 5 15 56 15485342
  17. [20]Margulies EH Chen CW Green ED Differences between pair-wise and multi-sequence alignment methods affect vertebrate genome comparisons Trends Genet. 2006 22 187 193 16499991
  18. [21]Clarke SL VanderMeer JE Wenger AM Schaar BT Ahituv N Bejerano G Human developmental enhancers conserved between deuterostomes and protostomes PLoS Genet. 2012 8 e1002852 22876195 PMC3410860
  19. [22]Sodergren E Weinstock GM Davidson EH Cameron RA Gibbs RA Angerer RC Angerer LM Arnone MI Burgess DR Burke RD The genome of the sea urchin Strongylocentrotus purpuratus Science 2006 314 941 952 17095691 PMC3159423
  20. [23]Putnam NH Butts T Ferrier DE Furlong RF Hellsten U Kawashima T Robinson-Rechavi M Shoguchi E Terry A Yu JK The amphioxus genome and the evolution of the chordate karyotype Nature 2008 453 1064 1071 18563158
  21. [24]Hellsten U Harland RM Gilchrist MJ Hendrix D Jurka J Kapitonov V Ovcharenko I Putnam NH Shu S Taher L The genome of the Western clawed frog Xenopus tropicalis Science 2010 328 633 636 20431018 PMC2994648
  22. [26]Chapman JA Kirkness EF Simakov O Hampson SE Mitros T Weinmaier T Rattei T Balasubramanian PG Borman J Busam D The dynamic genome of Hydra Nature 2010 464 592 596 20228792 PMC4479502
  23. [28]Dreszer TR Karolchik D Zweig AS Hinrichs AS Raney BJ Kuhn RM Meyer LR Wong M Sloan CA Rosenbloom KR The UCSC Genome Browser database: extensions and updates 2011 Nucleic Acids Res. 2012 40 D918 D923 22086951 PMC3245018
  24. [30]Lieschke GJ Currie PD Animal models of human disease: zebrafish swim into view Nat. Rev. Genet. 2007 8 353 367 17440532
  25. [31]Becker TS Rinkwitz S Zebrafish as a genomics model for human neurological and polygenic disorders Dev. Neurobiol. 2012 72 415 428 21465670
  26. [33]Woolfe A Goode DK Cooke J Callaway H Smith S Snell P McEwen GK Elgar G CONDOR: a database resource of developmentally associated conserved non-coding elements BMC Dev. Biol. 2007 7 100 17760977 PMC2020477
  27. [34]Engstrom PG Fredman D Lenhard B Ancora: a web resource for exploring highly conserved noncoding elements and their association with developmental regulatory genes Genome Biol. 2008 9 R34 18279518 PMC2374709
  28. [35]Persampieri J Ritter DI Lees D Lehoczky J Li Q Guo S Chuang JH cneViewer: a database of conserved non-coding elements for studies of tissue-specific gene regulation Bioinformatics 2008 24 2418 2419 18718943 PMC2562007
  29. [36]Kai W Kikuchi K Tohari S Chew AK Tay A Fujiwara A Hosoya S Suetake H Naruse K Brenner S Integration of the genetic map and genome assembly of fugu facilitates insights into distinct features of genome evolution in teleosts and mammals Genome Biol. Evol. 2011 3 424 442 21551351 PMC5654407
  30. [37]Schwartz S Kent WJ Smit A Zhang Z Baertsch R Hardison RC Haussler D Miller W Human-mouse alignments with BLASTZ Genome Res. 2003 13 103 107 12529312 PMC430961
  31. [38]Altschul SF Gish W Miller W Myers EW Lipman DJ Basic local alignment search tool J. Mol. Biol. 1990 215 403 410 2231712
  32. [39]Kent WJ Baertsch R Hinrichs A Miller W Haussler D Evolution's cauldron: duplication, deletion, and rearrangement in the mouse and human genomes Proc. Natl Acad. Sci. USA 2003 100 11484 11489 14500911 PMC208784
  33. [40]Akalin A Fredman D Arner E Dong X Bryne JC Suzuki H Daub CO Hayashizaki Y Lenhard B Transcriptional features of genomic regulatory blocks Genome Biol. 2009 10 R38 19374772 PMC2688929
