Phylogenetic simulation of promoter evolution: estimation and modeling of binding site turnover events and assessment of their impact on alignment tools

Huang, Weichun; Nevins, Joseph R.; Ohler, Uwe

doi:10.1186/gb-2007-8-10-r225

Cited by 26 publications

(23 citation statements)

References 82 publications

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“…However, we note that insertions and deletions are a major source of sequence variation in Drosophila , with D. melanogaster having a strong deletion bias [44] and deletion is thought to contribute significantly to binding site turnover [45]. Taking this into account, we expect to observe reduced turnover in even functionally independent binding sites if they are overlapping or adjacent, as some fraction of the deletions that would remove a binding site with a complementary site elsewhere would also affect adjacent, and presumably uncompensated sites.…”

Section: Discussionmentioning

confidence: 86%

Sepsid even-skipped Enhancers Are Functionally Conserved in Drosophila Despite Lack of Sequence Conservation

et al. 2008

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The gene expression pattern specified by an animal regulatory sequence is generally viewed as arising from the particular arrangement of transcription factor binding sites it contains. However, we demonstrate here that regulatory sequences whose binding sites have been almost completely rearranged can still produce identical outputs. We sequenced the even-skipped locus from six species of scavenger flies (Sepsidae) that are highly diverged from the model species Drosophila melanogaster, but share its basic patterns of developmental gene expression. Although there is little sequence similarity between the sepsid eve enhancers and their well-characterized D. melanogaster counterparts, the sepsid and Drosophila enhancers drive nearly identical expression patterns in transgenic D. melanogaster embryos. We conclude that the molecular machinery that connects regulatory sequences to the transcription apparatus is more flexible than previously appreciated. In exploring this diverse collection of sequences to identify the shared features that account for their similar functions, we found a small number of short (20–30 bp) sequences nearly perfectly conserved among the species. These highly conserved sequences are strongly enriched for pairs of overlapping or adjacent binding sites. Together, these observations suggest that the local arrangement of binding sites relative to each other is more important than their overall arrangement into larger units of cis-regulatory function.

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Section: Discussionmentioning

confidence: 86%

Sepsid even-skipped Enhancers Are Functionally Conserved in Drosophila Despite Lack of Sequence Conservation

et al. 2008

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“…The regulatory effects of a TF often vary already significantly between different strains of the same bacterial species (122). The structure and sequence of cis-regulatory elements may change even when gene expression patterns are conserved because there is a significant turnover of binding site sequences (74,136,187). In such a turnover event, a new TFBS bound by the same TF evolves next to the original TFBS, after which the original TFBS degenerates (100).…”

Section: Evolution Of Regulatory Networkmentioning

confidence: 99%

Mechanisms and Evolution of Control Logic in Prokaryotic Transcriptional Regulation

Hijum

Medema

Kuipers

2009

Microbiol Mol Biol Rev

140

149

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SUMMARY A major part of organismal complexity and versatility of prokaryotes resides in their ability to fine-tune gene expression to adequately respond to internal and external stimuli. Evolution has been very innovative in creating intricate mechanisms by which different regulatory signals operate and interact at promoters to drive gene expression. The regulation of target gene expression by transcription factors (TFs) is governed by control logic brought about by the interaction of regulators with TF binding sites (TFBSs) in cis-regulatory regions. A factor that in large part determines the strength of the response of a target to a given TF is motif stringency, the extent to which the TFBS fits the optimal TFBS sequence for a given TF. Advances in high-throughput technologies and computational genomics allow reconstruction of transcriptional regulatory networks in silico. To optimize the prediction of transcriptional regulatory networks, i.e., to separate direct regulation from indirect regulation, a thorough understanding of the control logic underlying the regulation of gene expression is required. This review summarizes the state of the art of the elements that determine the functionality of TFBSs by focusing on the molecular biological mechanisms and evolutionary origins of cis-regulatory regions.

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“…The difficulty of reliably aligning noncoding sequences of distant species was recognized early by the research community, which has developed several models to assess inference errors (Pollard et al 2006;Huang et al 2007;Kim and Sinha 2010). Extensive work has been done to provide further insight into the functional constraints on TFBS organization, concluding that clustered and/or overlapping TFBSs are common requirements for enhancer activity (e.g., Hu et al 2007;Gotea et al 2010;Lusk and Eisen 2010).…”

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confidence: 99%

Genome-wide identification of conserved regulatory function in diverged sequences

et al. 2011

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Plasticity of gene regulatory encryption can permit DNA sequence divergence without loss of function. Functional information is preserved through conservation of the composition of transcription factor binding sites (TFBS) in a regulatory element. We have developed a method that can accurately identify pairs of functional noncoding orthologs at evolutionarily diverged loci by searching for conserved TFBS arrangements. With an estimated 5% false-positive rate (FPR) in approximately 3000 human and zebrafish syntenic loci, we detected approximately 300 pairs of diverged elements that are likely to share common ancestry and have similar regulatory activity. By analyzing a pool of experimentally validated human enhancers, we demonstrated that 7/8 (88%) of their predicted functional orthologs retained in vivo regulatory control. Moreover, in 5/7 (71%) of assayed enhancer pairs, we observed concordant expression patterns. We argue that TFBS composition is often necessary to retain and sufficient to predict regulatory function in the absence of overt sequence conservation, revealing an entire class of functionally conserved, evolutionarily diverged regulatory elements that we term ''covert.''

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Phylogenetic simulation of promoter evolution: estimation and modeling of binding site turnover events and assessment of their impact on alignment tools

Cited by 26 publications

References 82 publications

Sepsid even-skipped Enhancers Are Functionally Conserved in Drosophila Despite Lack of Sequence Conservation

Sepsid even-skipped Enhancers Are Functionally Conserved in Drosophila Despite Lack of Sequence Conservation

Mechanisms and Evolution of Control Logic in Prokaryotic Transcriptional Regulation

Genome-wide identification of conserved regulatory function in diverged sequences

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