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I. Searching for human splice-regulatory motifs & II. Network analysis of synthetic-lethal interactions IPAM Workshop Jan 2006 Fritz Roth Harvard Medical School Dept. of Biological Chemistry & Molecular Pharmacology

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Searching for human splice-regulatory motifs & II. Network analysis of synthetic-lethal interactions. Fritz Roth Harvard Medical School Dept. of Biological Chemistry & Molecular Pharmacology. IPAM WorkshopJan 2006. Outline. Human alternative-splicing motif search - PowerPoint PPT Presentation

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Page 1: IPAM WorkshopJan 2006

I. Searching for human splice-regulatory motifs

&

II. Network analysis of synthetic-lethal interactions

IPAM Workshop Jan 2006

Fritz RothHarvard Medical School

Dept. of Biological Chemistry & Molecular Pharmacology

Page 2: IPAM WorkshopJan 2006

Outline

Human alternative-splicing motif search

Yeast synthetic-lethal network analysis

Page 3: IPAM WorkshopJan 2006

Outline

Human alternative-splicing motif search Review mRNA splicing Splice-junction expression data Sequence neighborhoods Clustering splice-junctions by usage Results

Yeast synthetic-lethal network analysis

Page 4: IPAM WorkshopJan 2006

Adapted from Molecular Cell Biology, Lodish et al.

Brief review of canonical mRNA splicing

Page 5: IPAM WorkshopJan 2006

~100,000 genes

Antiquity 2001 2004

35,000

25,000 human genes5% alt. spliced

~70% of human multi-exon genes

alternatively spliced

Importance of alternative splicing

Page 6: IPAM WorkshopJan 2006

From correlation to regulatory mechanism

Roth et al , 1998, Hughes et al, 2000 Tavazoie et al 1999, Slides adapted from S. Tavazoie

Page 7: IPAM WorkshopJan 2006

Sequence neighborhood of a splice junction

Page 8: IPAM WorkshopJan 2006

(Sorek & Ast, Gen. Research, 2003)

Conservation: constitutive vs. alternative

3’ acceptorneighborhood

5’ donor neighborhood

Page 9: IPAM WorkshopJan 2006

Previous splicing motif searches

Canonical splicing enhancers/repressors not associated with specific tissues (e.g. Brudno et al., Burge et al, Chasin et al)

Based on small (curated literature) set of alternatively spliced genes (e.g. , Brudno et al, Stamm et al., Fedorov et al.)

Based on expressed sequence tag (EST) datasets (Xu et al), biased towards 3’ ends of genes, can contain artificial splice variants due to Unigene clustering (Modrek & Lee, 2002)

Page 10: IPAM WorkshopJan 2006

• Every splice junction for ~11K reference mRNAs for ~10K genes

• ~100K probe sequences on five arrays

• 49 tissues & cell lines run in fluor-reversed pairs

• full-length mRNA amplification

Johnson et al. Science. 2003 Dec 19;302(5653):2141-4.Castle et al. Genome Biology. 2003;4(10):R66.

Pre-mRNA

Alternative mature mRNAs 18 nt 18 nt+

Cassette exon

Exon-exon splice junction expression data

Page 11: IPAM WorkshopJan 2006

Tissue-specific probes & data

Page 12: IPAM WorkshopJan 2006

splice junction usage data

Flowchart

Page 13: IPAM WorkshopJan 2006

original intensities

probes5’ 3’

tissues

NPTB

Tissue-specific splice junction expression

Page 14: IPAM WorkshopJan 2006

original intensities

probes5’ 3’

tissues rescaled intensities

NPTB

Tissue-specific splice junction expression

Page 15: IPAM WorkshopJan 2006

original intensities

probes5’ 3’

tissues relative splicing

rescaled intensities

NPTB

Tissue-specific splice junction expression

Page 16: IPAM WorkshopJan 2006

Synexin (ANXA7)

