MONKEY: identifying conserved transcription-factor binding sites in multiple alignments using a binding site-specific evolutionary model

Moses, Alan M.; Chiang, Derek Y.; Pollard, Daniel A.; Iyer, Venky N.; Eisen, Michael B.

doi:10.1186/gb-2004-5-12-r98

Cited by 142 publications

(85 citation statements)

References 53 publications

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“…We find a substantial improvement of the predictive quality already at the level of two species and a further improvement for three species. This confirms the results of a recent study of conserved sites in several Saccharomyces species, where the significance of the evolutionary information as a function of evolutionary distances is discussed in detail (15). Of course, elementary evolutionary steps other than point mutations are expected to become important in eukaryotes.…”

Section: Improving Binding Site Searches Requires a Quantitative Evolsupporting

confidence: 89%

“…14 for protein-coding sequences and has been used in ref. 15. For binding sites, however, the factorized form is a heuristic approximation, because generic fitness landscapes are not additive.…”

Section: Q͑a͒ [4]mentioning

confidence: 99%

“…This model demonstrates the possibility of rapid adaptive formation of binding sites under positive selection and provides evolutionary constraints on eukaryotic promoter architecture. A similar evolutionary model (14) underlies a recently introduced method to identify conserved binding sites in multiple alignments (15).…”

mentioning

confidence: 99%

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Evolutionary population genetics of promoters: Predicting binding sites and functional phylogenies

Mustonen

Lässig

2005

Proc. Natl. Acad. Sci. U.S.A.

109

125

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We study the evolution of transcription factor-binding sites in prokaryotes, using an empirically grounded model with point mutations and genetic drift. Selection acts on the site sequence via its binding affinity to the corresponding transcription factor. Calibrating the model with populations of functional binding sites, we verify this form of selection and show that typical sites are under substantial selection pressure for functionality: for cAMP response protein sites in Escherichia coli, the product of fitness difference and effective population size takes values 2N⌬F of order 10. We apply this model to cross-species comparisons of binding sites in bacteria and obtain a prediction method for binding sites that uses evolutionary information in a quantitative way. At the same time, this method predicts the functional histories of orthologous sites in a phylogeny, evaluating the likelihood for conservation or loss or gain of function during evolution. We have performed, as an example, a cross-species analysis of E. coli, Salmonella typhimurium, and Yersinia pseudotuberculosis. Detailed lists of predicted sites and their functional phylogenies are available.R egulatory interactions between genes are believed to provide an important mode of evolution, which accounts for a substantial part of the differentiation between species (1). This is reflected by the sequence variability of regulatory DNA: there is ample case evidence of compensatory evolution at conserved function but also of rapid functional changes even between closely related species (2). Lacking a quantitative model of regulatory evolution, however, alignments of regulatory sequences and predictions of their functionality have proven notoriously difficult.A large body of existing work has focused on the identification of transcription factor-binding sites as the main functional elements of regulatory DNA. For factors with known binding specificity (given in the form of a position weight matrix), putative binding sites are identified from their conservation in cross-species comparisons. Different measures of conservation have been introduced, which involve, e.g., the sequence similarity of aligned loci or their independent high scoring in all species compared (3-7). These methods are powerful prediction tools for binding sites. From an evolutionary point of view, however, the conservation criteria are heuristic. Hence, it is difficult to quantify the statistical significance of the results, which depends on the number and evolutionary distance of the species compared. Sequence conservation tends to be too restrictive in cases where substantial sequence variation is compatible with the position weight matrix, in particular for distant species. Simple sequence similarity measures implicitly assume neutral evolution, whereas independent scoring of orthologous sites ignores the evolutionary link between the species altogether. Most importantly, none of these conservation measures allows a consistent statistical treatment of functional innovations in the e...

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Section: Improving Binding Site Searches Requires a Quantitative Evolsupporting

confidence: 89%

Section: Q͑a͒ [4]mentioning

confidence: 99%

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Evolutionary population genetics of promoters: Predicting binding sites and functional phylogenies

Mustonen

Lässig

2005

Proc. Natl. Acad. Sci. U.S.A.

