Functionally conserved enhancers with divergent sequences in distant vertebrates

BMC Genomics. 2015 Oct 30;16:882. doi: 10.1186/s12864-015-2070-7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Binding Sites
  • Computational Biology / methods
  • Conserved Sequence*
  • Enhancer Elements, Genetic*
  • Evolution, Molecular
  • Gene Expression Profiling
  • Genetic Variation*
  • Genome-Wide Association Study
  • Nucleotide Motifs
  • Position-Specific Scoring Matrices
  • Protein Binding
  • Reproducibility of Results
  • Transcription Factors / metabolism
  • Vertebrates / genetics*


  • Transcription Factors