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 genomics.
Highlights
Evolution produces heritable phenotypic variation within and between populations and species on relatively short timescales
By combining a biophysically realistic model for how cells read out information in transcription factor binding sites with model for DNA sequence evolution, we explore these timescales and ask what factors crucially affect them
We identify two factors that can speed up the emergence of transcription factor binding sites (TFBS): the existence of an initial sequence distribution biased towards the mutational neighborhood of strongly binding sequences, which suggests that ancient evolutionary history can play a major role in the emergence of “novelties” [54]; and the biophysical cooperativity between transcription factors, which can partially account for the lack of observed correlation between identifiable binding sequences and transcriptional activity [11]
Summary
Evolution produces heritable phenotypic variation within and between populations and species on relatively short timescales. Part of this variation is due to differences in gene regulation, which determines how much of each gene product exists in every cell. Transcription factor proteins (TFs) recognize and bind specific DNA sequences called binding sites, thereby affecting the expression of target genes. Eukaryotic regulatory sequences, i.e., enhancers and promoters, are typically between a hundred and several thousand base pairs (bp) in length [6], and can harbor many transcription factor binding sites (TFBSs), each typically consisting of 6–12 bp. A theoretical understanding of the relationship between the evolution of the regulatory sequence and the evolution of gene expression levels remains elusive, mostly because of the complex interaction of evolutionary forces and biophysical processes [11]
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