Tissue-specific splice junction expression

Page 17: IPAM WorkshopJan 2006

splice junction usage data cassette exons

alternative donors / acceptors

skipped cassette exons

Flowchart

Clustered splice junctions

allcassette exons

alternative

donors / acceptors

Probe set choice

Page 18: IPAM WorkshopJan 2006

Cassette exons skipped in heart & skeletal muscle

Results: heart & muscle

Page 19: IPAM WorkshopJan 2006

splice junction usage data

Flowchart

clustered splice junctions

allcassette exons

alternative

donors / acceptors

Probe set choice

all exonic intronicSequence neighborhoo

d choiceproximalto donor

proximal to

acceptor

sequence neighborhoods

Page 20: IPAM WorkshopJan 2006

Sequence neighborhood of a splice junction

Page 21: IPAM WorkshopJan 2006

1. Immediate neighborhood2. Neighborhood of junctions with shared splice site 3. Neighborhood of junctions of other competing junctions

1

2

33

Alternative splice junction neighborhoods

Page 22: IPAM WorkshopJan 2006

splice junction usage data

Flowchart

clustered splice junctions

allcassette exons

alternative

donors / acceptors

Probe set choice

all exonic intronicSequence neighborhoo

d choiceproximalto donor

proximal to

acceptor

sequence neighborhoods

Pattern findingword-based

motif-based

enriched sequence patterns

Page 23: IPAM WorkshopJan 2006

Cassette exons skipped in heart & skeletal muscle

ACTAAC @ end of intron- 8 out of 39 probes- 14-fold enrichment- strong position bias

(often nearby)

Results: heart & muscle

Page 24: IPAM WorkshopJan 2006

Cassette exons skipped in brain

26% of probes (9-fold enrichment)

Results: brain

Page 25: IPAM WorkshopJan 2006

76% (3-fold)

65% (15-fold)

Results: ileum

Page 26: IPAM WorkshopJan 2006

Results: jejunum, liver, pancreas Cluster

Page 27: IPAM WorkshopJan 2006

HNRPLClusterResults: jejunum, liver, pancreas

Page 28: IPAM WorkshopJan 2006

RRM1 RRM2 RRM3 RRM4

HNRPL

Results: jejunum, liver, pancreasHNRPLCluster

Page 29: IPAM WorkshopJan 2006

RRM1 RRM2 RRM3 RRM4

RRM1 RRM2 RRM3 RRM4

PTB

HNRPLProtein interaction

Results: jejunum, liver, pancreasHNRPLCluster

Page 30: IPAM WorkshopJan 2006

RRM1 RRM2 RRM3 RRM4

RRM1 RRM2 RRM3 RRM4

PTB

HNRPLProtein interaction

Results: jejunum, liver, pancreasHNRPLCluster

Page 31: IPAM WorkshopJan 2006

tissue-specificalternative

splicing

candidatecis-regulatory

motifs

Summary, Part I

validatedcis-regulatory

motifs

Map to trans-actingsplicing factors

candidatecis-regulatory

secondary strcture

Page 32: IPAM WorkshopJan 2006

Acknowledgments, Part I

Adnan Derti

George Church & Lab

Roth Lab

Rosetta/Merck Jason Johnson John Castle Lee Lim

Adrian Krainer

Page 33: IPAM WorkshopJan 2006

Outline

Human alternative-splicing motif search

Yeast synthetic-lethal network analysis

Page 34: IPAM WorkshopJan 2006

Outline

Human alternative-splicing motif search

Yeast synthetic-lethal network analysis Background

Overlap with other biological relationships

Network motifs

Predicting synthetic lethality

Role of transcription compensation in mutational robustness

SSL vs. protein interaction in predicting function

Page 35: IPAM WorkshopJan 2006

What is Synthetic Lethality?

Cells live

Cells live

Cells die

Gene XGene Y

Gene XGene Y

Gene XGene Y

Page 36: IPAM WorkshopJan 2006

What is Synthetic Sickness/Lethality (SSL)?

