791_my_lecture3

791_my_lecture3 - 7.91 Lecture #3 Michael Yaffe More...

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7.9 1 – Lecture #3 More Multiple Sequence Alignment -and- Motif Scanning, Database Searching Michael Yaffe
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Outline Multiple Sequence Alignment - Carillo & Lipman, Clustal(W) Position-Specific Scoring Matrices (PSSM) Information content, Shannon entropy Sequence logos Hidden Markov Models …Other approaches: Genetic algorithms, expectation maximization, MEME,Gibbs sampler FASTA, Blast searching, Smith-Waterman Psi-Blast Reading - Mount p. 139-150, 152-157, 161-171, 185-198
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Multiple Sequence Alignments Sequences are aligned so as to bring the greatest number of single characters into register. If we include gaps, mismatches, then even dynamic programming becomes limited to ~ 3 sequences unless they are very short….need an alternative approach… Why?
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Consider the 2 sequence comparison …..an O(mn) problem – order n 2 i =0 1 2 3 4 5 j = Gap V D S C Y 0 0 4 -8 -4 -3 -8 -16 -24 -32 -40 -8 1 -8 4 -12 -20 -28 -1 2 -16 -6 -9 7 -17 2 1 -7 3 -24 -14 3 -6 9 4 -32 -22 -14 -30 3 0 5 -40 -22 -7 1 3 13 6 -48 -38 -30 -15 5 23
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For 3 sequences…. ARDFSHGLLENKLLGCDSMRWE .::. .:::. .:::: :::. GRDYKMALLEQWILGCD-MRWD .::. ::.: .. :. .::: SRDW--ALIEDCMV-CNFFRWD An O(mnj) problem ! Consider sequences each 300 amino acids Uh Oh !!! 2 sequences – (300) 2 Our polynomail problem 3 sequences – (300) 3 Just became exponential! but for v sequences – (300) v
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Consider pairwise alignments between 3 sequences Carillo and Lipman – Sum of Pairs method Sequence B C e c n u q S A-C A-B B-C A-B-C Do we need to Score each node? Sequence A Get the multiple alignment score within the cubic lattice by Adding together the scores of the pairwise alignments…
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In practice, doesn’t give optimal alignment…But we’re close! Seems reasonable that the optimal alignment won’t be far from the diagonal we were on…so we just set bounds on the location of the msa within the cube based on each pairwise-alignment. Then just do dynamic programing within the volume defined by the pre-imposed bounds
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Still takes too long for more than three sequences…need a better way! Progressive Methods of Multiple Sequence Alignment Concept – simple: 1-Use DP to build pairwise alignments of most closely related sequences 2- Then progressively add less related sequences or groups of sequences…
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ClustalW Higgins and Sharp 1988 •1 - Do pairwise analysis of all the sequences (you choose similarity matrix). 2- Use the alignment scores to make a phylogenetic tree. 3- Align the sequences to each other guided by the phylogenetic relationships in the tree. New features: Clustal ClustalW (allows weights) ClustalX (GUI-based Weighting is important to avoid biasing an alignment by many sequence Members that are closely related to each other evolutionarily!
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Pairwise Alignment Steps in Multiple Alignment Multiple alignment following the tree from A S 1 S 1 S 1 6 pairwise comparisons then cluster analysis similarity align most similar pair Gaps to optimize alignment
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791_my_lecture3 - 7.91 Lecture #3 Michael Yaffe More...

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