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.
Highlights
The state of a biological cell can be defined by the combined transcriptional status of each gene in a genome
Enhancers contain clusters of specific DNA sequences that are uniquely recognized by DNA binding proteins, whose activities are regulated in space and time
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
Summary
The state of a biological cell can be defined by the combined transcriptional status of each gene in a genome. The regulatory logic for these state transitions is encoded in cis-regulatory DNA sequences, which specify the transcriptional activity of each gene [1,2]. Each gene may be controlled by multiple locus-specific, independently acting cis-regulatory modules (CRMs), which function as transcriptional enhancers, silencers, and insulators [3,4]. Such a set of CRMs can function collectively to sculpt a robust, complex spatiotemporal expression pattern [5]. The relative importance of cis-regulatory versus proteincoding evolution has been debated because of a relative deficit of specific examples of functional CRM evolution [21]
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