Cells live

Cells live

Cells dieor grow slowly

Gene XGene Y

Gene XGene Y

Gene XGene Y

Page 37: IPAM WorkshopJan 2006

An engine can run without one cylinder

(from http://www.cs.unc.edu/~geom/collide/videos.shtml)

Page 38: IPAM WorkshopJan 2006

Scenarios resulting in synthetic genetic interaction

SSL

2 partially redundant pathways

A

B

D

C

E

F

H

G

I

Partially redundant

genes

C1

A

B

E

D

C2

3 compensatory pathways,

2 required

E

F

H

G

I

A

B

D

C

J

K

M

L

Protein complex

tolerating 1 but not

2 mutations

AC

F

D

E

B

Page 39: IPAM WorkshopJan 2006

A known sub-network of SSL interactions

A Canadian consortium (Boone et al.) has made many double mutants

As of 2001:

8 query genes

x

4500 nonessential “array” genes

≈ 36,000 tested pairs

(Tong et al., Science, 2001)

Page 40: IPAM WorkshopJan 2006

The known sub-network circa 2001

(Tong et al., Science, 2001)

Page 41: IPAM WorkshopJan 2006

The known SSL sub-network circa 2004160 query x 4500 nonessential ≈ 700,000 tested pairs (≈4% pairs)

(Tong et al., Science, 2004)

~3800 interactions

Page 42: IPAM WorkshopJan 2006

Outline

Human alternative-splicing motif search

Yeast synthetic-lethal network analysis Background

Overlap with other biological relationships

Network motifs

Predicting synthetic lethality

Role of transcription compensation in mutational robustness

SSL vs. protein interaction in predicting function

Page 43: IPAM WorkshopJan 2006

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Overlap between synthetic lethality & other “interactions”

Page 44: IPAM WorkshopJan 2006

Overlap between synthetic lethality & other “interactions”

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Page 45: IPAM WorkshopJan 2006

Overlap between synthetic lethality & other “interactions”

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Page 46: IPAM WorkshopJan 2006

Overlap between synthetic lethality & other “interactions”

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Page 47: IPAM WorkshopJan 2006

Overlap between synthetic lethality & other “interactions”

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Page 48: IPAM WorkshopJan 2006

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Overlap between synthetic lethality & other “interactions”

Page 49: IPAM WorkshopJan 2006

Overlap between synthetic lethality & other “interactions”

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Page 50: IPAM WorkshopJan 2006

Scenarios resulting in synthetic interaction

SSL

2 partially redundant pathways

A

B

D

C

E

F

H

G

I

Partially redundant

genes

C1

A

B

E

D

C2

3 partially redundant

pathways, 2 required

E

F

H

G

I

A

B

D

C

J

K

M

L

Protein complex

tolerating 1 but not

2 destabilizi

ng mutations

AC

F

D

E

B

< 2% < 4% *

Page 51: IPAM WorkshopJan 2006

Outline

Human alternative-splicing motif search

Yeast synthetic-lethal network analysis Background

Overlap with other biological relationships

Network motifs

Predicting synthetic lethality

Role of transcription compensation in mutational robustness

SSL vs. protein interaction in predicting function

Page 52: IPAM WorkshopJan 2006

“Network Motifs: Simple Building Blocks of Complex Networks”

R. Milo, S. Shen-Orr, , , U. Alon, Science (2003).

Page 53: IPAM WorkshopJan 2006

The synthetic lethal network has many triangles

Xiaofeng Xin, Boone Lab

Page 54: IPAM WorkshopJan 2006

Motifs in an integrated S. cerevisiae network

S: Synthetic sickness or lethality

H

X: Correlated expression

P: Stable physical interaction

R: Transcriptional regulation

S

H: Sequence homology

S: Synthetic sickness or lethality

H

X: Correlated expression

P: Stable physical interaction

R: Transcriptional regulation

S

H: Sequence homology

Page 55: IPAM WorkshopJan 2006

Motifs in an integrated S. cerevisiae network

R

R

R

A1A1

(2.6+0.5) ×102

4.7×102

Nrand:

Nreal:

(2.6+0.5) ×102

4.7×102

Nrand:

Nreal:

R

R

R

a

b

c

Mcm1 Sw i4

Yhp1

Clb2

Pcl1

Sim1

Gin4 Cdc6

Rax2

Yor315w

...R

R

R

Mcm1

Sw i4

Clb2

Motif Set A

a network motif a network theme

RR

P

Cox4

Hap2 Hap3

B2B1 B2B1

Nrand:

Nreal:

(2.3+1.1) ×1017.0+6.7

1.0×1022.0×102

Nrand:

Nreal:

(2.3+1.1) ×1017.0+6.7

1.0×1022.0×102RR

P/X/Ha b

c

R R

P

R R

X

Hap5

Cox4

Atp3

Ccc1

Apt17

Cox6

Qcr10 Isa1

Grx4

Ypl207w

Qcr9 Prp3

Hap4

Hap3Hap2

Motif Set B

a network motif a network theme

Hir1

Hhf1 Hht1

RR

P,X

C2C1 C2C1

Nrand:

Nreal:

(3.6+0.2) ×103(4.3+0.5)×102

1.5×1045.6×103

Nrand:

Nreal:

(3.6+0.2) ×103(4.3+0.5)×102

1.5×1045.6×103

R R

P

R R

X

a

b c

RR

P/X

Hir1 Hir2

Hhf1

Hhf2 Hht2

Hht1

Htb1

Htb2Hta2

Hta1Motif Set C

a network motif a network themeH H

H

S,HS,H

S,H

Pho85

Cla4 Slt2S

H H

D4D3D2D1 D4D3D2D1

(1.0+0.2) ×105

5.6×105

(1.3+0.1)×103

3.2×103

(1.7+0.1) ×103

2.7×103

Nrand:

Nreal:

(3.8+0.4) ×102

9.8×102

(1.0+0.2) ×105

5.6×105

(1.3+0.1)×103

3.2×103

(1.7+0.1) ×103

2.7×103

Nrand:

Nreal:

(3.8+0.4) ×102

9.8×102

S S

S

S S

HS/HS/H

S/H

a

b c Cla4 Slt2

Bck1

Yke2

Bni1

Smi1

ect.

Pho85

Motif Set D

a network motif a network theme

P,XP,X

P,X

Atp20

Atp14 Atp3

P P

P

X X

X

E4E3E2E1 E4E3E2E1

(2.7+0.4) ×105

1.5 ×106

(6.4+0.2) ×104

4.5×105

Nrand:

Nreal:

(1.7+0.1) ×106(2.6+0.5) ×102

9.5×1064.7×102

(2.7+0.4) ×105

1.5 ×106

(6.4+0.2) ×104

4.5×105

Nrand:

Nreal:

(1.7+0.1) ×106(2.6+0.5) ×102

9.5×1064.7×102

a

b c

P/XP/X

P/X

P P

X P

X X Atp2

Atp14 Atp3

Atp15

Atp20

ect.

Motif Set E

a network motif a network theme

P P

S

X X

S

F4 F5F3F2F1 F4 F5F3F2F1

(3.9+0.2) ×103

7.5×103

(1.4+0.1)×103

1.8×104

(8.4+0.2)×103

1.2×104

Nrand:

Nreal:

(1.3+0.1)×103(1.8+0.3)×102

3.2×1034.4×102

(3.9+0.2) ×103

7.5×103

(1.4+0.1)×103

1.8×104

(8.4+0.2)×103

1.2×104

Nrand:

Nreal:

(1.3+0.1)×103(1.8+0.3)×102

3.2×1034.4×102

P/XP/X

S/H

a

b c

X X

H

PX

H

P P

H

PP

S

Rpb5

Ssn8 Cdc73

Ssn8 Cdc73

Rpb3

Rpb5 Rpo21

Rpb9

Rpb4Rpb2

Rpb7

ect.

