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Tools for multiple sequence alignment

Methods course Multiple sequence alignment and Reconstruction of phylogenetic trees Burkhard Morgenstern, Fabian Schreiber Göttingen, October/November 2007. Tools for multiple sequence alignment. Multiple alignment basis of (almost) all methods for sequence analysis in bioinformatics.

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Tools for multiple sequence alignment

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  1. Methods courseMultiple sequence alignment andReconstruction of phylogenetic treesBurkhard Morgenstern, Fabian SchreiberGöttingen, October/November 2007

  2. Tools for multiple sequence alignment Multiple alignment basis of (almost) all methods for sequence analysis in bioinformatics

  3. Tools for multiple sequence alignment T Y I M R E A Q Y E T C I V M R E A Y E

  4. Tools for multiple sequence alignment T Y I - M R E A Q Y E T C I V M R E A - Y E

  5. Tools for multiple sequence alignment T Y I M R E A Q Y E T C I V M R E A Y E Y I M Q E V Q Q E Y I A M R E Q Y E

  6. Tools for multiple sequence alignment T Y I - M R E A Q Y E T C I V M R E A - Y E Y - I - M Q E V Q Q E Y – I A M R E - Q Y E

  7. Tools for multiple sequence alignment T Y I - M R E A Q Y E T C I V M R E A - Y E - Y I - M Q E V Q Q E Y – I A M R E - Q Y E Astronomical Number of possible alignments!

  8. Tools for multiple sequence alignment T Y I - M R E A Q Y E T C I V - M R E A Y E - Y I - M Q E V Q Q E Y – I A M R E - Q Y E Astronomical Number of possible alignments!

  9. Tools for multiple sequence alignment T Y I - M R E A Q Y E T C I V M R E A - Y E - Y I - M Q E V Q Q E Y – I A M R E - Q Y E Which one is the best ???

  10. Tools for multiple sequence alignment Questions in development of alignment programs: (1) What is a good alignment? → objective function (`score’) (2) How to find a good alignment? → optimization algorithm

  11. Tools for multiple sequence alignment • What is a biologically good alignment ??

  12. Tools for multiple sequence alignment Criteria for alignment quality: • 3D-Structure: align residues at corresponding positions in 3D structure of protein! • Evolution: align residues with common ancestors!

  13. Tools for multiple sequence alignment T Y I - M R E A Q Y E T C I V M - R E A Y E - Y I - M Q E V Q Q E - Y I A M R E - Q Y E Alignment hypothesis about sequence evolution Search for most plausible hypothesis!

  14. Tools for multiple sequence alignment T Y I - M R E A Q Y E T C I V - M R E A Y E - Y I - M Q E V Q Q E - Y I A M R E - Q Y E Alignment hypothesis about sequence evolution Search for most plausible hypothesis!

  15. Tools for multiple sequence alignment Compute for amino acids a and b • Probability pa,b of substitution a → b (or b → a), • Frequency qaof a Define similarity score s(a,b) based on pa,b , qa Result: similarity matrix (substitution matrix), e.g. PAM (Dayhoff matrix), BLOSUM, …

  16. Tools for multiple sequence alignment

  17. Tools for multiple sequence alignment Traditional objective functions: Define Score of alignments as • Sum of individual similarity scores s(a,b) of aligned amino acid residues • Gap penalty g for each gap in alignment Optimal alignment can be calculated for two sequences but in practice not for > 8 sequences

  18. T Y W I V T - - L V Example: Score = s(T,T) + s(I,L) + s (V,V) – 2 g

  19. Tools for multiple sequence alignment Most commonly used heuristic for multiple alignment: Progressive alignment (mid 1980s): Idea: • calculate multiple alignment as series of pairwise alignments of sequences and profiles • Use guide tree to determine order of pairwise alignments

  20. `Progressive´ Alignment WCEAQTKNGQGWVPSNYITPVN WWRLNDKEGYVPRNLLGLYP AVVIQDNSDIKVVPKAKIIRD YAVESEAHPGSFQPVAALERIN WLNYNETTGERGDFPGTYVEYIGRKKISP

  21. `Progressive´ Alignment WCEAQTKNGQGWVPSNYITPVN WWRLNDKEGYVPRNLLGLYP AVVIQDNSDIKVVPKAKIIRD YAVESEAHPGSFQPVAALERIN WLNYNETTGERGDFPGTYVEYIGRKKISP Guide tree

  22. `Progressive´ Alignment WCEAQTKNGQGWVPSNYITPVN WW--RLNDKEGYVPRNLLGLYP- AVVIQDNSDIKVVP--KAKIIRD YAVESEASFQPVAALERIN WLNYNEERGDFPGTYVEYIGRKKISP Profile alignment, “once a gap - always a gap”

