Evolution of cis-regulatory sequences in Drosophila.

Cross-species comparison is an emerging paradigm for identifying cis-regulatory sequences and understanding their function and evolution. In this chapter, we review probabilistic models of evolution of transcription factor binding sites, which provide the theoretical basis for a number of new bioinformatics tools for comparative sequence analysis. We illustrate how important functional and evolutionary insights on binding site gain and loss can be acquired through sequence comparison. This includes the observation that binding site turnover follows a molecular clock and that its rate correlates with the strength of binding sites and the presence of other sites in the neighborhood. We also comment on emerging trends that go beyond individual binding sites to a more holistic study of regulatory evolution. We point out common technical challenges, such as reliable sequence alignment and binding site prediction, when doing comparative regulatory sequence analysis and note some potential solutions thereof.