CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.
-
date post
20-Dec-2015 -
Category
Documents
-
view
228 -
download
3
Transcript of CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.
![Page 1: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/1.jpg)
CS273a Lecture 11, Aut 08, Batzoglou
Multiple Sequence Alignment
![Page 2: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/2.jpg)
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?
![Page 3: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/3.jpg)
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Local Alignments
![Page 4: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/4.jpg)
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
After chaining
![Page 5: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/5.jpg)
CS273a Lecture 11, Aut 08, Batzoglou
Chaining local alignments
1. Find local alignments
2. Chain -O(NlogN) L.I.S.
3. Restricted DP
![Page 6: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/6.jpg)
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)
![Page 7: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/7.jpg)
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Threaded Blockset Aligner
Human–Cow
HMR – CDRestricted AreaProfile Alignment
![Page 8: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/8.jpg)
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
![Page 9: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/9.jpg)
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Neutral Substitution Rates
![Page 10: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/10.jpg)
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
![Page 11: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/11.jpg)
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
![Page 12: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/12.jpg)
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Finding Conserved Elements
![Page 13: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/13.jpg)
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Finding Conserved Elements (3)
GERP
![Page 14: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/14.jpg)
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Phylo HMMs
HMM
Phylogenetic Tree Model
Phylo HMM
![Page 15: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/15.jpg)
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
Finding Conserved Elements (3)
![Page 16: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/16.jpg)
CS273a Lecture 11, Aut 08, BatzoglouCS273a Lecture 11, Fall 2008
How do the methods agree/disagree?
![Page 17: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/17.jpg)
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
![Page 18: CS273a Lecture 11, Aut 08, Batzoglou Multiple Sequence Alignment.](https://reader036.fdocuments.net/reader036/viewer/2022062407/56649d415503460f94a1b358/html5/thumbnails/18.jpg)
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