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dc.contributor.author Majoros, WH
dc.contributor.author Ohler, U
dc.coverage.spatial United States
dc.date.accessioned 2011-06-21T17:31:13Z
dc.date.issued 2010-12-16
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/21187896
dc.identifier.citation PLoS Comput Biol, 2010, 6 (12), pp. e1001037 - ?
dc.identifier.uri http://hdl.handle.net/10161/4455
dc.description.abstract The computational detection of regulatory elements in DNA is a difficult but important problem impacting our progress in understanding the complex nature of eukaryotic gene regulation. Attempts to utilize cross-species conservation for this task have been hampered both by evolutionary changes of functional sites and poor performance of general-purpose alignment programs when applied to non-coding sequence. We describe a new and flexible framework for modeling binding site evolution in multiple related genomes, based on phylogenetic pair hidden Markov models which explicitly model the gain and loss of binding sites along a phylogeny. We demonstrate the value of this framework for both the alignment of regulatory regions and the inference of precise binding-site locations within those regions. As the underlying formalism is a stochastic, generative model, it can also be used to simulate the evolution of regulatory elements. Our implementation is scalable in terms of numbers of species and sequence lengths and can produce alignments and binding-site predictions with accuracy rivaling or exceeding current systems that specialize in only alignment or only binding-site prediction. We demonstrate the validity and power of various model components on extensive simulations of realistic sequence data and apply a specific model to study Drosophila enhancers in as many as ten related genomes and in the presence of gain and loss of binding sites. Different models and modeling assumptions can be easily specified, thus providing an invaluable tool for the exploration of biological hypotheses that can drive improvements in our understanding of the mechanisms and evolution of gene regulation.
dc.format.extent e1001037 - ?
dc.language eng
dc.language.iso en_US en_US
dc.relation.ispartof PLoS Comput Biol
dc.relation.isversionof 10.1371/journal.pcbi.1001037
dc.subject Animals
dc.subject Base Sequence
dc.subject Computational Biology
dc.subject Computer Simulation
dc.subject Drosophila melanogaster
dc.subject Evolution, Molecular
dc.subject Gene Expression Regulation
dc.subject Markov Chains
dc.subject Molecular Sequence Data
dc.subject Phylogeny
dc.subject ROC Curve
dc.subject Regulatory Elements, Transcriptional
dc.subject Sequence Alignment
dc.subject Sequence Analysis, DNA
dc.title Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US
duke.date.pubdate 2010-12-0 en_US
duke.description.endpage e1001037 en_US
duke.description.issue 12 en_US
duke.description.startpage e1001037 en_US
duke.description.volume 6 en_US
dc.relation.journal Plos Computational Biology en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/21187896
pubs.issue 12
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Biostatistics & Bioinformatics
pubs.publication-status Published online
pubs.volume 6
dc.identifier.eissn 1553-7358

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