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Common binding by redundant group B Sox proteins is evolutionarily conserved in Drosophila.

Carl SH, Russell S - BMC Genomics (2015)

Bottom Line: To determine whether common binding between Dichaete and SoxNeuro is conserved, we performed a detailed analysis of the binding patterns of both factors in two species.Nonetheless, binding is preferentially conserved at known cis-regulatory modules and core, independently verified binding sites.We observed the strongest binding conservation at sites that are commonly bound by Dichaete and SoxNeuro, suggesting that these sites are functionally important.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Cambridge Systems Biology Centre, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK. s.carl@gen.cam.ac.uk.

ABSTRACT

Background: Group B Sox proteins are a highly conserved group of transcription factors that act extensively to coordinate nervous system development in higher metazoans while showing both co-expression and functional redundancy across a broad group of taxa. In Drosophila melanogaster, the two group B Sox proteins Dichaete and SoxNeuro show widespread common binding across the genome. While some instances of functional compensation have been observed in Drosophila, the function of common binding and the extent of its evolutionary conservation is not known.

Results: We used DamID-seq to examine the genome-wide binding patterns of Dichaete and SoxNeuro in four species of Drosophila. Through a quantitative comparison of Dichaete binding, we evaluated the rate of binding site turnover across the genome as well as at specific functional sites. We also examined the presence of Sox motifs within binding intervals and the correlation between sequence conservation and binding conservation. To determine whether common binding between Dichaete and SoxNeuro is conserved, we performed a detailed analysis of the binding patterns of both factors in two species.

Conclusion: We find that, while the regulatory networks driven by Dichaete and SoxNeuro are largely conserved across the drosophilids studied, binding site turnover is widespread and correlated with phylogenetic distance. Nonetheless, binding is preferentially conserved at known cis-regulatory modules and core, independently verified binding sites. We observed the strongest binding conservation at sites that are commonly bound by Dichaete and SoxNeuro, suggesting that these sites are functionally important. Our analysis provides insights into the evolution of group B Sox function, highlighting the specific conservation of shared binding sites and suggesting alternative sources of neofunctionalisation between paralogous family members.

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Density and conservation of Sox motifs are higher in Dichaete intervals with binding conservation. (A) On average, Dichaete binding intervals that are conserved between all four species (“4-way conserved”) have more Sox motifs than intervals that are unique to D. melanogaster (“D. mel unique”) (p = 3.03e-193). (B) Dichaete binding intervals that are conserved between all four species do not show an increased rate of total nucleotide conservation on average than intervals that are unique to D. melanogaster. (C) Sox motifs in Dichaete intervals that are bound in all four species (“4-way Sox”) have a greater percentage of perfectly conserved nucleotides across all species than either Sox motifs in intervals that are unique to D. melanogaster (“D. mel Sox”, p = 9.56e-36), randomly shuffled control motifs in intervals that are bound in all four species (“4-way control”, p = 1.62e-43) or randomly shuffled control motifs in intervals that are unique to D. melanogaster (“D. mel control”, p = 1.67e-9). (D) On average, Dichaete intervals that are bound in all four species have more Sox motifs that are both positionally conserved and show 100% nucleotide conservation across all species than intervals that are only bound in D. melanogaster (p = 6.04e-28). The multiple alignment illustrates a positionally conserved Sox motif with 100% nucleotide conservation (highlighted in purple).
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Fig5: Density and conservation of Sox motifs are higher in Dichaete intervals with binding conservation. (A) On average, Dichaete binding intervals that are conserved between all four species (“4-way conserved”) have more Sox motifs than intervals that are unique to D. melanogaster (“D. mel unique”) (p = 3.03e-193). (B) Dichaete binding intervals that are conserved between all four species do not show an increased rate of total nucleotide conservation on average than intervals that are unique to D. melanogaster. (C) Sox motifs in Dichaete intervals that are bound in all four species (“4-way Sox”) have a greater percentage of perfectly conserved nucleotides across all species than either Sox motifs in intervals that are unique to D. melanogaster (“D. mel Sox”, p = 9.56e-36), randomly shuffled control motifs in intervals that are bound in all four species (“4-way control”, p = 1.62e-43) or randomly shuffled control motifs in intervals that are unique to D. melanogaster (“D. mel control”, p = 1.67e-9). (D) On average, Dichaete intervals that are bound in all four species have more Sox motifs that are both positionally conserved and show 100% nucleotide conservation across all species than intervals that are only bound in D. melanogaster (p = 6.04e-28). The multiple alignment illustrates a positionally conserved Sox motif with 100% nucleotide conservation (highlighted in purple).

Mentions: We used the reference genome sequence for each species to assess the contribution to binding conservation of sequence conservation within binding intervals and at TF-specific binding motifs. In order to examine the patterns of motif conservation in Dichaete binding intervals, we first identified all matches to the best de novo Sox motif discovered in each set of intervals [90]. We did the same with control binding intervals that had been randomly shuffled to different locations in each genome [91]. In all cases, significantly more Sox motifs were found in Dichaete binding intervals than in control intervals (p < 4.03e-15, Wilcoxon rank sum test with continuity correction). Focusing on Dichaete binding intervals, we compared intervals that are bound in all four species, including D. pseudoobscura, to those that are unique to D. melanogaster. The highly conserved intervals contain significantly more Sox motifs on average (mean = 4.53) than the binding intervals unique to D. melanogaster (mean = 1.29, p = 3.03e-193, Wilcoxon rank sum test with continuity correction), showing that the presence and number of Sox motifs is positively correlated with Dichaete binding conservation (Figure 5A).Figure 5


Common binding by redundant group B Sox proteins is evolutionarily conserved in Drosophila.

