Multiple Alignment

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Multiple Alignment

• Stuart M. Brown
• NYU School of Medicine

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Pairwise Alignment

• The alignment of two sequences (DNA or protein)
  is a relatively straightforward computational
  problem.
• The best solution seems to be an approach called
  Dynamic Programming.

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Dynamic Programming

• Dynamic Programming is a very general programming
  technique.
• It is applicable when a large search space can be
  structured into a succession of stages, such
  that
• the initial stage contains trivial solutions to
  sub-problems
• each partial solution in a later stage can be
  calculated by recurring a fixed number of partial
  solutions in an earlier stage
• the final stage contains the overall solution

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Global vs. Local Alignments

• Global alignment algorithms start at the
  beginning of two sequences and add gaps to each
  until the end of one is reached.
• Local alignment algorithms finds the region (or
  regions) of highest similarity between two
  sequences and build the alignment outward from
  there.

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Global Alignment

• Global algorithms are often not effective for
  highly diverged sequences and do not reflect the
  biological reality that two sequences may only
  share limited regions of conserved sequence.
• Sometimes two sequences may be derived from
  ancient recombination events where only a single
  functional domain is shared.
• Global alignment is useful when you want to force
  two sequences to align over their entire length

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Local Alignment

• The Smith-Waterman algorithm does an optimal
  local alignment
• FASTA and BLAST are local alignment algorithms
• NCBI has a BLAST 2 Sequences feature on its
  website
• http//www.ncbi.nlm.nih.gov/gorf/bl2.html

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Multiple Alignments

• In theory, making an optimal alignment between
  two sequences is computationally straightforward
  (Smith-Waterman algorithm), but aligning a large
  number of sequences using the same method is
  almost impossible.
• The problem increases exponentially with the
  number of sequences involved
• (the product of the sequence lengths)

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Optimal Alignment

• For a given group of sequences, there is no
  single "correct" alignment, only an alignment
  that is "optimal" according to some set of
  calculations.
• Determining what alignment is best for a given
  set of sequences is really up to the judgement of
  the investigator.

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Progressive PairwiseMethods

• Most of the available multiple alignment programs
  use some sort of incremental or progressive
  method that makes pairwise alignments, then adds
  new sequences one at a time to these
  aligned groups.
• This is an approximate method!

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CLUSTAL

• CLUSTAL is a stand-alone multiple alignment
  program
• Gap penalties can be adjusted based on specific
  amino acid residues, regions of hydrophobicity,
  proximity to other gaps, or secondary structure.
• it can re-align just selected sequences or
  selected regions in an existing alignment
• It can compute phylogenetic trees from a set of
  aligned sequences.
• There are also Mac and PC versions with a nice
  graphical interface (CLUSTALX).

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Multiple Alignment tools on the Web

• There are a variety of multiple alignment tools
  available for free on the web.
• CLUSTAL is available from a number of sites (with
  a variety of restrictions)
• Other algorithms are available too
• Watch out for experimental algorithms there
  may be a good reason why you have never heard of
  some oddball program

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Some URLs

• EMBL-EBI
• http//www.ebi.ac.uk/clustalw/
• BCM Search Launcher Multiple Alignment
• http//dot.imgen.bcm.tmc.edu9331/multi-align/mult
  i-align.html
• Multiple Sequence Alignment for Proteins (Wash.
  U. St. Louis)
• http//www.ibc.wustl.edu/service/msa/

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Editing Multiple Alignments

• There are a variety of tools that can be used to
  modify a multiple alignment.
• These programs can be very useful in formatting
  and annotating an alignment for publication.
• An editor can also be used to make modifications
  by hand to improve biologically significant
  regions in a multiple alignment created by one of
  the automated alignment programs.

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Other editors

• The MACAW and SeqVu program for Macintosh and
  GeneDoc and DCSE for PCs are free and provide
  excellent editor functionality.
• Many comprehensive molecular biology programs
  include multiple alignment functions
• MacVector, OMIGA, Vector NTI, and
  GeneTool/PepTool all include a built-in version
  of CLUSTAL

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SeqVu
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Editors on the Web

• Check out CINEMA (Colour INteractive Editor for
  Multiple Alignments)
• It is an editor created completely in JAVA (old
  browsers beware)
• It includes a fully functional version of
  CLUSTAL, BLAST, and a DotPlot module

http//www.bioinf.man.ac.uk/dbbrowser/CINEMA2.1/
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