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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

Single TF binding site gain rates at an isolated DNA region.A) The dependence of the gain rate, 1/⟨t⟩𝓢 ← k shown in units of point mutation rate, from sequences in different initial mismatch classes k (blue: k = 2, red: k = 5), as a function of selection strength. Results with point mutations only (θ = 0) are shown by dashed line; with admixture of indel mutations (θ = 0.15) by a solid line. For strong selection, Ns ≫ n log(2)/2, the rates scale with Ns, which is captured well by the “shortest path” approximation (black dashed lines in the main figure) of Eq (24). The biophysical parameters are: site length n = 7 bp; binding specificity ϵ = 2 kBT; chemical potential μ = 4 kBT. Points correspond to Wright-Fisher simulations with Nu = 0.01 where error bars cover ±2 SEM (standard error of mean). Inset shows the behavior of the gain rates as a function of the initial mismatch class k for Ns = 0 and Ns = 100. B, C) Gain rates from redundancy rich classes (k ∼ 3n/4, typical of evolution from random “virgin” sequence) under strong selection, without (B) and with (C) indel mutations supplementing the point mutations. Red crosshairs denote the cases depicted in panel A. Contour lines show constant gain rates in units of Nsu as a function of biophysical parameters n and ϵ. Wiggles in the contour lines are not a numerical artefact but a consequence of discrete mismatch classes.
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pgen.1005639.g002: Single TF binding site gain rates at an isolated DNA region.A) The dependence of the gain rate, 1/⟨t⟩𝓢 ← k shown in units of point mutation rate, from sequences in different initial mismatch classes k (blue: k = 2, red: k = 5), as a function of selection strength. Results with point mutations only (θ = 0) are shown by dashed line; with admixture of indel mutations (θ = 0.15) by a solid line. For strong selection, Ns ≫ n log(2)/2, the rates scale with Ns, which is captured well by the “shortest path” approximation (black dashed lines in the main figure) of Eq (24). The biophysical parameters are: site length n = 7 bp; binding specificity ϵ = 2 kBT; chemical potential μ = 4 kBT. Points correspond to Wright-Fisher simulations with Nu = 0.01 where error bars cover ±2 SEM (standard error of mean). Inset shows the behavior of the gain rates as a function of the initial mismatch class k for Ns = 0 and Ns = 100. B, C) Gain rates from redundancy rich classes (k ∼ 3n/4, typical of evolution from random “virgin” sequence) under strong selection, without (B) and with (C) indel mutations supplementing the point mutations. Red crosshairs denote the cases depicted in panel A. Contour lines show constant gain rates in units of Nsu as a function of biophysical parameters n and ϵ. Wiggles in the contour lines are not a numerical artefact but a consequence of discrete mismatch classes.

Mentions: Fig 2A shows the dependence of the TFBS gain rate on the selection strength (with respect to genetic drift), Ns. For parameters typical of eukaryotic binding sites (length n = 7 bp, specificity ϵ = 2 kBT), the TFBS gain rates are extremely slow (practically no evolution) when there is negligible selection pressure (Ns ∼ 0), indicating the importance of selection for TFBS emergence. Indeed, the effective selection needs to be very strong, e.g., Ns > 100, for TFBS evolution to exceed the per-nucleotide mutation rate by orders of magnitude and become comparable to speciation rates.


Dynamics of Transcription Factor Binding Site Evolution.

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

Single TF binding site gain rates at an isolated DNA region.A) The dependence of the gain rate, 1/⟨t⟩𝓢 ← k shown in units of point mutation rate, from sequences in different initial mismatch classes k (blue: k = 2, red: k = 5), as a function of selection strength. Results with point mutations only (θ = 0) are shown by dashed line; with admixture of indel mutations (θ = 0.15) by a solid line. For strong selection, Ns ≫ n log(2)/2, the rates scale with Ns, which is captured well by the “shortest path” approximation (black dashed lines in the main figure) of Eq (24). The biophysical parameters are: site length n = 7 bp; binding specificity ϵ = 2 kBT; chemical potential μ = 4 kBT. Points correspond to Wright-Fisher simulations with Nu = 0.01 where error bars cover ±2 SEM (standard error of mean). Inset shows the behavior of the gain rates as a function of the initial mismatch class k for Ns = 0 and Ns = 100. B, C) Gain rates from redundancy rich classes (k ∼ 3n/4, typical of evolution from random “virgin” sequence) under strong selection, without (B) and with (C) indel mutations supplementing the point mutations. Red crosshairs denote the cases depicted in panel A. Contour lines show constant gain rates in units of Nsu as a function of biophysical parameters n and ϵ. Wiggles in the contour lines are not a numerical artefact but a consequence of discrete mismatch classes.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4636380&req=5

pgen.1005639.g002: Single TF binding site gain rates at an isolated DNA region.A) The dependence of the gain rate, 1/⟨t⟩𝓢 ← k shown in units of point mutation rate, from sequences in different initial mismatch classes k (blue: k = 2, red: k = 5), as a function of selection strength. Results with point mutations only (θ = 0) are shown by dashed line; with admixture of indel mutations (θ = 0.15) by a solid line. For strong selection, Ns ≫ n log(2)/2, the rates scale with Ns, which is captured well by the “shortest path” approximation (black dashed lines in the main figure) of Eq (24). The biophysical parameters are: site length n = 7 bp; binding specificity ϵ = 2 kBT; chemical potential μ = 4 kBT. Points correspond to Wright-Fisher simulations with Nu = 0.01 where error bars cover ±2 SEM (standard error of mean). Inset shows the behavior of the gain rates as a function of the initial mismatch class k for Ns = 0 and Ns = 100. B, C) Gain rates from redundancy rich classes (k ∼ 3n/4, typical of evolution from random “virgin” sequence) under strong selection, without (B) and with (C) indel mutations supplementing the point mutations. Red crosshairs denote the cases depicted in panel A. Contour lines show constant gain rates in units of Nsu as a function of biophysical parameters n and ϵ. Wiggles in the contour lines are not a numerical artefact but a consequence of discrete mismatch classes.
Mentions: Fig 2A shows the dependence of the TFBS gain rate on the selection strength (with respect to genetic drift), Ns. For parameters typical of eukaryotic binding sites (length n = 7 bp, specificity ϵ = 2 kBT), the TFBS gain rates are extremely slow (practically no evolution) when there is negligible selection pressure (Ns ∼ 0), indicating the importance of selection for TFBS emergence. Indeed, the effective selection needs to be very strong, e.g., Ns > 100, for TFBS evolution to exceed the per-nucleotide mutation rate by orders of magnitude and become comparable to speciation rates.

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