# Moreover, the circular logic

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1 Moreover, the circular logic How do we know what is the right distance without a good alignment? And how do we construct a good alignment without knowing what substitutions were made previously? ATGCGT--GCAAGT --GCGGCGGCAGTT ATGCGT--GCAAGT- --GCGGCGGC-AGTT Which is better? Less gaps but 7matches More gaps but 8 matches

2 Substitution matrices for proteins We need to compare, DNA or protein sequences, estimate their distances etc (e.g. Helpful for inferring molecular function by finding similarity to a sequence with known function). For that purpose we need: Good alignment of sequences. For that purpose we need: A measure for judging the quality of an alignment in relation to other possible alignments, a scoring system.

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5 A practical aspect as well, since we don t study very diverged DNA sequences

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25 Commonly multiplied by a power of 10 to deal with decimals

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28 A sample substitution matrix 134 LQQGELDLVMTSDILPRSELHYSPMFDFEVRLVLAPDHPLASKTQITPEDLASETLLI 137 LDSNSVDLVLMGVPPRNVEVEAEAFMDNPLVVIAPPDHPLAGERAISLARLAEETFVM BLOSUM62 D:D = +6 C 9 S -1 4 T P A G D:R = -2 N D E Q H R K M I L V F Y W C S T P A G N D E Q H R K M I L V F Y W

29 BLOSUM Brief Overview Based purely on counts and alignment BLOSUM65 < BLOSUM45 in evolutionary distance a set of sequences S = S...S, where S = s...s, ij 20 j i j i i= 1 j= 1 i= 1 1 k i i1 in s is the j-th amino acid in sequence S. The probability of observing each amino acid X =p(x) p(x) cx (, S)/ cx (, S) where cx (, S k = j i k ) is the count of amino acid X in sequence S PX X random= px px orpx ifl= m 2 ( l, m ) 2 ( l). ( m) ( l), i j i

30 In general log-odds for alignment PX (, X data) = # of X, X combinations/all possible pairwise combinations l m l m finally take the log2-odds likelihood ratio and multiply by 2 for easy representation { } Note: all possible pairwise combinations=k. nn ( 1)/2 Blosum does use pseudo count to accomadate for combinations not observed: add 1 in numerator, add 210 (20*19+20) in denominator ie P(X,X data) = l m count(x l,x m) k. ( 1) / { nn } P(X l,x m data) λ.log = subs. matrix P (X,X random) l m λ being a scaling factor for representation

31 BLOSUM vs PAM vs others? BLOSUM: Based on a range of evolutionary periods -- Each matrix constructed separately Indirectly accounts for interdependence of residues Range of sequences, range of replacements PAM Based on extrapolation from a short evolutionary period -- Errors in PAM1 are magnified through PAM250 Assumes Markov process too much extrapolation Rare replacements too infrequent to be represented accurately Others Incorporation of secondary structure/structural alignments Use of structural alignments Transmemberane protein-specific matrices

32 How do we use the matrices for sequence alignment? AGGCTATCACCTGACCTCCAGGCCGATGCCC TAGCTATCACGACCGCGGTCGATTTGCCCGAC -AGGCTATCACCTGACCTCCAGGCCGA--TGCCC--- TAG-CTATCAC--GACCGC--GGTCGATTTGCCCGAC Definition Given two strings x = x 1 x 2...x M, y = y 1 y 2 y N, An alignment of two sequences x and y is an arrangement of x and y by position, where a and b can be padded with gap symbols to achieve the same length.

33 Why do we bother aligning? Finding important molecular regions that are conserved across species Given a new sequence, infer its function based on similarity to another Seq. Determining the evolutionary constraints at work Mutations in a population or a family of genes Find similar looking sequences in a database Inferring the secondary or tertiary structure of a sequence of interest -Molecular modeling using a template (homology modeling)

34 Alignment is a path in the alignment matrix X: ACACACTA Y: AGCACACA X: AGCACAC-A Y: A-CACACTA m+ n! mn!! m+ n 2 Alignments possible!