  34. [41]Blanchette M Kent WJ Riemer C Elnitski L Smit AF Roskin KM Baertsch R Rosenbloom K Clawson H Green ED Aligning multiple genomic sequences with the threaded blockset aligner Genome Res. 2004 14 708 715 15060014 PMC383317
  35. [42]Wenger AM Clarke SL Guturu H Chen J Schaar BT McLean CY Bejerano G PRISM offers a comprehensive genomic approach to transcription factor function prediction Genome Res. 2013 23 889 904 23382538 PMC3638144
  36. [43]Venkatesh B Kirkness EF Loh YH Halpern AL Lee AP Johnson J Dandona N Viswanathan LD Tay A Venter JC Survey sequencing and comparative analysis of the elephant shark (Callorhinchus milii) genome PLoS Biol. 2007 5 e101 17407382 PMC1845163
  37. [44]Washietl S Findeiss S Muller SA Kalkhof S von Bergen M Hofacker IL Stadler PF Goldman N RNAcode: robust discrimination of coding and noncoding regions in comparative sequence data RNA 2011 17 578 594 21357752 PMC3062170
  38. [45]Taher L McGaughey DM Maragh S Aneas I Bessling SL Miller W Nobrega MA McCallion AS Ovcharenko I Genome-wide identification of conserved regulatory function in diverged sequences Genome Res. 2011 21 1139 1149 21628450 PMC3129256
  39. [47]Blanchette M Green ED Miller W Haussler D Reconstructing large regions of an ancestral mammalian genome in silico Genome Res. 2004 14 2412 2423 15574820 PMC534665
  40. [48]Hubisz MJ Pollard KS Siepel A PHAST and RPHAST: phylogenetic analysis with space/time models Brief Bioinform. 2011 12 41 51 21278375 PMC3030812
  41. [49]Lowe CB Kellis M Siepel A Raney BJ Clamp M Salama SR Kingsley DM Lindblad-Toh K Haussler D Three periods of regulatory innovation during vertebrate evolution Science 2011 333 1019 1024 21852499 PMC3511857
  42. [50]Creyghton MP Cheng AW Welstead GG Kooistra T Carey BW Steine EJ Hanna J Lodato MA Frampton GM Sharp PA Histone H3K27ac separates active from poised enhancers and predicts developmental state Proc. Natl Acad. Sci. USA 2010 107 21931 21936 21106759 PMC3003124
  43. [51]Aday AW Zhu LJ Lakshmanan A Wang J Lawson ND Identification of cis regulatory features in the embryonic zebrafish genome through large-scale profiling of H3K4me1 and H3K4me3 binding sites Dev. Biol. 2011 357 450 462 21435340 PMC3273848
  44. [52]Bogdanovic O Fernandez-Minan A Tena JJ de la Calle-Mustienes E Hidalgo C van Kruysbergen I van Heeringen SJ Veenstra GJ Gomez-Skarmeta JL Dynamics of enhancer chromatin signatures mark the transition from pluripotency to cell specification during embryogenesis Genome Res. 2012 22 2043 2053 22593555 PMC3460198
  45. [53]Visel A Minovitsky S Dubchak I Pennacchio LA VISTA Enhancer Browser—a database of tissue-specific human enhancers Nucleic Acids Res. 2007 35 D88 D92 17130149 PMC1716724
  46. [54]Lowe CB Bejerano G Haussler D Thousands of human mobile element fragments undergo strong purifying selection near developmental genes Proc. Natl Acad. Sci. USA 2007 104 8005 8010 17463089 PMC1876562
  47. [56]Scharff C Petri J Evo-devo, deep homology and FoxP2: implications for the evolution of speech and language Philos. Trans. R Soc. Lond. B Biol. Sci. 2011 366 2124 2140 21690130 PMC3130369
  48. [57]Qin Z Ren F Xu X Ren Y Li H Wang Y Zhai Y Chang Z ZNF536, a novel zinc finger protein specifically expressed in the brain, negatively regulates neuron differentiation by repressing retinoic acid-induced gene transcription Mol. Cell. Biol. 2009 29 3633 3643 19398580 PMC2698762
  49. [58]Bartsch O Schindler D Beyer V Gesk S van't Slot R Feddersen I Buijs A Jaspers NG Siebert R Haaf T A girl with an atypical form of ataxia telangiectasia and an additional de novo 3.14 Mb microduplication in region 19q12 Eur. J. Med. Genet. 2012 55 49 55 21893220