Motif Set F

a network motif a network themeSec72

Yke2 Gim5

SS

P,X

G5 G6G4G3G2G1 G5 G6G4G3G2G1

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

H H

P

SH

PP

S S H H

X

SH

X

S S

X

a

b c

S/HS/H

P/X

Sec72

Gim4

Yke2 Gim5

Pac10Gim3

Motif Set G

a network motif a network theme

H

R X R X

S

H5

H1

H6H4H3H2 H5

H1

H6H4H3H2

P

P

R H

H

R

(5.3+0.5)×102

1.9×103

(8.0+2.3)×101

6.1×102

(1.8+0.6) ×101

5.8×101

(4.0+0.4) ×102

8.2×102

(6.6+1.0) ×102

1.1×103

Nrand:

Nreal:

(2.5+0.2)×103

3.2×103

(5.3+0.5)×102

1.9×103

(8.0+2.3)×101

6.1×102

(1.8+0.6) ×101

5.8×101

(4.0+0.4) ×102

8.2×102

(6.6+1.0) ×102

1.1×103

Nrand:

Nreal:

(2.5+0.2)×103

3.2×103

R R

HR R

H

Motif Set H

S: Synthetic sickness or lethality

H

X: Correlated expression

P: Stable physical interaction

R: Transcriptional regulation

S

H: Sequence homology

S: Synthetic sickness or lethality

H

X: Correlated expression

P: Stable physical interaction

R: Transcriptional regulation

S

H: Sequence homology

Page 56: IPAM WorkshopJan 2006

R

R

R

A1A1

(2.6+0.5) ×102

4.7×102

Nrand:

Nreal:

(2.6+0.5) ×102

4.7×102

Nrand:

Nreal:

R

R

R

a

b

c

Mcm1 Sw i4

Yhp1

Clb2

Pcl1

Sim1

Gin4 Cdc6Rax2

Yor315w

...R

R

R

Mcm1

Sw i4

Clb2

Motif Set A

a network motif a network theme

RR

P

Cox4

Hap2 Hap3

B2B1 B2B1

Nrand:

Nreal:

(2.3+1.1) ×1017.0+6.7

1.0×1022.0×102

Nrand:

Nreal:

(2.3+1.1) ×1017.0+6.7

1.0×1022.0×102RR

P/X/Ha b

c

R R

P

R R

X

Hap5

Cox4

Atp3

Ccc1

Apt17

Cox6

Qcr10 Isa1

Grx4

Ypl207w

Qcr9 Prp3

Hap4

Hap3Hap2

Motif Set B

a network motif a network theme

Hir1

Hhf1 Hht1

RR

P,X

C2C1 C2C1

Nrand:

Nreal:

(3.6+0.2) ×103(4.3+0.5)×102

1.5×1045.6×103

Nrand:

Nreal:

(3.6+0.2) ×103(4.3+0.5)×102

1.5×1045.6×103

R R

P

R R

X

a

b c

RR

P/X

Hir1 Hir2

Hhf1

Hhf2 Hht2

Hht1

Htb1

Htb2Hta2

Hta1Motif Set C

a network motif a network themeH H

H

S,HS,H

S,H

Pho85

Cla4 Slt2S

H H

D4D3D2D1 D4D3D2D1

(1.0+0.2) ×105

5.6×105

(1.3+0.1)×103

3.2×103

(1.7+0.1) ×103

2.7×103

Nrand:

Nreal:

(3.8+0.4) ×102

9.8×102

(1.0+0.2) ×105

5.6×105

(1.3+0.1)×103

3.2×103

(1.7+0.1) ×103

2.7×103

Nrand:

Nreal:

(3.8+0.4) ×102

9.8×102

S S

S

S S

HS/HS/H

S/H

a

b c Cla4 Slt2

Bck1

Yke2

Bni1

Smi1

ect.

