Open Access Highly Accessed Research article

Differences in enhancer activity in mouse and zebrafish reporter assays are often associated with changes in gene expression

Ana Ariza-Cosano1, Axel Visel23, Len A Pennacchio23, Hunter B Fraser4, José Luis Gómez-Skarmeta1*, Manuel Irimia45* and José Bessa1*

Author Affiliations

1 Centro Andaluz de Biología del Desarrollo (CABD), CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Ctra. Utrera Km 1, Seville, 41013, Spain

2 Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA

3 U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA, 94598, USA

4 Department of Biology, Stanford University, Stanford, CA, 94305, USA

5 The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario, M5S 3E1, Canada

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BMC Genomics 2012, 13:713  doi:10.1186/1471-2164-13-713

Published: 19 December 2012



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.


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.


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.

Evolution; Vertebrates; Trans-changes; Trans-evolution; Enhancers