Introduction to RNA Bioinformatics

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Introduction to RNA Bioinformatics

• Craig L. Zirbel
• October 5, 2010
• Based on a talk originally given by Anton Petrov.

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Outline

• Lecture 1
• Importance of RNA, examples (miRNA,
  riboswitches).
• RNA 2D and 3D structure.
• RNA structure prediction.
• Lecture 2
• RNA basepairs and 3D motifs
• Predicting secondary structure from sequence
  (mfold)
• Lecture 3
• Statistical variability of protein and RNA
  sequences

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• In the human, out of approximately 3 billion
  nucleotides, only about 1.5 code for proteins,
  although up to 93 are transcribed into RNA. What
  is this non-coding RNA doing?

ENCODE Project Consortium, Identification and
analysis of functional elements in 1 of the
human genome by the ENCODE pilot project. Nature.
2007 Jun 14447(7146)799-816
Mattick, J.S. (2004) The hidden genetic program
of complex organisms. Scientific American 291
(4) 60-67.
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DNA
Transcription
RNA
tRNA Ribosomal RNA
Translation
Protein
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DNA
Reverse Transcription
Transcription
tRNA Ribosomal RNA Many other types of ncRNA
RNA
micro RNA
Splicing
Introns (RNA)
Protein
Translation of exons
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Mattick, J.S. (2004) The hidden genetic program
of complex organisms. Scientific American 291
(4) 60-67.
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microRNA
miRNAs in a transcript, waiting to be diced out
Mattick, J.S. (2004) The hidden genetic program
of complex organisms. Scientific American 291
(4) 60-67.
Bioinformatical challenge given a DNA sequence,
predict microRNA genes and their respective
targets.
Kim VN, MicroRNA biogenesis coordinated cropping
and dicing. Nat Rev Mol Cell Biol. 2005
May6(5)376-85
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Acquisition of novel microRNAs (shown in white
boxes) may be a driving force of recent
evolution. Also a factor in cancers?
There are 84 mammal-specific microRNAs, and 84
more that are found exclusively in apes.
Peterson, K.J., Dietrich, M.R. and McPeek, M.A.
(2009) MicroRNAs and metazoan macroevolutioninsi
ghts into canalization, complexity, and the
Cambrian explosion. BioEssays 31736747.
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RIBOSWITCHES
RNAs which bind to other molecules when they are
present, altering the shape and function of the
RNA.
Bioinformatic challenges find riboswitches in
genomic sequences, design novel riboswitches.
Montange, R. K., Batey, R. T. (2008).
Riboswitches emerging themes in RNA structure
and function. Annu Rev Biophys 37117-133.
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Types of RNA
Bioinformatic challenges Is this list final?
Could there be more types of non-coding (ncRNA)
that we dont know yet? How to search for novel
ncRNAs in genomes?
http//en.wikipedia.org/wiki/List_of_RNAs
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Goals of RNA bioinformatics

• Find and classify RNA genes in genomic sequences
  (using both experimental and computational
  methods).
• Predict secondary and 3D structure from RNA
  sequence.
• Infer function from structure.
• Rationally design RNA molecules for
  biotechnology.
• Find diseases associated with RNAs (e.g., cancer
  and miRNA)

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Why RNA is unique

• Similar to DNA in chemical composition, primary
  and secondary structure, and information content,
  but with more complicated structure than helices
• Similar to Proteins in tertiary and 3D
  structure and function, but also very different,
  mostly base-base interactions, fewer
  backbone-backbone
• Binds substrates and catalyzes reactions, just
  as proteins.
• Participates in all stages of gene expression
  and information transfer transcription,
  splicing, translation. Frequent target of
  antibiotics.

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Similarities Between Protein and RNA 3D Structures

• Compact folding
• Hierarchical organization
• Modular domains
• Specific tertiary interactions
• Molecular mimicry -- Proteins that mimic RNA

The tertiary structures of tRNA-mimic translation
factors and tRNA. (a) Thermus thermophilus
EF-GGDP (PDB accession code 1DAR). (b) Thermus
aquaticus EF-TuGDPNPPhe-tRNAPhe (1TTT). (c)
Thermus thermophilus RRF (1EH1). (d) Yeast
Phe-tRNAPhe.
LIANG, H., LANDWEBER, L. F. (2005). Molecular
mimicry Quantitative methods to study structural
similarity between protein and RNA. RNA, 11(8),
1167-1172.
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RNAs are not linear - they fold back on
themselves to match up complementary strands
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RNA 2D Structure Elements
Basepairs are the basic units of secondary
structure.
Bioinformatics sequence and genome analysis By
David W. Mount
Bioinformatic challenges predict most stable 2D
structures, resolve pseudoknotted regions etc.
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2d to 3d structure of RNA