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Cited by 153Genomics and Chromatin DynamicsGenomics and Phylogenetic StudiesFungal and yeast genetics research

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

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Moses, Alan M, Chiang, Derek Y, Pollard, Daniel A, Iyer, Venky N, Eisen, Michael B·2004·Genome Biology
DOI 10.1186/gb-2004-5-12-r98PMC PMC545801
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Abstract

We introduce a method (MONKEY) to identify conserved transcription-factor binding sites in multispecies alignments. MONKEY employs probabilistic models of factor specificity and binding-site evolution, on which basis we compute the likelihood that putative sites are conserved and assign statistical significance to each hit. Using genomes from the genus Saccharomyces , we illustrate how the significance of real sites increases with evolutionary distance and explore the relationship between conservation and function.

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Figure 1 Accuracy of p-value estimations. To examine the accuracy of our p-value estimates, we compared the empirical p-value (computed from the observed distribution of scores) to p-values computed using either the exact method described above (black points) or Gaussian approximation (gray points). The scores represent the simple score at a distance of 0.1 substitutions per site calculated using the Gcn4p matrix from SCPD [33]. Other models and matrices produce similar results.
Figure 1 Accuracy of p-value estimations. To examine the accuracy of our p-value estimates, we compared the empirical p-value (computed from the observed distribution of scores) to p-values computed using either the exact method described above (black points) or Gaussian approximation (gray points). The scores represent the simple score at a distance of 0.1 substitutions per site calculated using the Gcn4p matrix from SCPD [33]. Other models and matrices produce similar results.CC BY · PubMed Central
Figure 2 Significance of matches increases with evolutionary distance. Median p-values for the positive (black squares) and negative (white triangles or white triangle points) sets of binding sites for (a) Gal4p and (b) Rpn4p at different evolutionary distances represented by comparing S. cerevisiae to different subsets of the available species. For both factors, as evolutionary distance increases, the median p-value of the functional matches decreases, indicating that they are less likely to have appeared by chance. Conversely, the median p-value of the nonfunctional matches (negative set, white symbols) increases. These observations agree with our predictions for the behavior of the p-values (solid traces) under either the HB evolution for the motif or HKY evolution for the background. There is little difference between these predictions and similar ones that assume that all the comparisons were pairwise (dotted traces).
Figure 2 Significance of matches increases with evolutionary distance. Median p-values for the positive (black squares) and negative (white triangles or white triangle points) sets of binding sites for (a) Gal4p and (b) Rpn4p at different evolutionary distances represented by comparing S. cerevisiae to different subsets of the available species. For both factors, as evolutionary distance increases, the median p-value of the functional matches decreases, indicating that they are less likely to have appeared by chance. Conversely, the median p-value of the nonfunctional matches (negative set, white symbols) increases. These observations agree with our predictions for the behavior of the p-values (solid traces) under either the HB evolution for the motif or HKY evolution for the background. There is little difference between these predictions and similar ones that assume that all the comparisons were pairwise (dotted traces).CC BY · PubMed Central
Figure 3 Significance of binding sites in pairwise or three-way comparisons at similar evolutionary distance. (a) Histogram of the percent identities of all aligned noncoding regions of S. cerevisiae and S. kudriavzevii (open squares) and S. cerevisiae, S. paradoxus and S. mikatae (filled squares). (b) Median p-values of functional matches (positive set, gray bars) and the nonfunctional matches (negative set, open bars) for S. cerevisiae and S. kudriavzevii alignments (left) and S. cerevisiae, S. paradoxus and S. mikatae alignments (right). The similarity of these p-values supports the idea that multiple similar genomes can be used to span longer evolutionary distances, but at these close evolutionary distances provide little additional power.
Figure 3 Significance of binding sites in pairwise or three-way comparisons at similar evolutionary distance. (a) Histogram of the percent identities of all aligned noncoding regions of S. cerevisiae and S. kudriavzevii (open squares) and S. cerevisiae, S. paradoxus and S. mikatae (filled squares). (b) Median p-values of functional matches (positive set, gray bars) and the nonfunctional matches (negative set, open bars) for S. cerevisiae and S. kudriavzevii alignments (left) and S. cerevisiae, S. paradoxus and S. mikatae alignments (right). The similarity of these p-values supports the idea that multiple similar genomes can be used to span longer evolutionary distances, but at these close evolutionary distances provide little additional power.CC BY · PubMed Central
Figure 4 Relationship between conserved Rpn4p-binding sites and expression. (a) We identified 56 Rpn4p-binding sites with p-values below 1.85 × 10-8 using all five species and the HB model. The expression patterns of these genes (clustered and displayed as in [44]) fall into two major groups: the 'stereotypical' proteasomal pattern (indicated by a blue bar at the right), and a second group expressed in these and additional conditions (indicated by the green bar). The orange bars above the expression data correspond to (left to right) temperature changes, treatment with H2O2, treatment with the superoxide generating drug menadione, treatment with the sulfhydryl oxidant diamide, deletions of YAP1 and MSN2/4, treatment with the DNA damaging agent methylmethanesulfonate (MMS), and heat shock in deletions of MEC1 and DUN1 [48,49]. (b) Examples of conserved Rpn4p sites (boxed) that do not fall in either expression group (neither blue nor green bar).
Figure 4 Relationship between conserved Rpn4p-binding sites and expression. (a) We identified 56 Rpn4p-binding sites with p-values below 1.85 × 10-8 using all five species and the HB model. The expression patterns of these genes (clustered and displayed as in [44]) fall into two major groups: the 'stereotypical' proteasomal pattern (indicated by a blue bar at the right), and a second group expressed in these and additional conditions (indicated by the green bar). The orange bars above the expression data correspond to (left to right) temperature changes, treatment with H2O2, treatment with the superoxide generating drug menadione, treatment with the sulfhydryl oxidant diamide, deletions of YAP1 and MSN2/4, treatment with the DNA damaging agent methylmethanesulfonate (MMS), and heat shock in deletions of MEC1 and DUN1 [48,49]. (b) Examples of conserved Rpn4p sites (boxed) that do not fall in either expression group (neither blue nor green bar).CC BY · PubMed Central
Figure 5 Some apparently functional Rpn4p-binding sites are not conserved. (a) The MONKEY p-values (points) of all putatively functional Rpn4p-binding sites at varying evolutionary distances, along with the expected values under the HB and HKY models (solid traces). The majority of sites behave as expected for conserved binding sites (lower trace). Several, however, behave as expected for unconstrained sites (upper trace). (b) The predicted binding site (indicated by a box) in REH1, which encodes a protein of unknown function in S. cerevisiae, is not conserved, whereas a binding site with a lower score is conserved (indicated by a black bar). (c) A very poorly conserved match upstream of PTC3; in this case no other sites can be found in the region.
Figure 5 Some apparently functional Rpn4p-binding sites are not conserved. (a) The MONKEY p-values (points) of all putatively functional Rpn4p-binding sites at varying evolutionary distances, along with the expected values under the HB and HKY models (solid traces). The majority of sites behave as expected for conserved binding sites (lower trace). Several, however, behave as expected for unconstrained sites (upper trace). (b) The predicted binding site (indicated by a box) in REH1, which encodes a protein of unknown function in S. cerevisiae, is not conserved, whereas a binding site with a lower score is conserved (indicated by a black bar). (c) A very poorly conserved match upstream of PTC3; in this case no other sites can be found in the region.CC BY · PubMed Central
Figure 6 The evolutionary distance required to confidently identify conserved binding sites varies among transcription factors. (a) Median p-values for functional binding sites for various factors at different evolutionary distances. The evolutionary distance needed to obtain a desired significance varies between factors. (b) Predicted dependence of the p-values on evolutionary distance. Specificity data and functional binding sites were obtained from the SCPD.
Figure 6 The evolutionary distance required to confidently identify conserved binding sites varies among transcription factors. (a) Median p-values for functional binding sites for various factors at different evolutionary distances. The evolutionary distance needed to obtain a desired significance varies between factors. (b) Predicted dependence of the p-values on evolutionary distance. Specificity data and functional binding sites were obtained from the SCPD.CC BY · PubMed Central

