Modelling the evolution of transcription factor binding preferences in complex eukaryotes

TL;DR

This paper presents an evolutionary model explaining how transcription factor binding preferences and motif family organizations have evolved in complex eukaryotes, revealing key forces and deviations in this process.

Contribution

It introduces a one-parameter Birth-Death-Innovation model that explains TF motif family distributions and highlights evolutionary forces shaping transcriptional regulation.

Findings

The model fits human TF motif family data well.

Identifies over-expanded TF families like HOX and FOX.

Shows increased redundancy of TF binding in more complex organisms.

Abstract

Transcription factors (TFs) exert their regulatory action by binding to DNA with specific sequence preferences. However, different TFs can partially share their binding sequences due to their common evolutionary origin. This `redundancy' of binding defines a way of organizing TFs in `motif families' by grouping TFs with similar binding preferences. Since these ultimately define the TF target genes, the motif family organization entails information about the structure of transcriptional regulation as it has been shaped by evolution. Focusing on the human TF repertoire, we show that a one-parameter evolutionary model of the Birth-Death-Innovation type can explain the TF empirical ripartition in motif families, and allows to highlight the relevant evolutionary forces at the origin of this organization. Moreover, the model allows to pinpoint few deviations from the neutral scenario it assumes: three over-expanded families (including HOX and FOX genes), a set of `singleton' TFs for which duplication seems to be selected against, and a higher-than-average rate of diversification of the binding preferences of TFs with a Zinc Finger DNA binding domain. Finally, a comparison of the TF motif family organization in different eukaryotic species suggests an increase of redundancy of binding with organism complexity.