Pairwise alignment
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Pairwise alignment
Now we know how to do it: How do we get a multiple
alignment (three or more sequences)?
Multiple alignment: much greater combinatorial explosion than with pairwise alignment…..
Multi-dimensional dynamic programming(Murata et al. 1985)
Simultaneous Multiple alignmentMulti-dimensional dynamic programming
MSA (Lipman et al., 1989, PNAS 86, 4412)
extremely slow and memory intensive up to 8-9 sequences of ~250 residues
DCA (Stoye et al., 1997, CABIOS 13, 625)
still very slow
Alternative multiple alignment methods
Biopat (first method ever) MULTAL (Taylor 1987) DIALIGN (Morgenstern 1996) PRRP (Gotoh 1996) Clustal (Thompson Higgins Gibson
1994) Praline (Heringa 1999) T Coffee (Notredame 2000) HMMER (Eddy 1998) [Hidden Marcov
Models] SAGA (Notredame 1996) [Genetic
algorithms]
Progressive multiple alignment general principles
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Guide tree Multiple alignment
Score 1-2
Score 1-3
Score 4-5
Scores Similaritymatrix5×5
Scores to distances Iteration possibilities
General progressive multiple alignment technique(follow generated tree)
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d
root
Progressive multiple alignment
Problem: Accuracy is very important Errors are propagated into the
progressive steps
“Once a gap, always a gap”
Feng & Doolittle, 1987
Multiple alignment profilesGribskov et al. 1987
ACDWY
Gappenalties
i0.30.100.30.3
0.51.0
Position dependent gap penalties
ACD……VWY
sequence
profile
Profile-sequence alignment
ACD..Y
ACD……VWY
profile
profileProfile-profile alignment
Clustal, ClustalW, ClustalX CLUSTAL W/X (Thompson et al., 1994) uses Neighbour
Joining (NJ) algorithm (Saitou and Nei, 1984), widely used in phylogenetic analysis, to construct guide tree.
Sequence blocks are represented by profiles, in which the individual sequences are additionally weighted according to the branch lengths in the NJ tree.
Further carefully crafted heuristics include: (i) local gap penalties (ii) automatic selection of the amino acid substitution matrix,
(iii) automatic gap penalty adjustment (iv) mechanism to delay alignment of sequences that appear to
be distant at the time they are considered. CLUSTAL (W/X) does not allow iteration (Hogeweg and
Hesper, 1984; Corpet, 1988, Gotoh, 1996; Heringa, 1999, 2002)
Profile pre-processing Secondary structure-induced
alignment Globalised local alignment Matrix extension
Objective: try to avoid (early) errors
Strategies for multiple sequence alignment
Pre-profile generation1213
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Score 1-2
Score 1-3
Score 4-5
ACD..Y
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1ACD..Y
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Pre-profilesPre-alignments
512354
ACD..Y
Cut-off
Profile pre-processing Secondary structure-induced
alignment Globalised local alignment Matrix extension
Objective: try to avoid (early) errors
Strategies for multiple sequence alignment
VHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
PRIMARY STRUCTURE (amino acid sequence)
QUATERNARY STRUCTURE (oligomers)
SECONDARY STRUCTURE (helices, strands)
TERTIARY STRUCTURE (fold)
Protein structure hierarchical levels
Profile pre-processing Secondary structure-induced
alignment Globalised local alignment Matrix extension
Objective: try to avoid (early) errors
Strategies for multiple sequence alignment
Globalised local alignment
+ =
1. Local (SW) alignment (M + Po,e)
2. Global (NW) alignment (no M or Po,e)
Double dynamic programming
Profile pre-processing Secondary structure-induced
alignment Globalised local alignment Matrix extension
Objective: try to avoid (early) errors
Strategies for multiple sequence alignment
Matrix extension – T COFFEE
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Summary
Weighting schemes simulating simultaneous multiple alignment Profile pre-processing (global/local) Matrix extension (well balanced scheme)
Smoothing alignment signals globalised local alignment
Using additional information secondary structure driven alignment
Schemes strike balance between speed and sensitivity
References Heringa, J. (1999) Two strategies for sequence
comparison: profile-preprocessed and secondary structure-induced multiple alignment. Comp. Chem. 23, 341-364.
Notredame, C., Higgins, D.G., Heringa, J. (2000) T-Coffee: a novel method for fast and accurate multiple sequence alignment. J. Mol. Biol., 302, 205-217.
Heringa, J. (2002) Local weighting schemes for protein multiple sequence alignment. Comput. Chem., 26(5), 459-477.
Where to find this….http://www.cs.vu.nl/~ibivu/teaching