Sequence Analysis

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Sequence Analysis
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Programme

• A Motif-based Framework for Recognizing Sequence
  FamiliesSharan, Myers 945-1010am
• 1010-1040am Coffee Break
• An HMM Posterior Decoder for Sequence Feature
  Prediction that Includes Homology
  InformationKäll, Krogh, Sonnhammer
  1040-1105am
• Self-Organized Clustering Methods for Familial
  Binding ProfilesMahony, Golden, Smith, Benos
  1105-1130am
• 1215-130pm ISCB Open Business Meeting
• Statistics of Local Multiple AlignmentsPrakash,
  Tompa 145-210pm
• Computing the P-value of the Information Content
  from an Alignment of Multiple SequencesNagarajan,
  Jones, Keich 210-235pm

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What Controls Gene Expression?

• Transcription factors
• Regulatory RNAs
• miRNA
• smRNA
• siRNA
• Methylation
• Chromatin

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Wasserman and Sandelin, (2004) Applied
Bioinformatics for the identification of
regulatory elements Nature Reviews Genetics
(5) 276-287.
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Transcription Factors

• Proteins which bind DNA
• Enhance or repress gene expression
• Families e.g.
• Homeodomain (Hox)
• POU domain (Oct-1)
• Helix-loop-Helix (c-Myc)
• Zinc Fingers (TFIIIA)
• Leucine Zipper (c/EBP)
• Winged Helix (Fox family)
• Approx 10 of genes in Human genome are TFs

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TF Noise
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TF Problems

• TFBS are small and degenerate
• TGTGGT AML-1a
• NNNWAAAYAAAYANNNNN FOXJ2_1
• AYMAYAATATTTKN FOXJ2_2
• TYAAGTG NKX2-5
• Upstream sequences (even conserved) are large

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Wasserman and Sandelin, (2004)
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Conserved Sites
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Motifs Collections?

• Databases/experimental data
• Transfac
• Jaspar
• De novo searches/motif finding
• Xiaohui Xie, Jun Lu, EJ. Kulbokas, Todd Golub,
  Vamsi Mootha, Kerstin Lindblad-Toh, Eric Lander,
  Manolis Kellis (2005) Systematic discovery of
  regulatory motifs in human promoters and 3' UTRs
  by comparison of several mammals Nature, 2005
  Feb 27, doi10.1038/nature03441

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Motif Finding

• From unaligned DNA?
• Pattern finding
• local multiple alignment
• Benchmark test sets
• M. Tompa, N. Li, T. L. Bailey , G. M. Church , B.
  De Moor, E. Eskin, A. V. Favorov, M. C. Frith, Y.
  Fu, W. J. Kent, V. J. Makeev, A. A. Mironov, W.
  S. Noble, G. Pavesi, G. Pesole, M. Regnier, N.
  Simonis, S. Sinha, G. Thijs, J. van Helden, M.
  Vandenbogaert, Z. Weng, C. Workman, C. Ye, and Z.
  Zhu (2005) Assessing Computational Tools for the
  Discovery of Transcription Factor Binding Sites.
  Nature Biotechnology, vol. 23, no. 1, 137 - 144.
  
• Compared 13 motif finders AlignACE, ANN-Spec,
  Consensus, GLAM, Improbizer, MEME, MEME3, MITRA,
  MotifSampler, oligo/dyad-analysis, QuickScore,
  SeSiMCMC, Weeder, YMF

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TFBS frequency?
Cre-bp1_c_Jun 7.7 HSF2 13.0
Cart-1 17.4 ER 22.1
HSF 80.4 SP1 86
.7 so how do we determine significance?