PUBLICATION
The Importance of Being Cis: Evolution of Orthologous Fish and Mammalian Enhancer Activity
- Authors
- Ritter, D.I., Li, Q., Kostka, D., Pollard, K.S., Guo, S., and Chuang, J.H.
- ID
- ZDB-PUB-100525-21
- Date
- 2010
- Source
- Mol. Biol. Evol. 27(10): 2322-2332 (Journal)
- Registered Authors
- Guo, Su, Li, Qiang
- Keywords
- enhancer, conserved non-coding elements, evolution, development, transcription factor, expression, cis, trans
- MeSH Terms
-
- Animals
- Conserved Sequence/genetics
- DNA, Intergenic/genetics
- Enhancer Elements, Genetic/genetics*
- Evolution, Molecular*
- Gene Expression Profiling
- Gene Regulatory Networks/genetics*
- Humans
- Mice
- ROC Curve
- Transcription Factors/genetics*
- Zebrafish
- PubMed
- 20494938 Full text @ Mol. Biol. Evol.
Citation
Ritter, D.I., Li, Q., Kostka, D., Pollard, K.S., Guo, S., and Chuang, J.H. (2010) The Importance of Being Cis: Evolution of Orthologous Fish and Mammalian Enhancer Activity. Mol. Biol. Evol.. 27(10):2322-2332.
Abstract
Conserved noncoding elements (CNEs) in vertebrate genomes often act as developmental enhancers, but a critical issue is how well orthologous CNE sequences retain the same activity in their respective species, a characteristic important for generalization of model organism studies. To quantify how well CNE enhancer activity has been preserved, we compared the anatomy-specific activities of 41 zebrafish CNEs in zebrafish embryos to the activities of orthologous human CNEs in mouse embryos. We found that 13/41 ( approximately 30%) of the orthologous CNE pairs exhibit conserved positive activity in zebrafish and mouse. Conserved positive activity is only weakly associated with either sequence conservation or the absence of bases undergoing accelerated evolution. A stronger effect is that disparate activity is associated with transcription factor binding site divergence. To distinguish the contributions of cis- versus trans- regulatory changes, we analyzed 13 CNEs in a three-way experimental comparison: human CNE tested in zebrafish, human CNE tested in mouse, and orthologous zebrafish CNE tested in zebrafish. Both cis- and trans- changes affect a significant fraction of CNEs, though human and zebrafish sequences exhibit disparate activity in zebrafish (indicating cis regulatory changes) twice as often as human sequences show disparate activity when tested in mouse and zebrafish (indicating trans regulatory changes). In all four cases where the zebrafish and human CNE display a similar expression pattern in zebrafish, the human CNE also displays a similar expression pattern in mouse. This suggests that the endogenous enhancer activity of approximately 30% of human CNEs can be determined from experiments in zebrafish alone, and to identify these CNEs both the zebrafish and human sequence should be tested.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping