Dynamics of transcription factor binding site evolution

TL;DR

This paper models the evolution of transcription factor binding sites, showing that their gain and loss are generally slow and unlikely for longer sites, but can be facilitated by multiple factors like sequence length and cooperativity.

Contribution

It introduces a biophysical model to estimate TFBS evolution rates, highlighting factors that influence their gain and loss in finite populations.

Findings

Rates of TFBS gain/loss are slow for sites longer than ~10 bp.

Evolution of binding sites converges slowly to equilibrium.

Multiple factors can accelerate TFBS evolution, aligning theory with observed data.

Abstract

Evolution of gene regulation is crucial for our understanding of the phenotypic differences between species, populations and individuals. Sequence-specific binding of transcription factors to the regulatory regions on the DNA is a key regulatory mechanism that determines gene expression and hence heritable phenotypic variation. We use a biophysical model for directional selection on gene expression to estimate the rates of gain and loss of transcription factor binding sites (TFBS) in finite populations under both point and insertion/deletion mutations. Our results show that these rates are typically slow for a single TFBS in an isolated DNA region, unless the selection is extremely strong. These rates decrease drastically with increasing TFBS length or increasingly specific protein-DNA interactions, making the evolution of sites longer than ~10 bp unlikely on typical eukaryotic speciation timescales. Similarly, evolution converges to the stationary distribution of binding sequences very slowly, making the equilibrium assumption questionable. The availability of longer regulatory sequences in which multiple binding sites can evolve simultaneously, the presence of "pre-sites" or partially decayed old sites in the initial sequence, and biophysical cooperativity between transcription factors, can all facilitate gain of TFBS and reconcile theoretical calculations with timescales inferred from comparative genetics.