109

125

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“…However, these methods are all based completely on substitution rates and ignore other sources of information about natural selection, such as patterns of substitution (Moses et al 2004;Pedersen et al 2006) or rates and patterns of insertion and deletion Siepel and Haussler 2004a;Lunter et al 2006). A recently introduced method, called SiPhy, attempts to exploit the pattern of substitution by using an LRT similar to phyloP's all-branch test, except that it treats the equilibrium nucleotide frequencies as free parameters to be estimated at each site for the alternative model (together with a branch-length scaling parameter) (Garber et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Detection of nonneutral substitution rates on mammalian phylogenies

Pollard¹,

Hubisz²,

Rosenbloom³

et al. 2009

Genome Res.

2,065

1,980

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Methods for detecting nucleotide substitution rates that are faster or slower than expected under neutral drift are widely used to identify candidate functional elements in genomic sequences. However, most existing methods consider either reductions (conservation) or increases (acceleration) in rate but not both, or assume that selection acts uniformly across the branches of a phylogeny. Here we examine the more general problem of detecting departures from the neutral rate of substitution in either direction, possibly in a clade-specific manner. We consider four statistical, phylogenetic tests for addressing this problem: a likelihood ratio test, a score test, a test based on exact distributions of numbers of substitutions, and the genomic evolutionary rate profiling (GERP) test. All four tests have been implemented in a freely available program called phyloP. Based on extensive simulation experiments, these tests are remarkably similar in statistical power. With 36 mammalian species, they all appear to be capable of fairly good sensitivity with low false-positive rates in detecting strong selection at individual nucleotides, moderate selection in 3-bp elements, and weaker or clade-specific selection in longer elements. By applying phyloP to mammalian multiple alignments from the ENCODE project, we shed light on patterns of conservation/acceleration in known and predicted functional elements, approximate fractions of sites subject to constraint, and differences in clade-specific selection in the primate and glires clades. We also describe new ''Conservation'' tracks in the UCSC Genome Browser that display both phyloP and phastCons scores for genome-wide alignments of 44 vertebrate species.

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“…By searching for highly conserved sequences across multiple species, scientists have identified critical functional elements (Bejerano et al 2004;Pennacchio et al 2006;Prabhakar et al 2006). Sequence conservation is commonly used as input to programs that predict genes (Dewey et al 2004;Majoros et al 2005;Gross and Brent 2006), find transcription factor binding sites (Lenhard et al 2003;Moses et al 2004), and find other regulatory elements (de la Calle-Mustienes et al 2005;Abbasi et al 2007). The conservation signal used by all of these applications is based on alignments between the input genomic sequences.…”

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confidence: 99%

Multiple whole-genome alignments without a reference organism

Dubchak

Poliakov²,

Kislyuk³

et al. 2009

Genome Res.

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Multiple sequence alignments have become one of the most commonly used resources in genomics research. Most algorithms for multiple alignment of whole genomes rely either on a reference genome, against which all of the other sequences are laid out, or require a one-to-one mapping between the nucleotides of the genomes, preventing the alignment of recently duplicated regions. Both approaches have drawbacks for whole-genome comparisons. In this paper we present a novel symmetric alignment algorithm. The resulting alignments not only represent all of the genomes equally well, but also include all relevant duplications that occurred since the divergence from the last common ancestor. Our algorithm, implemented as a part of the VISTA Genome Pipeline (VGP), was used to align seven vertebrate and six Drosophila genomes. The resulting whole-genome alignments demonstrate a higher sensitivity and specificity than the pairwise alignments previously available through the VGP and have higher exon alignment accuracy than comparable public whole-genome alignments. Of the multiple alignment methods tested, ours performed the best at aligning genes from multigene families—perhaps the most challenging test for whole-genome alignments. Our whole-genome multiple alignments are available through the VISTA Browser at http://genome.lbl.gov/vista/index.shtml.

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MONKEY: identifying conserved transcription-factor binding sites in multiple alignments using a binding site-specific evolutionary model

Cited by 142 publications

References 53 publications

Evolutionary population genetics of promoters: Predicting binding sites and functional phylogenies

Evolutionary population genetics of promoters: Predicting binding sites and functional phylogenies

Detection of nonneutral substitution rates on mammalian phylogenies

Multiple whole-genome alignments without a reference organism

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