The evolution of complex gene regulation by low specificity binding sites

TL;DR

This study uses a population-genetic model to show that complex gene regulatory modules tend to have less specific binding sites, explaining observed trends across species and gene regulatory networks.

Contribution

It demonstrates that larger regulatory modules evolve to have less specific binding sites due to limitations of stabilizing selection, a novel insight into gene regulation evolution.

Findings

More complex modules have less specific binding sites.

Genes with many regulators show less variance in binding site specificity.

Higher eukaryotes have lower specificity in transcription factor binding sites.

Abstract

Transcription factor binding sites vary in their specificity, both within and between species. Binding specificity has a strong impact on the evolution of gene expression, because it determines how easily regulatory interactions are gained and lost. Nevertheless, we have a relatively poor understanding of what evolutionary forces determine the specificity of binding sites. Here we address this question by studying regulatory modules composed of multiple binding sites. Using a population-genetic model, we show that more complex regulatory modules, composed of a greater number of binding sites, must employ binding sites that are individually less specific, compared to less complex regulatory modules. This effect is extremely general, and it hold regardless of the regulatory logic of a module. We attribute this phenomenon to the inability of stabilising selection to maintain highly specific sites in large regulatory modules. Our analysis helps to explain broad empirical trends in the yeast regulatory network: those genes with a greater number of transcriptional regulators feature by less specific binding sites, and there is less variance in their specificity, compared to genes with fewer regulators. Likewise, our results also help to explain the well-known trend towards lower specificity in the transcription factor binding sites of higher eukaryotes, which perform complex regulatory tasks, compared to prokaryotes.