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PLoS Biol. Nov 2008; 6(11): e263.
Published online Nov 4, 2008. doi:  10.1371/journal.pbio.0060263
PMCID: PMC2577699

Evolution Acts on Enhancer Organization to Fine-Tune Gradient Threshold Readouts

Michael B Eisen, Academic Editor

Abstract

The elucidation of principles governing evolution of gene regulatory sequence is critical to the study of metazoan diversification. We are therefore exploring the structure and organizational constraints of regulatory sequences by studying functionally equivalent cis-regulatory modules (CRMs) that have been evolving in parallel across several loci. Such an independent dataset allows a multi-locus study that is not hampered by nonfunctional or constrained homology. The neurogenic ectoderm enhancers (NEEs) of Drosophila melanogaster are one such class of coordinately regulated CRMs. The NEEs share a common organization of binding sites and as a set would be useful to study the relationship between CRM organization and CRM activity across evolving lineages. We used the D. melanogaster transgenic system to screen for functional adaptations in the NEEs from divergent drosophilid species. We show that the individual NEE modules across a genome in any one lineage have independently evolved adaptations to compensate for lineage-specific developmental and/or genomic changes. Specifically, we show that both the site composition and the site organization of NEEs have been finely tuned by distinct, lineage-specific selection pressures in each of the three divergent species that we have examined: D. melanogaster, D. pseudoobscura, and D. virilis. Furthermore, by precisely altering the organization of NEEs with different morphogen gradient threshold readouts, we show that CRM organizational evolution is sufficient for explaining changes in enhancer activity. Thus, evolution can act on CRM organization to fine-tune morphogen gradient threshold readouts over a wide dynamic range. Our study demonstrates that equivalence classes of CRMs are powerful tools for detecting lineage-specific adaptations by gene regulatory sequences.

Author Summary

The regulatory control of genes allows an organism to generate a diversity of cell types throughout its body. Gene regulation involves specialized DNA sequences called transcriptional enhancers that increase the expression of genes in specific places and times. Enhancers contain clusters of specific DNA sequences that are uniquely recognized by DNA binding proteins, whose activities are also regulated in space and time. The critical role that DNA enhancers play in generating the diversity of cell types within a single organism suggests that changes in these DNA sequences may also underlie the diversity of organismal forms produced by evolution. However, few examples linking specific changes in enhancer sequences to functional adaptations have been documented. We studied a group of neuro-embryonic enhancers that turn on a certain group of genes in different fruit fly species that have been diverging from each other for ~50 million years. Each species has experienced unique changes in its protein-coding sequences, gene regulatory sequences, egg morphology, and developmental timing. We found that the organizational spacing between the protein binding sites in these enhancers has evolved in a manner that is consistent with functional adaptations compensating for the dynamic and idiosyncratic evolutionary history of each species.


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