Carl SH, Russell S - BMC Genomics (2015)

Density and conservation of Sox motifs are higher in Dichaete intervals with binding conservation. (A) On average, Dichaete binding intervals that are conserved between all four species (“4-way conserved”) have more Sox motifs than intervals that are unique to D. melanogaster (“D. mel unique”) (p = 3.03e-193). (B) Dichaete binding intervals that are conserved between all four species do not show an increased rate of total nucleotide conservation on average than intervals that are unique to D. melanogaster. (C) Sox motifs in Dichaete intervals that are bound in all four species (“4-way Sox”) have a greater percentage of perfectly conserved nucleotides across all species than either Sox motifs in intervals that are unique to D. melanogaster (“D. mel Sox”, p = 9.56e-36), randomly shuffled control motifs in intervals that are bound in all four species (“4-way control”, p = 1.62e-43) or randomly shuffled control motifs in intervals that are unique to D. melanogaster (“D. mel control”, p = 1.67e-9). (D) On average, Dichaete intervals that are bound in all four species have more Sox motifs that are both positionally conserved and show 100% nucleotide conservation across all species than intervals that are only bound in D. melanogaster (p = 6.04e-28). The multiple alignment illustrates a positionally conserved Sox motif with 100% nucleotide conservation (highlighted in purple).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig5: Density and conservation of Sox motifs are higher in Dichaete intervals with binding conservation. (A) On average, Dichaete binding intervals that are conserved between all four species (“4-way conserved”) have more Sox motifs than intervals that are unique to D. melanogaster (“D. mel unique”) (p = 3.03e-193). (B) Dichaete binding intervals that are conserved between all four species do not show an increased rate of total nucleotide conservation on average than intervals that are unique to D. melanogaster. (C) Sox motifs in Dichaete intervals that are bound in all four species (“4-way Sox”) have a greater percentage of perfectly conserved nucleotides across all species than either Sox motifs in intervals that are unique to D. melanogaster (“D. mel Sox”, p = 9.56e-36), randomly shuffled control motifs in intervals that are bound in all four species (“4-way control”, p = 1.62e-43) or randomly shuffled control motifs in intervals that are unique to D. melanogaster (“D. mel control”, p = 1.67e-9). (D) On average, Dichaete intervals that are bound in all four species have more Sox motifs that are both positionally conserved and show 100% nucleotide conservation across all species than intervals that are only bound in D. melanogaster (p = 6.04e-28). The multiple alignment illustrates a positionally conserved Sox motif with 100% nucleotide conservation (highlighted in purple).
Mentions: We used the reference genome sequence for each species to assess the contribution to binding conservation of sequence conservation within binding intervals and at TF-specific binding motifs. In order to examine the patterns of motif conservation in Dichaete binding intervals, we first identified all matches to the best de novo Sox motif discovered in each set of intervals [90]. We did the same with control binding intervals that had been randomly shuffled to different locations in each genome [91]. In all cases, significantly more Sox motifs were found in Dichaete binding intervals than in control intervals (p < 4.03e-15, Wilcoxon rank sum test with continuity correction). Focusing on Dichaete binding intervals, we compared intervals that are bound in all four species, including D. pseudoobscura, to those that are unique to D. melanogaster. The highly conserved intervals contain significantly more Sox motifs on average (mean = 4.53) than the binding intervals unique to D. melanogaster (mean = 1.29, p = 3.03e-193, Wilcoxon rank sum test with continuity correction), showing that the presence and number of Sox motifs is positively correlated with Dichaete binding conservation (Figure 5A).Figure 5

Bottom Line: To determine whether common binding between Dichaete and SoxNeuro is conserved, we performed a detailed analysis of the binding patterns of both factors in two species.Nonetheless, binding is preferentially conserved at known cis-regulatory modules and core, independently verified binding sites.We observed the strongest binding conservation at sites that are commonly bound by Dichaete and SoxNeuro, suggesting that these sites are functionally important.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Cambridge Systems Biology Centre, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK. s.carl@gen.cam.ac.uk.

ABSTRACT

Background: Group B Sox proteins are a highly conserved group of transcription factors that act extensively to coordinate nervous system development in higher metazoans while showing both co-expression and functional redundancy across a broad group of taxa. In Drosophila melanogaster, the two group B Sox proteins Dichaete and SoxNeuro show widespread common binding across the genome. While some instances of functional compensation have been observed in Drosophila, the function of common binding and the extent of its evolutionary conservation is not known.

Results: We used DamID-seq to examine the genome-wide binding patterns of Dichaete and SoxNeuro in four species of Drosophila. Through a quantitative comparison of Dichaete binding, we evaluated the rate of binding site turnover across the genome as well as at specific functional sites. We also examined the presence of Sox motifs within binding intervals and the correlation between sequence conservation and binding conservation. To determine whether common binding between Dichaete and SoxNeuro is conserved, we performed a detailed analysis of the binding patterns of both factors in two species.

Conclusion: We find that, while the regulatory networks driven by Dichaete and SoxNeuro are largely conserved across the drosophilids studied, binding site turnover is widespread and correlated with phylogenetic distance. Nonetheless, binding is preferentially conserved at known cis-regulatory modules and core, independently verified binding sites. We observed the strongest binding conservation at sites that are commonly bound by Dichaete and SoxNeuro, suggesting that these sites are functionally important. Our analysis provides insights into the evolution of group B Sox function, highlighting the specific conservation of shared binding sites and suggesting alternative sources of neofunctionalisation between paralogous family members.

Show MeSH
Related in: MedlinePlus