TCoffee Whats New in The Grinder Mixing MSAs

What’s in a Multiple Alignment? l Structural Criteria – l Evolutive Criteria – l

What’s in a Multiple Alignment? l l The MSA contains what you put inside…

Multiple Alignments: What Are They Good For? ? ?

Computing the Correct Alignement is a Complicated Problem

A Taxonomy of Multiple Sequence Alignment Packages APPROXIMATE FAST ACCURATE SLOW Entropy

Three Types of Algorithms l Progressive: Clustal. W l Iterative: Muscle l Concistency Based:

Concistency Based Algorithms: T-Coffee l Gotoh (1990) – l Martin Vingron (1991) – –

T-Coffee and Concistency… l Each Library Line is a Soft Constraint (a wish) l

Validation Using Bali. Base T-Coffee Results

Evaluating Methods… Who is the best? Says who…?

Who is the Best ? ? ? N T-Coffee Probcons Clustal. W Muscle Hom+50

Too Many Methods for ONE Alignment M-Coffee

Combining Many MSAs into ONE Clustal. W MAFFT T-Coffee MUSCLE ? ? ? ?

www. tcoffee. org www. vital-it. ch/prd/smoretti/cgi-bin/Tcoffee/tcoffee_cgi/index. cgi

When Sequences Are not Enough 3 D-Coffee and Expresso

3 D-Coffee: Combining Sequences and Structures Within Multiple Sequence Alignments

• Threading: 1 -Select 967 pairs of sequences in HOMSTRAD Fugue wins 2

• Superposition: SAP 1 -Select 967 pairs of sequences in HOMSTRAD 2 -Align

The More Structures The Merrier Average Improvement over T-Coffee Struc/Seq Ratio

Expresso: Finding the Right Structure Why Not Using Structure Based Alignments

Expresso: Finding the Right Structure Sources BLAST SAP Templates Template Alignment Source Template Alignment

14% Correct >1 aaza >1 ego >1 thx >2 trxa >3 trx >3 grx

Conclusion l The best Recipy For Good Sequence Alignments Structures!!! l A Better Recipy

Conclusion l l l Concistency Based Methods Have an Edge Hard to tell Methods

www. tcoffee. org l l l l Fabrice Armougom (CNRS) Sebastien Moretti (CNRS) Olivier

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T-Coffee: What’s New in The Grinder Mixing MSAs, Sequences and Structures Cédric Notredame Information Génétique et Structurale CNRS-Marseille, France

What’s in a Multiple Alignment? l Structural Criteria – l Evolutive Criteria – l Residues are arranged so that those playing a similar role end up in the same column. Residues are arranged so that those having the same ancestor end up in the same column. Similarity Criteria – As many similar residues as possible in the same column

What’s in a Multiple Alignment? l l The MSA contains what you put inside… You can view your MSA as: – – – A record of evolution A summary of a protein family A collection of experiments made for you by Nature…

Multiple Alignments: What Are They Good For? ? ?

Computing the Correct Alignement is a Complicated Problem

Off the Shelf Methods

A Taxonomy of Multiple Sequence Alignment Packages APPROXIMATE FAST ACCURATE SLOW Entropy

Three Types of Algorithms l Progressive: Clustal. W l Iterative: Muscle l Concistency Based: T-Coffee and Probcons

Clustal. W

Muscle Algorithm: Using The Iteration

Concistency Based Algorithms: T-Coffee l Gotoh (1990) – l Martin Vingron (1991) – – l Concistency Agglomerative Assembly T-Coffee (2000, Notredame) – – l Dot Matrices Multiplications Accurate but too stringeant Dialign (1996, Morgenstern) – – l Iterative strategy using concistency Concistency Progressive algorithm Prob. Cons (2004, Do) – T-Coffee with a Bayesian Treatment

T-Coffee and Concistency…

T-Coffee and Concistency… l Each Library Line is a Soft Constraint (a wish) l You can’t satisfy them all l You must satisfy as many as possible (The easy ones)

Validation Using Bali. Base T-Coffee Results

T-Coffee and Concistency…

Evaluating Methods… Who is the best? Says who…?

Structures Vs Sequences

Who is the Best ? ? ? N T-Coffee Probcons Clustal. W Muscle Hom+50 40 49. 71 51. 59 36. 77 46. 90 SABs+50 209 21. 85 22. 53 12. 34 19. 61 SABf+50 425 45. 18 44. 85 34. 95 38. 17 Prefab 1675 67. 96 67. 95 59. 45 66. 05

The Alignments Methods MAFFT

Too Many Methods for ONE Alignment M-Coffee

Combining Many MSAs into ONE Clustal. W MAFFT T-Coffee MUSCLE ? ? ? ?

Combining Many MSAs into ONE

The Right Mixt of Methods

Resisting Noise M-Coffee 8

Going Further

Place your Bets…

www. tcoffee. org www. vital-it. ch/prd/smoretti/cgi-bin/Tcoffee/tcoffee_cgi/index. cgi

When Sequences Are not Enough 3 D-Coffee and Expresso

3 D-Coffee: Combining Sequences and Structures Within Multiple Sequence Alignments

• Threading: 1 -Select 967 pairs of sequences in HOMSTRAD Fugue wins 2 -Align each pair with T-Coffee and Fugue. 3 -Compare the Two Alignments TCdef wins Fugue TCdef: 58. 81% Fugue: 61. 81%

• Superposition: SAP 1 -Select 967 pairs of sequences in HOMSTRAD 2 -Align each pair with T-Coffee and SAP. 3 -Compare the Two Alignments TCdef: 58. 81% SAP: 86. 31%

3 D-Coffee: Combining Sequences and Structures Within Multiple Sequence Alignments

The More Structures The Merrier Average Improvement over T-Coffee Struc/Seq Ratio

Expresso: Finding the Right Structure

Expresso: Finding the Right Structure Why Not Using Structure Based Alignments

Expresso: Finding the Right Structure Sources BLAST SAP Templates Template Alignment Source Template Alignment Remove Templates Library

14% Correct >1 aaza >1 ego >1 thx >2 trxa >3 trx >3 grx 1 DE 2 A 1 EGR 1 THX 2 BTOT 4 TRX 3 GRX 50% Correct

Conclusion l The best Recipy For Good Sequence Alignments Structures!!! l A Better Recipy More Structures!!!

Conclusion l l l Concistency Based Methods Have an Edge Hard to tell Methods Apart Sequence Alignment is NOT solved

www. tcoffee. org l l l l Fabrice Armougom (CNRS) Sebastien Moretti (CNRS) Olivier Poirot (CNRS) Frederic Reinier (CNRS, CRS 4) Karsten Suhre (CNRS) Vladimir Saudek (Sanofi-Aventis) Des Higgins (UCD) Orla O’Sullivan (UCD) Iain Wallace (UCD) Bruno Nyfler (Vital. IT) Victor Jongeneel (SIB, Vital. IT) Roger Hersch (EPFL) Pierre Dumas (EPFL) Basile Schaeli (EPFL) cedric. notredame@europe. com

Cadrie Notredom et Michael Claverie