Pho85

Motif Set D

a network motif a network theme

P,XP,X

P,X

Atp20

Atp14 Atp3

P P

P

X X

X

E4E3E2E1 E4E3E2E1

(2.7+0.4) ×105

1.5 ×106

(6.4+0.2) ×104

4.5×105

Nrand:

Nreal:

(1.7+0.1) ×106(2.6+0.5) ×102

9.5×1064.7×102

(2.7+0.4) ×105

1.5 ×106

(6.4+0.2) ×104

4.5×105

Nrand:

Nreal:

(1.7+0.1) ×106(2.6+0.5) ×102

9.5×1064.7×102

a

b c

P/XP/X

P/X

P P

X P

X X Atp2

Atp14 Atp3

Atp15

Atp20

ect.

Motif Set E

a network motif a network theme

P P

S

X X

S

F4 F5F3F2F1 F4 F5F3F2F1

(3.9+0.2) ×103

7.5×103

(1.4+0.1)×103

1.8×104

(8.4+0.2)×103

1.2×104

Nrand:

Nreal:

(1.3+0.1)×103(1.8+0.3)×102

3.2×1034.4×102

(3.9+0.2) ×103

7.5×103

(1.4+0.1)×103

1.8×104

(8.4+0.2)×103

1.2×104

Nrand:

Nreal:

(1.3+0.1)×103(1.8+0.3)×102

3.2×1034.4×102

P/XP/X

S/H

a

b c

X X

H

PX

H

P P

H

PP

S

Rpb5

Ssn8 Cdc73

Ssn8 Cdc73

Rpb3

Rpb5 Rpo21

Rpb9

Rpb4Rpb2

Rpb7

ect.

Motif Set F

a network motif a network themeSec72

Yke2 Gim5

SS

P,X

G5 G6G4G3G2G1 G5 G6G4G3G2G1

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

H H

P

SH

PP

S S H H

X

SH

X

S S

X

a

b c

S/HS/H

P/X

Sec72

Gim4

Yke2 Gim5

Pac10Gim3

Motif Set G

a network motif a network theme

H

R X R X

S

H5

H1

H6H4H3H2 H5

H1

H6H4H3H2

P

P

R H

H

R

(5.3+0.5)×102

1.9×103

(8.0+2.3)×101

6.1×102

(1.8+0.6) ×101

5.8×101

(4.0+0.4) ×102

8.2×102

(6.6+1.0) ×102

1.1×103

Nrand:

Nreal:

(2.5+0.2)×103

3.2×103

(5.3+0.5)×102

1.9×103

(8.0+2.3)×101

6.1×102

(1.8+0.6) ×101

5.8×101

(4.0+0.4) ×102

8.2×102

(6.6+1.0) ×102

1.1×103

Nrand:

Nreal:

(2.5+0.2)×103

3.2×103

R R

HR R

H

Motif Set H

Motifs Themes

one gene synthetic lethal with a

complex?

Sec72

Yke2 Gim5

SS

P,X

G5 G6G4G3G2G1 G5 G6G4G3G2G1

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

H H

P

SH

PP

S S H H

X

SH

X

S S

X

a

b c

S/HS/H

P/X

Sec72

Gim4

Yke2 Gim5

Pac10Gim3

Motif Set G

a network motif a network theme

Sec72

Yke2 Gim5

SS

P,X

G5 G6G4G3G2G1 G5 G6G4G3G2G1

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

H H

P

SH

PP

S S H H

X

SH

X

S S

X

a

b c

S/HS/H

P/X

Sec72

Gim4

Yke2 Gim5

Pac10Gim3

Motif Set G

a network motif a network theme

Sec72

Yke2 Gim5

SS

P,X

G5 G6G4G3G2G1 G5 G6G4G3G2G1

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

H H

P

SH

PP

S S H H

X

SH

X

S S

X

a

b c

S/HS/H

P/X

Sec72

Gim4

Yke2 Gim5

Pac10Gim3

Motif Set G

a network motif a network theme

Sec72

Yke2 Gim5

SS

P,X

G5 G6G4G3G2G1 G5 G6G4G3G2G1

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

(8.3+0.6) ×102

1.2×103

Nrand:

Nreal:

(3.1+0.1) ×104(6.1+0.5) ×102(1.7+0.1)×103(7.2+1.2) ×101(9.0+1.6)×101

6.7×1041.5×1038.6×1032.9×1021.7×103

H H

P

SH

PP

S S H H

X

SH

X

S S

X

a

b c

S/HS/H

P/X

Sec72

Gim4

Yke2 Gim5

Pac10Gim3

Motif Set G

a network motif a network theme

Page 57: IPAM WorkshopJan 2006

Motifs Themes

pair of synthetic lethal complexes?

… …… …S/H S/H S/HS/H

P/X

P/X

Sec72 Sec66

Gim5Yke2

SSS

P,X

S

P Sec72

Gim4

Yke2 Gim5

Pac10

Gim3

Sec66

Sec63Sec62

a network motif a network theme

… …… …S/H S/H S/HS/H

P/X

P/X

Sec72 Sec66

Gim5Yke2

SSS

P,X

S

P Sec72

Gim4

Yke2 Gim5

Pac10

Gim3

Sec66

Sec63Sec62

a network motif a network theme

… …… …S/H S/H S/HS/H

P/X

P/X

Sec72 Sec66

Gim5Yke2

SSS

P,X

S

P Sec72

Gim4

Yke2 Gim5

Pac10

Gim3

Sec66

Sec63Sec62

a network motif a network theme

… …… …S/H S/H S/HS/H

P/X

P/X

Sec72 Sec66

Gim5Yke2

SSS

P,X

S

P Sec72

Gim4

Yke2 Gim5

Pac10

Gim3

Sec66

Sec63Sec62

a network motif a network theme

Page 58: IPAM WorkshopJan 2006

Thematic map ofsynthetic-lethal complexes

Page 59: IPAM WorkshopJan 2006

Mapping pairs ofsynthetic-lethal complexes

Page 60: IPAM WorkshopJan 2006

Outline

Human alternative-splicing motif search

Yeast synthetic-lethal network analysis Background

Overlap with other biological relationships

Network motifs

Predicting synthetic lethality

Role of transcription compensation in mutational robustness

SSL vs. protein interaction in predicting function

Page 61: IPAM WorkshopJan 2006

Predicting Synthetic Lethality: Why?

Especially if the consortia led by Boone and Boeke

are testing all yeast gene pairs

Simple Answer:

Even finished, this project is one strain, one organism, one phenotype (growth), and one growth condition.

Page 62: IPAM WorkshopJan 2006

Predicting Synthetic Lethality: Many weak predictors

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Query Characteristic S+C S only C only Neither P(C|S) Odds P(S|C) P-valueSimilar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Similar GO annotation 779 1746 27256 698373 0.31 8 0.03 3E-460Same MIPS phenotype 389 2136 9453 716176 0.15 12 0.04 1E-273Same GO annotation 385 2140 8361 717268 0.15 13 0.04 6E-288Same subcellular localization 113 2412 3500 722129 0.04 9 0.03 7E-68Same MIPS complex 82 2443 1445 724184 0.03 16 0.05 1E-67Physical interaction 96 2429 2586 723043 0.04 11 0.04 5E-63Sequence homology (BLAST Eval < 10E-3) 47 2478 1769 723860 0.02 8 0.03 1E-25Same MIPS complex (with no subcomplexes) 20 2505 166 725463 0.01 35 0.11 1E-23Same MIPS protein class 29 2496 1023 724606 0.01 8 0.03 4E-17Same MCODE complex 26 2499 906 724723 0.01 8 0.03 1E-15Common physical interaction partner 33 2492 2911 722718 0.01 3 0.01 1E-08Correlated mRNA expr (Cho, CC >0.7) 46 2479 6171 719458 0.02 2 7E-03 3E-06Physical interaction: APMS 14 2511 1032 724597 0.01 4 0.01 3E-05Physical interaction: APMS: HMS-PCI 9 2516 699 724930 4E-03 4 0.01 1E-03Phys interaction: Y2H U APMS "spoke" 5 2520 290 725339 2E-03 5 0.02 4E-03