  50. [59]Blow MJ McCulley DJ Li Z Zhang T Akiyama JA Holt A Plajzer-Frick I Shoukry M Wright C Chen F ChIP-Seq identification of weakly conserved heart enhancers Nat. Genet. 2010 42 806 810 20729851 PMC3138496
  51. [60]McEwen GK Goode DK Parker HJ Woolfe A Callaway H Elgar G Early evolution of conserved regulatory sequences associated with development in vertebrates PLoS Genet. 2009 5 e1000762 20011110 PMC2781166
  52. [61]Prabhakar S Poulin F Shoukry M Afzal V Rubin EM Couronne O Pennacchio LA Close sequence comparisons are sufficient to identify human cis-regulatory elements Genome Res. 2006 16 855 863 16769978 PMC1484452
  53. [62]Bradford Y Conlin T Dunn N Fashena D Frazer K Howe DG Knight J Mani P Martin R Moxon SA ZFIN: enhancements and updates to the Zebrafish Model Organism Database Nucleic Acids Res. 2011 39 D822 D829 21036866 PMC3013679
  54. [63]Flicek P Amode MR Barrell D Beal K Brent S Carvalho-Silva D Clapham P Coates G Fairley S Fitzgerald S Ensembl 2012 Nucleic Acids Res. 2012 40 D84 D90 22086963 PMC3245178
  55. [64]Mayden RL Tang KL Conway KW Freyhof J Chamberlain S Haskins M Schneider L Sudkamp M Wood RM Agnew M Phylogenetic relationships of Danio within the order Cypriniformes: a framework for comparative and evolutionary studies of a model species J. Exp. Zool. B Mol. Dev. Evol. 2007 308 642 654 17554749
  56. [65]Kong X Wang X Gan X Li J He S Phylogenetic relationships of Cyprinidae (Teleostei: Cypriniformes) inferred from the partial S6K1 gene sequences and implication of indel sites in intron 1 Sci. China C Life Sci. 2007 50 780 788 17882385
  57. [66]Bernardi G Wiley EO Mansour H Miller MR Orti G Haussler D O'Brien SJ Ryder OA Venkatesh B The fishes of Genome 10K Mar. Genomics 2012 7 3 6 22897955
  58. [67]McGaughey DM Vinton RM Huynh J Al-Saif A Beer MA McCallion AS Metrics of sequence constraint overlook regulatory sequences in an exhaustive analysis at phox2b Genome Res. 2008 18 252 260 18071029 PMC2203623

Cited by

Sorted by citations

Authors
Hiller, M., Agarwal, S., Notwell, J. H., Parikh, R., Guturu, H., Wenger, A. M., & Bejerano, G.
Affiliations
Stanford University (US)
Corresponding author
  • Hiller, Michael
  • Bejerano, Gill
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2013-06-27
Volume
41
Issue
15
Pages
e151-e151
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkt557
PMC
PMC3753653
OpenAlex
W2170009799
Cited by
72
References
8
Citations by year
2026: 2 · 2025: 1 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 6 · 2020: 5 · 2019: 15 · 2018: 9 · 2017: 6 · 2016: 4 · 2015: 2 · 2014: 1
FWCI
0.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
  • University of California, Santa Cruz
  • Centre National d’Etudes Spatiales
  • National Human Genome Research Institute (R01HG005058)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD059862)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
Keywords
zebrafish, cis-regulatory elements, enhancers, comparative genomics, genome alignment, ancestral sequence reconstruction, local alignment, ChIP-seq
MeSH terms
Animals, Base Sequence, Phylogeny, Regulatory Sequences, Nucleic Acid, Sensitivity and Specificity, Zebrafish, Sequence Alignment, Conserved Sequence, Sequence Analysis, DNA, Evolution, Molecular, Computational Biology, Internet, Genomics, Synteny, Molecular Sequence Annotation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review