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Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor of Biological Statistics and Computational Biology Cornell University
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Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Dec 22, 2015

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Page 1: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Short Primer on Comparative Genomics

Today: Special guest lecture12pm, Alway M108 Comparative genomics of animals and plants

Adam SiepelAssistant Professor of Biological Statistics and Computational Biology Cornell University

Page 2: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Evolution at the DNA level

…ACGGTGCAGTTACCA…

…AC----CAGTCCACCA…

Mutation

SEQUENCE EDITS

REARRANGEMENTS

Deletion

InversionTranslocationDuplication

Page 3: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Orthology and Paralogy

HB HumanHB Human

WB WormWB Worm

HA1 HumanHA1 Human

HA2 HumanHA2 Human

YeastYeast

WA WormWA Worm

Orthologs:Derived by speciation

Paralogs:Everything else

Page 4: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Orthology, Paralogy, Inparalogs, Outparalogs

Page 5: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Synteny maps

Comparison of human and mouse

Page 6: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Synteny maps

Page 7: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Building synteny maps

Recommended local aligners• BLASTZ

Most accurate, especially for genes Chains local alignments

• WU-BLAST Good tradeoff of efficiency/sensitivity Best command-line options

• BLAT Fast, less sensitive Good for

• comparing very similar sequences • finding rough homology map

Page 8: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

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 9: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Local Alignments

Page 10: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

After chaining

Page 11: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Chaining local alignments

1. Find local alignments

2. Chain -O(NlogN) L.I.S.

3. Restricted DP

Page 12: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

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

z

Page 13: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Threaded Blockset Aligner

Human–Cow

HMR – CDRestricted AreaProfile Alignment

Page 14: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Reconstructing the Ancestral Mammalian Genome

Human: C

Baboon: C

Cat: C

Dog: G

C

C or G

G

Page 15: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Neutral Substitution Rates

Page 16: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

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 17: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

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 18: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Finding Conserved Elements

Page 19: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Finding Conserved Elements (3)

GERP

Page 20: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Phylo HMMs

HMM

Phylogenetic Tree Model

Phylo HMM

Page 21: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Finding Conserved Elements (3)

Page 22: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

How do the methods agree/disagree?

Page 23: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Statistical Power to Detect Constraint

L

N

C: cutoff # mutationsD: neutral mutation rate: constraint mutation rate relative to neutral

Page 24: Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor.

Statistical Power to Detect Constraint

L

N

C: cutoff # mutationsD: neutral mutation rate: constraint mutation rate relative to neutral