  23. `Progressive´ Alignment WCEAQTKNGQGWVPSNYITPVN WW--RLNDKEGYVPRNLLGLYP- AVVIQDNSDIKVVP--KAKIIRD YAVESEASVQ--PVAALERIN------ WLN-YNEERGDFPGTYVEYIGRKKISP Profile alignment, “once a gap - always a gap”

  24. `Progressive´ Alignment WCEAQTKNGQGWVPSNYITPVN- WW--RLNDKEGYVPRNLLGLYP- AVVIQDNSDIKVVP--KAKIIRD YAVESEASVQ--PVAALERIN------ WLN-YNEERGDFPGTYVEYIGRKKISP Profile alignment, “once a gap - always a gap”

  25. `Progressive´ Alignment WCEAQTKNGQGWVPSNYITPVN-------- WW--RLNDKEGYVPRNLLGLYP-------- AVVIQDNSDIKVVP--KAKIIRD------- YAVESEA---SVQ--PVAALERIN------ WLN-YNE---ERGDFPGTYVEYIGRKKISP Profile alignment, “once a gap - always a gap”

  26. CLUSTAL W Most important software program: CLUSTAL W: J. Thompson, T. Gibson, D. Higgins (1994, Nuc. Acids Res.) (22,327 citations in the literaterature!, Oct 2007)

  27. Tools for multiple sequence alignment Problems with traditional approach: • Results depend on gap penalty • Heuristic guide tree determines alignment; alignment used for phylogeny reconstruction • Algorithm produces global alignments.

  28. Tools for multiple sequence alignment Problems with traditional approach: But: Many sequence families share only local similarity E.g. sequences share one conserved motif

  29. Local sequence alignment EYENS ERYENS ERYAS Find common motif in sequences; ignore the rest

  30. Local sequence alignment E-YENS ERYENS ERYA-S Find common motif in sequences; ignore the rest

  31. Local sequence alignment E-YENS ERYENS ERYA-S Find common motif in sequences; ignore the rest – Local alignment

  32. Gibbs Motive Sampler Local multiple alignment without gaps: E.g. Gibbs sampling C.E. Lawrence et al. (1993, Science)

  33. Traditional alignment approaches: Either global or local methods!

  34. New question: sequence families with multiple local similarities Neither local nor global methods appliccable

  35. New question: sequence families with multiple local similarities Alignment possible if order conserved

  36. The DIALIGN approach Morgenstern, Dress, Werner (1996, Proc Natl. Acad. Sci.) • Combination of global and local methods • Assemble multiple alignment from gap-free local pairwise alignments (,,fragments“)

  37. The DIALIGN approach atctaatagttaaactcccccgtgcttag cagtgcgtgtattactaacggttcaatcgcg caaagagtatcacccctgaattgaataa

  38. The DIALIGN approach atctaatagttaaactcccccgtgcttag cagtgcgtgtattactaacggttcaatcgcg caaagagtatcacccctgaattgaataa

  39. The DIALIGN approach atctaatagttaaactcccccgtgcttag cagtgcgtgtattactaacggttcaatcgcg caaagagtatcacccctgaattgaataa

  40. The DIALIGN approach atctaatagttaaactcccccgtgcttag cagtgcgtgtattactaacggttcaatcgcg caaagagtatcacccctgaattgaataa

  41. The DIALIGN approach atctaatagttaaactcccccgtgcttag cagtgcgtgtattactaacggttcaatcgcg caaagagtatcacccctgaattgaataa

  42. The DIALIGN approach atctaatagttaaactcccccgtgcttag cagtgcgtgtattactaacggttcaatcgcg caaagagtatcacccctgaattgaataa

  43. The DIALIGN approach atc------taatagttaaactcccccgtgcttag cagtgcgtgtattactaacggttcaatcgcg caaagagtatcacccctgaattgaataa

  44. The DIALIGN approach atc------taatagttaaactcccccgtgcttag cagtgcgtgtattactaacggttcaatcgcg caaa--gagtatcacccctgaattgaataa

  45. The DIALIGN approach atc------taatagttaaactcccccgtgcttag cagtgcgtgtattactaacggttcaatcgcg caaa--gagtatcacc----------cctgaattgaataa

  46. The DIALIGN approach atc------taatagttaaactcccccgtgc-ttag cagtgcgtgtattactaac----------gg-ttcaatcgcg caaa--gagtatcacc----------cctgaattgaataa

  47. The DIALIGN approach atc------taatagttaaactcccccgtgc-ttag cagtgcgtgtattactaac----------gg-ttcaatcgcg caaa--gagtatcacc----------cctgaattgaataa Consistency!

  48. The DIALIGN approach atc------TAATAGTTAaactccccCGTGC-TTag cagtgcGTGTATTACTAAc----------GG-TTCAATcgcg caaa--GAGTATCAcc----------CCTGaaTTGAATaa

  49. The DIALIGN approach Advantages of segment-based approach: • Program can produce global and local alignments! • Sequence families alignable that cannot be aligned with standard methods

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