title: Functionally conserved enhancers with divergent sequences in distant vertebrates.
abstract: BACKGROUND
  To examine the contributions of sequence and function conservation in the evolution of enhancers, we systematically identified enhancers whose sequences are not conserved among distant groups of vertebrate species, but have homologous function and are likely to be derived from a common ancestral sequence. Our approach combined comparative genomics and epigenomics to identify potential enhancer sequences in the genomes of three groups of distantly related vertebrate species.
  
  
  RESULTS
  We searched for sequences that were conserved within groups of closely related species but not between groups of more distant species, and were associated with an epigenetic mark of enhancer activity. To facilitate inferring orthology between non-conserved sequences, we limited our search to introns whose orthology could be unambiguously established by mapping the bracketing exons. We show that a subset of these non-conserved but syntenic sequences from the mouse and zebrafish genomes have homologous functions in a zebrafish transgenic enhancer assay. The conserved expression patterns driven by these enhancers are probably associated with short transcription factor-binding motifs present in the divergent sequences.
  
  
  CONCLUSIONS
  We have identified numerous potential enhancers with divergent sequences but a conserved function. These results indicate that selection on function, rather than sequence, may be a common mode of enhancer evolution; evidence for selection at the sequence level is not a necessary criterion to define a gene regulatory element.
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA. syang@enders.tch.harvard.edu.
authors.forename: Song
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, 94158, USA. niroksenberg@gmail.com.|Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94158, USA. niroksenberg@gmail.com.
authors.forename: Nir
authors.initials: N
authors.lastname: Oksenberg
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, 94609, USA. sachiko.takayama@gmail.com.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Takayama
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, 94609, USA. sheo@chori.org.
authors.forename: Seok-Jin
authors.initials: SJ
authors.lastname: Heo
authors.affiliation: US Department of Energy Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, CA, 94598, USA. AVPoliakov@lbl.gov.
authors.forename: Alexander
authors.initials: A
authors.lastname: Poliakov
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, 94158, USA. nadav.ahituv@ucsf.edu.|Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94158, USA. nadav.ahituv@ucsf.edu.
authors.forename: Nadav
authors.initials: N
authors.lastname: Ahituv
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA. ildubchak@lbl.gov.|US Department of Energy Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, CA, 94598, USA. ildubchak@lbl.gov.
authors.forename: Inna
authors.initials: I
authors.lastname: Dubchak
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, 94609, USA. dboffelli@chori.org.
authors.forename: Dario
authors.initials: D
authors.lastname: Boffelli
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D059372:Nucleotide Motifs; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism; D014714:Vertebrates / Q000235:genetics*
chemical_list: D014157:Transcription Factors