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Molecular Biology and Evolution
Article . 2011 . Peer-reviewed
Data sources: Crossref
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Evolutionary Origins of Transcription Factor Binding Site Clusters

Authors: Xin, He; Thyago S P C, Duque; Saurabh, Sinha;

Evolutionary Origins of Transcription Factor Binding Site Clusters

Abstract

Empirical studies have revealed that regulatory DNA sequences such as enhancers or promoters often harbor multiple binding sites for the same transcription factor. Such "homotypic site clustering" has been hypothesized as arising out of functional requirements of the sequences. Here, we propose an alternative explanation of this phenomenon that multisite enhancers are common because they are favored by evolutionary sampling of the genotype-phenotype landscape. To test this hypothesis, we developed a new computational framework specialized for population genetic simulations of enhancer evolution. It uses a thermodynamics-based model of enhancer function, integrating information from strong as well as weak binding sites, to determine the strength of selection. Using this framework, we found that even when simpler genotypes exist for a desired strength of regulation, relatively complex genotypes (enhancers with more sites) are more readily reached by the simulated evolutionary process. We show that there are more ways to "build" a fit genotype with many weak sites than with a few strong sites, and this is why evolution finds complex genotypes more often. Our claims are consistent with an empirical analysis of binding site content in enhancers characterized in Drosophila melanogaster and their orthologs in other Drosophila species. We also characterized a subtle but significant difference between genotypes likely to be sampled by evolution and equally fit genotypes one would obtain by uniform sampling of the fitness landscape, that is, an "evolutionary signature" in enhancer sequences. Finally, we investigated potential effects of other factors, such as rugged fitness landscapes, short local duplications, and noise characteristics of enhancers, on the emergence of homotypic site clustering. Homotypic site clustering is an important contributor to the complexity and function of cis-regulatory sequences. This work provides a simple null hypothesis for its origin, against which alternative adaptationist explanations may be evaluated, and cautions against "evolutionary mirages" present in common features of genomic sequence. The quantitative framework we develop here can be used more generally to understand how mechanisms of enhancer action influence their composition and evolution.

Keywords

Population Density, Binding Sites, Genotype, Models, Genetic, Evolution, Molecular, Enhancer Elements, Genetic, Mutation Rate, Species Specificity, Animals, Computer Simulation, Drosophila, Transcription Factors

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
58
Top 10%
Top 10%
Top 10%
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