Large-Scale Turnover of Functional Transcription Factor Binding Sites in Drosophila

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Abstract
The gain and loss of functional transcription factor binding sites has been proposed as a major source of evolutionary change in cis-regulatory DNA and gene expression. We have developed an evolutionary model to study binding-site turnover that uses multiple sequence alignments to assess the evolutionary constraint on individual binding sites, and to map gain and loss events along a phylogenetic tree. We apply this model to study the evolutionary dynamics of binding sites of the Drosophila melanogaster transcription factor Zeste, using genome-wide in vivo (ChIP–chip) binding data to identify functional Zeste binding sites, and the genome sequences of D. melanogaster, D. simulans, D. erecta, and D. yakuba to study their evolution. We estimate that more than 5% of functional Zeste binding sites in D. melanogaster were gained along the D. melanogaster lineage or lost along one of the other lineages. We find that Zeste-bound regions have a reduced rate of binding-site loss and an increased rate of binding-site gain relative to flanking sequences. Finally, we show that binding-site gains and losses are asymmetrically distributed with respect to D. melanogaster, consistent with lineage-specific acquisition and loss of Zeste-responsive regulatory elements. Understanding the ways in which mutations in DNA result in alterations of an organism's form and function is a major goal of molecular evolutionary biology. Changes in gene expression were long-ago proposed as a source of evolutionary diversity, but it was only in the last few years that researchers described specific cases where identified changes in DNA cause differences in gene expression, which in turn affect morphology. Attention has now turned to understanding how such sequence changes produce their effect and whether additional examples of evolutionary novelty can be found by examining the growing number of available genome sequences. Moses et al. focus on transcription factor binding sites, pieces of DNA that serve as molecular switches to turn genes on and off. These switches are organized into larger units that function as molecular computers and ensure that genes are made when and where they are needed. Moses and colleagues introduce a set of new computational methods to study how these larger units of regulatory function evolve. While they find that most of these switches remain fixed in place, a substantial number are created or destroyed by mutations, yielding new insights into the evolutionary forces that shape animal morphology.