title: Differences in enhancer activity in mouse and zebrafish reporter assays are often associated with changes in gene expression.
abstract: BACKGROUND
  Phenotypic evolution in animals is thought to be driven in large part by differences in gene expression patterns, which can result from sequence changes in cis-regulatory elements (cis-changes) or from changes in the expression pattern or function of transcription factors (trans-changes). While isolated examples of trans-changes have been identified, the scale of their overall contribution to regulatory and phenotypic evolution remains unclear.
  
  
  RESULTS
  Here, we attempt to examine the prevalence of trans-effects and their potential impact on gene expression patterns in vertebrate evolution by comparing the function of identical human tissue-specific enhancer sequences in two highly divergent vertebrate model systems, mouse and zebrafish. Among 47 human conserved non-coding elements (CNEs) tested in transgenic mouse embryos and in stable zebrafish lines, at least one species-specific expression domain was observed in the majority (83%) of cases, and 36% presented dramatically different expression patterns between the two species. Although some of these discrepancies may be due to the use of different transgenesis systems in mouse and zebrafish, in some instances we found an association between differences in enhancer activity and changes in the endogenous gene expression patterns between mouse and zebrafish, suggesting a potential role for trans-changes in the evolution of gene expression.
  
  
  CONCLUSIONS
  In total, our results: (i) serve as a cautionary tale for studies investigating the role of human enhancers in different model organisms, and (ii) suggest that changes in the trans environment may play a significant role in the evolution of gene expression in vertebrates.
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD), CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Ctra. Utrera Km 1, Seville 41013, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ariza-Cosano
authors.forename: Axel
authors.initials: A
authors.lastname: Visel
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Hunter B
authors.initials: HB
authors.lastname: Fraser
authors.forename: José Luis
authors.initials: JL
authors.lastname: Gómez-Skarmeta
authors.forename: Manuel
authors.initials: M
authors.lastname: Irimia
authors.forename: José
authors.initials: J
authors.lastname: Bessa
mesh_terms: D000818:Animals; D017124:Conserved Sequence / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D019143:Evolution, Molecular; D005786:Gene Expression Regulation / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D014157:Transcription Factors