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Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs.

Publication ,  Journal Article
Majoros, WH; Ohler, U
Published in: PLoS Comput Biol
December 16, 2010

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.

Duke Scholars

Published In

PLoS Comput Biol

DOI

EISSN

1553-7358

Publication Date

December 16, 2010

Volume

6

Issue

12

Start / End Page

e1001037

Location

United States

Related Subject Headings

  • Sequence Analysis, DNA
  • Sequence Alignment
  • Regulatory Elements, Transcriptional
  • ROC Curve
  • Phylogeny
  • Molecular Sequence Data
  • Markov Chains
  • Gene Expression Regulation
  • Evolution, Molecular
  • Drosophila melanogaster
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Majoros, W. H., & Ohler, U. (2010). Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs. PLoS Comput Biol, 6(12), e1001037. https://doi.org/10.1371/journal.pcbi.1001037
Majoros, William H., and Uwe Ohler. “Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs.PLoS Comput Biol 6, no. 12 (December 16, 2010): e1001037. https://doi.org/10.1371/journal.pcbi.1001037.
Majoros, William H., and Uwe Ohler. “Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs.PLoS Comput Biol, vol. 6, no. 12, Dec. 2010, p. e1001037. Pubmed, doi:10.1371/journal.pcbi.1001037.

Published In

PLoS Comput Biol

DOI

EISSN

1553-7358

Publication Date

December 16, 2010

Volume

6

Issue

12

Start / End Page

e1001037

Location

United States

Related Subject Headings

  • Sequence Analysis, DNA
  • Sequence Alignment
  • Regulatory Elements, Transcriptional
  • ROC Curve
  • Phylogeny
  • Molecular Sequence Data
  • Markov Chains
  • Gene Expression Regulation
  • Evolution, Molecular
  • Drosophila melanogaster