35 Dynamic programming for global alignment simple case Consider two sequences: x[1.. M], and y[1.. N] for a new position to be aligned we have ONLY three choices 1. x i aligns to y j x 1 x i-1 x i Align x[1.. i] with y[1.. j] y 1 y j-1 y j 2. x i aligns to a gap x 1 x i-1 x i y 1 y j - 3. y j aligns to a gap x 1 x i - y 1 y j-1 y j x[1..(i-1)] is already aligned with y[1..(j)], so align x[i] with a gap in y x[1.. i] is already aligned with y[1.. (j-1)], so align a gap in x to y[j]

36 1. x i aligns to y j x 1 x i-1 y 1 y j-1 x i y j F (i,j) = F (i-1, j-1) + s(i,j) 2. x i aligns to a gap x 1 x i-1 x i y 1 y j - 3. y j aligns to a gap x 1 x i - y 1 y j-1 y j F (i,j) = F (i-1, j) gap_open_penalty (go) F (i,j) = F (i, j-1) gap_open_penalty (go)

37 If we could make F (i, j-1), F (i-1, j), F (i-1, j-1) optimal, then we can make the next ones optimal as well F (i-1, j-1) + s (x i, y j ) F (i, j) = max F (i-1, j) go F (i, j-1) go Where s (x i, y j ) = Score for a match, if x i = y j ; score for a mismatch, if x i y j ;

38 The Needleman-Wunsch Algorithm pioneering application of DP to biological sequences 1. Initialization. a. F(0, 0) = 0 b. F(0, j) = - j go c. F(i, 0) = - i go 2. Main Iteration. Filling-in partial alignments For each i = 1 M For each j = 1 N F(i-1,j-1) + s(x i, y j ) [case 1] F(i, j) = max F(i-1, j) go [case 2] F(i, j-1) go [case 3] DIAG, if [case 1] Ptr(i,j) = LEFT, if [case 2] UP, if [case 3] 3. Termination. F(M, N) is the optimal score, and from Ptr(M, N) can trace back optimal alignment

39 An example T C G C A F (i-1, j-1) + s (x i, y j ) F (i, j) = max F (i-1, j) go F (i, j-1) go T s (x i, y j )=1 for match, -1 for mismatch go=2 C C A Trace back arrows from lower right to upper left and Maximize the scores Alignment score = 2 T C G C A T C - C A

40 Are gaps that bad? Current model: Gap of length n incurs penalty n.go γ(n) Bunch of gaps are better than individual gaps Convex (saturating) gap penalty function: γ(n): for all n, γ(n + 1) - γ(n) γ(n) - γ(n 1) A common function is Affine gap penalty γ(n) = go + (n 1) ge gap gap open extend γ(n)

41 Convex gap dynamic programming Initialization: same as before Iteration: F(i-1, j-1) + s(x i, y j ) F(i, j) = max max k=0 i-1 F(k,j) γ(i-k) max k=0 j-1 F(i,k) γ(j-k) Termination: same Running Time: O(N 2 M) Space: O(NM) (assume N>M)

42 Fast implementation of affine gap penalty We need three matrices for tracking scores Matrix-1: a[i,j]= to store maximum score of an alignment that ends in x[i] matched to y[j] Matrix-2: b[i,j]= to store maximum score of an alignment that ends in gap matched to y[j] Matrix-3: c[i,j]= to store maximum score of an alignment that ends in gap matched to x[i] x i y j - y j.x i -

43 Implementation Cont d ai [ 1, j 1] ai [, j] = max bi [ 1, j 1] + si (, j) ci [ 1, j 1] ai [, j 1] + go bi [, j] = max bi [, j 1] + ge ci [, j 1] + go ai [ 1, j] + go ci [, j] = max bi [ 1, j] + go ci [ 1, j] + ge Pointer-matrices: Three matrices to figure out which state within each score matrix maximization was used to obtain the optimal alignment of position i,j. Of course you need to know which matrix yielded the best score in the end (m,n) as well Covered by assignment!

