Evolutionary Origins of Transcription Factor Binding Site Clusters

Homotypic site clustering is an important contributor to the complexity and function of cis-regulatory sequences. This work provides a simple null hypothesis for its origin, against which alternative adaptationist explanations may be evaluated, and cautions against evolutionary mirages present in common features of genomic sequence. The quantitative framework we develop here can be used more generally to understand how mechanisms of enhancer action influence their composition and evolution.