Abstract
The gene expression pattern specified by an animal regulatory sequence is generally viewed as arising from the particular arrangement of transcription factor binding sites it contains. However, we demonstrate here that regulatory sequences whose binding sites have been almost completely rearranged can still produce identical outputs. We sequenced the even-skipped locus from six species of scavenger flies (Sepsidae) that are highly diverged from the model species Drosophila melanogaster, but share its basic patterns of developmental gene expression. Although there is little sequence similarity between the sepsid eve enhancers and their well-characterized D. melanogaster counterparts, the sepsid and Drosophila enhancers drive nearly identical expression patterns in transgenic D. melanogaster embryos. We conclude that the molecular machinery that connects regulatory sequences to the transcription apparatus is more flexible than previously appreciated. In exploring this diverse collection of sequences to identify the shared features that account for their similar functions, we found a small number of short (20–30 bp) sequences nearly perfectly conserved among the species. These highly conserved sequences are strongly enriched for pairs of overlapping or adjacent binding sites. Together, these observations suggest that the local arrangement of binding sites relative to each other is more important than their overall arrangement into larger units of cis-regulatory function.
Highlights
Recent studies revealing how the gain, loss and repositioning of transcription factor binding sites within regulatory sequences can alter gene expression with observable phenotypic consequences [1] have focused efforts to understand the molecular basis for organismal diversity on the evolution of regulatory DNA
We began to explore the effectiveness of this approach with the extensively studied regulatory systems of the early D. melanogaster embryo [10], using the recently sequenced genomes of 12 Drosophila species to document the evolutionary fate of transcription factor binding sites in early embryonic enhancers (Peterson, Hare, Iyer, Eisen, unpublished)
We have demonstrated here that complex animal regulatory sequences can tolerate nearly complete rearrangement of their transcription factor binding sites without appreciably altering their transcriptional output
Summary
Recent studies revealing how the gain, loss and repositioning of transcription factor binding sites within regulatory sequences can alter gene expression with observable phenotypic consequences [1] have focused efforts to understand the molecular basis for organismal diversity on the evolution of regulatory DNA. The potential for significant changes in regulatory sequences to have no functional consequences complicates efforts to identify sequence changes that are likely to affect gene expression and phenotype. We began to explore the effectiveness of this approach with the extensively studied regulatory systems of the early D. melanogaster embryo [10], using the recently sequenced genomes of 12 Drosophila species to document the evolutionary fate of transcription factor binding sites in early embryonic enhancers (Peterson, Hare, Iyer, Eisen, unpublished). A consistent pattern emerged: while binding site turnover is common, a large fraction of the binding sites in most enhancers are conserved across the genus (see Figure 1)
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