44 For checking results of your code

45 Pair HMMs for alignment HMM for sequence alignment, which incorporates affine gap scores. Match (M) Insertion in x (X) insertion in y (Y) Hidden States Observation Symbols Match (M): {(a,b) a,b in }. Insertion in x (X): {(a,-) a in }. Insertion in y (Y): {(-,a) a in }.

46 Simple representation 1-δ M p xiyj 1-ε 1-ε X q xi δ δ Y q yj ε ε M X Y M 1-2δ 1- ε 1- ε X δ ε 0 Y δ 0 ε

47 Full representation δ ε Begin 1-2δ-τ M p xiyj δ X q xi 1-ε-τ τ τ End 1-2δ-τ δ δ 1-ε-τ Y q yj ε τ τ

48 Initialization: v M (0, 0) = 1. v X (0, 0) = v Y (0, 0) = 0 v * (-1, j) = v * (i, -1) = 0. Recurrence: i = 0,,n, j = 0,,m, except for(0,0); Termination: = = = 1), ( 1), ( max ), ( ) 1, ( ) 1, ( max ), ( 1) 1, ( ) (1 1) 1, ( ) (1 1) 1, ( ) 2 (1 max ), ( X M Y X M X Y X M M j i v j i v q j i v j i v j i v q j i v j i v j i v j i v p j i v j i j i y x y x ε δ ε δ τ ε τ ε τ δ )), ( ),, ( ),, ( max( Y X M E m n v m n v m n v v τ = Algorithm: Viterbi algorithm for pair HMMs

49 Viterbi Pair HMM is equivalent to global dynamic programming with affine gap! Proof (sketch) Add the following missing details to DEKM s summary Take the viterbi matrices and divide by the terms for random sequence probability, and take the log of resulting transformation i.e, (1 2 δ τ) v ( i 1, j 1). p q q (1 η) v i j v i j p q q M 2 xiyj xi yi M X 2 (, ) = max (1 ε τ) ( 1, 1). xiyj xi yi (1 η) Y 2 (1 ε τ) v ( i 1, j 1). pxiyj qxiqyi (1 η) M δv ( i 1, j). qxi qxi (1 η) (, ) = max i X εv ( i 1, j). qxi qxi (1 η) X v i j qx

50 Multiple Sequence Alignment (MSA) Si () = sx ( i, yi) all possible pairs How to score? and How to align? Scoring, common approach: Sum of pairs or its variants for each column Consider L aligned at all N positions, LL score =5 total score, Si ( ) = 5 NN ( -1) 2 Now consider one position being G, rest being L GL score=-4 ΔSi ( ) 5( N 1) + 4( N 1) 9( N 1) 9 = = = Si () Si () 2.5 NN ( 1) 2.5N Relative evidence decreases with N, opposed to having increased confidence in L being the "correct" residue at that position

51 Clustal W Pairwise alignment: calculation of distance matrix Rooted nj tree (guide tree) and calculation of sequence weights Progressive alignment following the guide tree

52 Step 1-Calculation of Distance Matrix using pairwise alignment Use the Distance Matrix to create a Guide Tree to determine the order of the sequences. Hbb-Hu 1 - Hbb-Ho Hba-Hu Hba-Ho Myg-Ph Gib-Pe Lgb-Lu D = 1 (I) D = Difference score I = # of identical aa s in pairwise global alignment total number of aa s in shortest sequence

53 Step 2-Create Rooted Tree and calculate weights Neighbor joining algorithm simple, to be discussed later Weight Alignment Order of alignment: 1 Hba-Hu vs Hba-Ho 2 Hbb-Hu vs Hbb-Ho 3 A vs B 4 Myg-Ph vs C 5 Gib-Pe vs D 6 Lgh-Lu vs E

54 Step 3-Progressive alignment

55 Step 3-Progressive alignment Scoring during progressive alignment

56 Recommended MSA Programs MUSCLE (fast and accurate) MAVID (genome-scale alignment) SAM ( hidden markov, powerful and wide range of options)

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