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Dynamics of Transcription Factor Binding Site Evolution.

Tuğrul M, Paixão T, Barton NH, Tkačik G - PLoS Genet. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Science and Technology Austria, Klosterneuburg, Austria.

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.

No MeSH data available.


Related in: MedlinePlus

Ancient sites and cooperativity can accelerate the emergence of TF binding sites in longer regulatory sequences.A) The expected number of newly evolved TFBS in the presence (red and brown) or absence (black) of an ancient site, for binding site length n = 10 bp, and specificity, ϵ = 3 kBT. In this example, the ancient site was a consensus site (k = 0) or two mismatches away from it (k = 2) that evolved under neutrality for t′ = 0.1/u prior to starting this simulation. Dashed lines show the predictions of a simple analytical model, Eq (30). The inset shows how the number of newly evolved TFBS at t = 0.001/u scales with the mismatch of the ancient site k (plot markers: simulation means; error bars: two standard errors of the mean; dashed curve: prediction). B) The expected number of newly evolved TFBS without (black) and with cooperative interactions (for different cooperativity strengths, magenta: Ec = −2 kBT, yellow: Ec = −3 kBT, cyan: Ec = −4 kBT, see Eq (11) in Methods and text) for binding site length n = 7 bp, and specificity, ϵ = 2 kBT. Both panels use μ = 4 kBT, strong selection (Ns = 100) and a combination of point and indel mutations (θ = 0.15), acting on a regulatory sequence of length L = 30 bp. Thick solid lines show an average over 1000 simulation replicates, shading denotes ±2 SEM.
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pgen.1005639.g005: Ancient sites and cooperativity can accelerate the emergence of TF binding sites in longer regulatory sequences.A) The expected number of newly evolved TFBS in the presence (red and brown) or absence (black) of an ancient site, for binding site length n = 10 bp, and specificity, ϵ = 3 kBT. In this example, the ancient site was a consensus site (k = 0) or two mismatches away from it (k = 2) that evolved under neutrality for t′ = 0.1/u prior to starting this simulation. Dashed lines show the predictions of a simple analytical model, Eq (30). The inset shows how the number of newly evolved TFBS at t = 0.001/u scales with the mismatch of the ancient site k (plot markers: simulation means; error bars: two standard errors of the mean; dashed curve: prediction). B) The expected number of newly evolved TFBS without (black) and with cooperative interactions (for different cooperativity strengths, magenta: Ec = −2 kBT, yellow: Ec = −3 kBT, cyan: Ec = −4 kBT, see Eq (11) in Methods and text) for binding site length n = 7 bp, and specificity, ϵ = 2 kBT. Both panels use μ = 4 kBT, strong selection (Ns = 100) and a combination of point and indel mutations (θ = 0.15), acting on a regulatory sequence of length L = 30 bp. Thick solid lines show an average over 1000 simulation replicates, shading denotes ±2 SEM.

Mentions: Fig 5A shows that the ancient site scenario can enhance the number of newly evolved sites by resurrecting the ancient site, even after it has decayed for t′ = 0.1u−1. Simulation results agree well with the simple analytical model using the biased initial sequence distribution of Eq (30). Importantly, such a mechanism is particularly effective for longer binding sites of high specificity, indicating that regulatory sequence reuse could be evolutionarily beneficial in this biophysical regime (see S8 Fig).


Dynamics of Transcription Factor Binding Site Evolution.

Tuğrul M, Paixão T, Barton NH, Tkačik G - PLoS Genet. (2015)

Ancient sites and cooperativity can accelerate the emergence of TF binding sites in longer regulatory sequences.A) The expected number of newly evolved TFBS in the presence (red and brown) or absence (black) of an ancient site, for binding site length n = 10 bp, and specificity, ϵ = 3 kBT. In this example, the ancient site was a consensus site (k = 0) or two mismatches away from it (k = 2) that evolved under neutrality for t′ = 0.1/u prior to starting this simulation. Dashed lines show the predictions of a simple analytical model, Eq (30). The inset shows how the number of newly evolved TFBS at t = 0.001/u scales with the mismatch of the ancient site k (plot markers: simulation means; error bars: two standard errors of the mean; dashed curve: prediction). B) The expected number of newly evolved TFBS without (black) and with cooperative interactions (for different cooperativity strengths, magenta: Ec = −2 kBT, yellow: Ec = −3 kBT, cyan: Ec = −4 kBT, see Eq (11) in Methods and text) for binding site length n = 7 bp, and specificity, ϵ = 2 kBT. Both panels use μ = 4 kBT, strong selection (Ns = 100) and a combination of point and indel mutations (θ = 0.15), acting on a regulatory sequence of length L = 30 bp. Thick solid lines show an average over 1000 simulation replicates, shading denotes ±2 SEM.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4636380&req=5

pgen.1005639.g005: Ancient sites and cooperativity can accelerate the emergence of TF binding sites in longer regulatory sequences.A) The expected number of newly evolved TFBS in the presence (red and brown) or absence (black) of an ancient site, for binding site length n = 10 bp, and specificity, ϵ = 3 kBT. In this example, the ancient site was a consensus site (k = 0) or two mismatches away from it (k = 2) that evolved under neutrality for t′ = 0.1/u prior to starting this simulation. Dashed lines show the predictions of a simple analytical model, Eq (30). The inset shows how the number of newly evolved TFBS at t = 0.001/u scales with the mismatch of the ancient site k (plot markers: simulation means; error bars: two standard errors of the mean; dashed curve: prediction). B) The expected number of newly evolved TFBS without (black) and with cooperative interactions (for different cooperativity strengths, magenta: Ec = −2 kBT, yellow: Ec = −3 kBT, cyan: Ec = −4 kBT, see Eq (11) in Methods and text) for binding site length n = 7 bp, and specificity, ϵ = 2 kBT. Both panels use μ = 4 kBT, strong selection (Ns = 100) and a combination of point and indel mutations (θ = 0.15), acting on a regulatory sequence of length L = 30 bp. Thick solid lines show an average over 1000 simulation replicates, shading denotes ±2 SEM.
Mentions: Fig 5A shows that the ancient site scenario can enhance the number of newly evolved sites by resurrecting the ancient site, even after it has decayed for t′ = 0.1u−1. Simulation results agree well with the simple analytical model using the biased initial sequence distribution of Eq (30). Importantly, such a mechanism is particularly effective for longer binding sites of high specificity, indicating that regulatory sequence reuse could be evolutionarily beneficial in this biophysical regime (see S8 Fig).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Science and Technology Austria, Klosterneuburg, Austria.

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.

No MeSH data available.


Related in: MedlinePlus