Large-Scale Turnover of Functional Transcription Factor Binding Sites in Drosophila

Moses, Alan M.; Pollard, Daniel A.; Nix, David A.; Iyer, Venky N.; Li, Xiaoyong; Biggin, Mark D.; Eisen, Michael B.

doi:10.1371/journal.pcbi.0020130

Cited by 241 publications

(190 citation statements)

References 63 publications

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“…Additionally, higherresolution functional annotations and the development of experimental platforms for model organism "sister" species are also likely to clarify this relationship (Brown et al 2007;Margulies et al 2007). Second, these results also point to the influence of functional sequence turnover (Ludwig et al 2000;Moses et al 2006;Odom et al 2007). We note that this phenomenon may apply to even developmentally important functionality, particularly for comparisons of distantly related species to discover elements that are individually minor contributors to the overall functional output (McGaughey et al 2008).…”

Section: Discussionmentioning

confidence: 75%

Qualifying the relationship between sequence conservation and molecular function

Cooper¹,

Brown²

2008

Genome Res.

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Quantification of evolutionary constraints via sequence conservation can be leveraged to annotate genomic functional sequences. Recent efforts addressing the converse of this relationship have identified many sites in metazoan genomes with molecular function but without detectable conservation between related species. Here, we discuss explanations and implications for these results considering both practical and theoretical issues. In particular, phylogenetic scope influences the relationship between sequence conservation and function. Comparisons of distantly related species can detect constraint with high specificity due to the loss of conserved neutral sequence, but sensitivity is sacrificed as a result of functional changes related to lineage-specific biology. The strength of natural selection operating on functional sequence is also important. Mutations to functional sequences that result in small fitness effects are subject to weaker constraints. Therefore, particularly when comparing highly divergent species, functional sequences that are degenerate or biologically redundant will be prone to turnover, wherein functional sequences are replaced by effectively equivalent, but nonorthologous counterparts. Finally, considering the size and complexity of metazoan genomes and the fact that many nonconserved sequences are associated with sequence-degenerate, low-level molecular functions, we find it likely that there exist many biochemically functional sequences that are not under constraint. This hypothesis does not lead to the conclusion that huge amounts of vertebrate genomes are functionally important, but rather that such "functionality" represents molecular noise that has weak or no effect on organismal phenotypes.

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Section: Discussionmentioning

confidence: 75%

Qualifying the relationship between sequence conservation and molecular function

Cooper¹,

Brown²

2008

Genome Res.

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“…Similarly, one would expect that high information content positions (the most conserved positions of the motif) are critical for the binding and thus would also be most conserved across species. This assumption does not take into consideration possible differences in the binding protein residues between species, but it has been shown to be correct for individual yeast and fruit fly transcription factors [43,44]. However, this dependence appears to become weaker when average conservation data are calculated over positions from different vertebrate transcription factors.…”

Section: Resultsmentioning

confidence: 99%

Regulatory conservation of protein coding and microRNA genes in vertebrates: lessons from the opossum genome

et al. 2007

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Regulatory conservation

A study of conservation of non-coding sequences, cis-regulatory elements and biological functions of regulated genes in opossum and other vertebrates enables better estimation of promoter conservation and transcription factor binding site turnover among mammals

Abstract Background: Being the first noneutherian mammal sequenced, Monodelphis domestica (opossum) offers great potential for enhancing our understanding of the evolutionary processes that take place in mammals. This study focuses on the evolutionary relationships between conservation of noncoding sequences, cis-regulatory elements, and biologic functions of regulated genes in opossum and eight vertebrate species.

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“…Our studies, comparing the level of enhancer activity between occupied sites with and without constraint on the motifs, and those of Brown et al (2007) both show that high enhancer activity is associated with strong purifying selection on the binding site motifs. Other studies emphasize turnover (Dermitzakis and Clark 2002;Moses et al 2006) and compensatory changes (Ludwig and Kreitman 1995;Ludwig et al 2000) in binding site motifs when orthologous enhancers are compared. Both conservation and turnover of binding sites motifs have been observed in multiple comparative studies in a range of species (Dermitzakis et al 2003;Moses et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional enhancement by GATA1-occupied DNA segments is strongly associated with evolutionary constraint on the binding site motif

Cheng¹,

King²,

Doré³

et al. 2008

Genome Res.

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Tissue development and function are exquisitely dependent on proper regulation of gene expression, but it remains controversial whether the genomic signals controlling this process are subject to strong selective constraint. While some studies show that highly constrained noncoding regions act to enhance transcription, other studies show that DNA segments with biochemical signatures of regulatory regions, such as occupancy by a transcription factor, are seemingly unconstrained across mammalian evolution. To test the possible correlation of selective constraint with enhancer activity, we used chromatin immunoprecipitation as an approach unbiased by either evolutionary constraint or prior knowledge of regulatory activity to identify DNA segments within a 66-Mb region of mouse chromosome 7 that are occupied by the erythroid transcription factor GATA1. DNA segments bound by GATA1 were identified by hybridization to high-density tiling arrays, validated by quantitative PCR, and tested for gene regulatory activity in erythroid cells. Whereas almost all of the occupied segments contain canonical WGATAR binding site motifs for GATA1, in only 45% of the cases is the motif deeply preserved (found at the orthologous position in placental mammals or more distant species). However, GATA1-bound segments with high enhancer activity tend to be the ones with an evolutionarily preserved WGATAR motif, and this relationship was confirmed by a loss-of-function assay. Thus, GATA1 binding sites that regulate gene expression during erythroid maturation are under strong selective constraint, while nonconstrained binding may have only a limited or indirect role in regulation.

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Large-Scale Turnover of Functional Transcription Factor Binding Sites in Drosophila

Cited by 241 publications

References 63 publications

Qualifying the relationship between sequence conservation and molecular function

Qualifying the relationship between sequence conservation and molecular function

Regulatory conservation of protein coding and microRNA genes in vertebrates: lessons from the opossum genome

Transcriptional enhancement by GATA1-occupied DNA segments is strongly associated with evolutionary constraint on the binding site motif

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