Abstract
Author SummaryThe differentiation of cells, tissues, and organs during animal development is established by a process in which genes that control cell identity and behavior are turned on and off at specific times and places. This process is choreographed, to a large extent, by a collection of proteins known as transcription factors that bind to specific sequences in DNA and thereby modulate the expression of neighboring genes. Because of the central role that transcription factors play in shaping organismal form and function, they have long been suggested to be major players in phenotypic evolution. However, we have a poor understanding of how changes to DNA affect transcription factor binding in living systems. Here, we use a combination of biochemical and genomic techniques to compare, between two closely related species of fruit flies in the genus Drosophila, the binding of six transcription factors that help establish the characteristic segments that form along the anterior-posterior (head to tail) axis in developing flies. We show that the patterns of transcription factor binding between these closely related species are broadly conserved, consistent with the nearly identical development and appearance of these species. However, we also show that, whereas the DNA changes that have accumulated between these species in the five million years since their divergence—roughly one difference per 10 basepairs—have not altered the locations where these factors bind, they have had a considerable effect on the amount of factor bound at each site across a population of embryos. We can trace these quantitative differences in binding to the gain and loss of the short sequences known to be preferentially recognized by these factors, giving us key insights into the effect that sequence changes have on the biochemical events that underlie animal development.
Highlights
Despite four decades of interest in the evolution of transcriptional regulation, we still have a poor understanding of the molecular bases for regulatory divergence and the constraints under which cis-regulatory sequences evolve
This process is choreographed, to a large extent, by a collection of proteins known as transcription factors that bind to specific sequences in DNA and thereby modulate the expression of neighboring genes
We have a poor understanding of how changes to DNA affect transcription factor binding in living systems
Summary
Despite four decades of interest in the evolution of transcriptional regulation, we still have a poor understanding of the molecular bases for regulatory divergence and the constraints under which cis-regulatory sequences evolve. Even in regulatory sequences with highly conserved function, transcription factor binding sites can be gained and lost over time at a high rate, leading to considerable differences in the composition and arrangement of binding sites between even closely related species [2,3,4,5,6,7,8,9,10]. Among yeasts of the genus Saccharomyces [11,12] and between human and mouse [13,14], a substantial fraction of experimentally observed interactions between transcription factors and DNA are speciesspecific While these differences could, in principle, be due to divergence of transcription factors and other trans-acting factors, binding differences appear to be driven primarily in cis [13], suggesting that differences in the sequences, and not the factors binding to them, drive the divergence in binding. Species-specific binding is generally associated with the gain/loss of sequence
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