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CS273a Lecture 11, Aut 08, Batzoglou
Multiple Sequence Alignment
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Index-based local alignment
Dictionary:
All words of length k (~10)
Alignment initiated between words of alignment score T
(typically T = k)
Alignment:
Ungapped extensions until score
below statistical threshold
Output:
All local alignments with score
> statistical threshold
……
……
query
DB
query
scan
Question: Using an idea from overlap detection, better way to find all local alignments between two genomes?
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Local Alignments
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
After chaining
CS273a Lecture 11, Aut 08, Batzoglou
Chaining local alignments
1. Find local alignments
2. Chain -O(NlogN) L.I.S.
3. Restricted DP
CS273a Lecture 11, Aut 08, Batzoglou
Progressive Alignment
• When evolutionary tree is known:
Align closest first, in the order of the tree In each step, align two sequences x, y, or profiles px, py, to generate a new
alignment with associated profile presult
Weighted version: Tree edges have weights, proportional to the divergence in that edge New profile is a weighted average of two old profiles
x
w
y
zExample
Profile: (A, C, G, T, -)px = (0.8, 0.2, 0, 0, 0)py = (0.6, 0, 0, 0, 0.4)
s(px, py) = 0.8*0.6*s(A, A) + 0.2*0.6*s(C, A) + 0.8*0.4*s(A, -) + 0.2*0.4*s(C, -)
Result: pxy = (0.7, 0.1, 0, 0, 0.2)
s(px, -) = 0.8*1.0*s(A, -) + 0.2*1.0*s(C, -)
Result: px- = (0.4, 0.1, 0, 0, 0.5)
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Threaded Blockset Aligner
Human–Cow
HMR – CDRestricted AreaProfile Alignment
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Reconstructing the Ancestral Mammalian Genome
Human: C
Baboon: C
Cat: C
Dog: G
C
C or G
C
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Neutral Substitution Rates
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Finding Conserved Elements (1)
• Binomial method 25-bp window in the human genome Binomial distribution of k matches in N bases given the neutral
probability of substitution
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Finding Conserved Elements (2)
• Parsimony Method Count minimum # of mutations explaining each column Assign a probability to this parsimony score given neutral model Multiply probabilities across 25-bp window of human genome
A
CAAG
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Finding Conserved Elements
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Finding Conserved Elements (3)
GERP
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Phylo HMMs
HMM
Phylogenetic Tree Model
Phylo HMM
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Finding Conserved Elements (3)
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
How do the methods agree/disagree?
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Statistical Power to Detect Constraint
L
N
C: cutoff # mutationsD: neutral mutation rate: constraint mutation rate relative to neutral
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Statistical Power to Detect Constraint
L
N
C: cutoff # mutationsD: neutral mutation rate: constraint mutation rate relative to neutral