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Metadata

Authors
Moses, A. M., Chiang, D. Y., Pollard, D. A., Iyer, V. N., & Eisen, M. B.
Affiliations
  • University of California, Berkeley (US)
  • Lawrence Berkeley National Laboratory (US)
Corresponding author
Eisen, Michael B
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2004-11-30
Volume
5
Issue
12
Pages
R98-R98
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/gb-2004-5-12-r98
PMC
PMC545801
OpenAlex
W2109314645
Cited by
153
References
53
Citations by year
2026: 1 · 2025: 1 · 2023: 1 · 2022: 1 · 2021: 4 · 2018: 1 · 2017: 4 · 2016: 4 · 2015: 3 · 2014: 4 · 2013: 6 · 2012: 12
FWCI
6.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of North Texas Digital Library (University of North Texas) (submittedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders
National Human Genome Research Institute (R01HG002779)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords
transcription factor binding sites, conserved binding sites, binding site evolution, Saccharomyces, phylogenetic distance
MeSH terms
Binding Sites, DNA, DNA-Binding Proteins, DNA, Fungal, Biological Evolution, Gene Expression Regulation, Models, Genetic, Saccharomyces cerevisiae, Software, Species Specificity, Transcription Factors, Sequence Alignment, Conserved Sequence, Saccharomyces cerevisiae Proteins

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