Page 63: IPAM WorkshopJan 2006

Predicting Synthetic Lethality: Probabilistic decision trees

Page 64: IPAM WorkshopJan 2006

0

0.2

0.4

0.6

0.8

1

0 0.2 0.4 0.6 0.8 1

False Positive Rate

True

Pos

itive

Rat

e (S

ensi

tivity

)

xval: all characteristics

xval: no 2hop characteristics

random

Predicting Synthetic Lethality: Cross-validation success

~80% sensitivity by testing ~20% of gene pairs (80/20 Rule!)

Page 65: IPAM WorkshopJan 2006

Outline

Human alternative-splicing motif search

Yeast synthetic-lethal network analysis Background

Overlap with other biological relationships

Network motifs

Predicting synthetic lethality

Role of transcription compensation in mutational robustness

SSL vs. protein interaction in predicting function

Page 66: IPAM WorkshopJan 2006

Upregulation of compensatory genes?

Gene MSSL

Gene G

Anecdotally, this is rare (Lesage et al, 2004)

Page 67: IPAM WorkshopJan 2006

Upregulation of compensatory genes:Data sets examined

mRNA expression, mutant vs. wild type

(Rosetta compendium, Hughes et al, 2000)

SSL genetic interactions (Tong et al.)

Page 68: IPAM WorkshopJan 2006

0

0.02

0.04

0.06

0.08

0.1

-2 -1 0 1 2

non-SSL

SSL

Log ratios

Fra

ctio

n o

f ge

nes

116,863935

Upregulation of compensatory genes:Distribution of log (Gmutant_M / Gwt)]

Page 69: IPAM WorkshopJan 2006

Upregulation of compensatory genes:How common is it?

Of 935 SSL M:G pairs examined, only thirteen went up significantly

That is only four more than expected given the fraction that went up in 120,000 non-SSL pairs

Page 70: IPAM WorkshopJan 2006

Six previously observed examplesFKS1 RLM1 Zhao, 1998FKS1 SLT2 Lesage, 2004GAS1 CHS3 Lesage, 2004GAS1 KRE11 Lesage, 2004GAS1 SLT2 Lesage, 2004GAS1 YALO53W Lesage, 2004

Seven new examplesBNI1 SLT2CDC42 GIC2 (translational compensation; Jacquenoud, 1998)FKS1 KAI1FKS1 PAL2GAS1 YMR316C-ASHE4 ARC40SHE4 CHS7

Thirteen examples of compensatory upregulation

Page 71: IPAM WorkshopJan 2006

Transcriptional compensation for gene loss.

exists for a few SSL pairs is extremely rare

Page 72: IPAM WorkshopJan 2006

Rationalization

Regulatory apparatus to detect gene loss… Provides only a weak benefit if gene loss is rare Large mutational target

Page 73: IPAM WorkshopJan 2006

Outline

Human alternative-splicing motif search

Yeast synthetic-lethal network analysis Background

Overlap with other biological relationships

Network motifs

Predicting synthetic lethality

Role of transcription compensation in mutational robustness

SSL vs. protein interaction in predicting function

Page 74: IPAM WorkshopJan 2006

Tested forProtein intxnTested

for genetic intxn

Tested for both

data sets: 1 genetic, 5 protein

SSL vs protein interaction: The arena

Page 75: IPAM WorkshopJan 2006

phys data set (overlapping w/

genetic) gene pairs

predictive interaction GO characteristic accuracy sensitivity

TAP spoke 104409 physical 0.42 0.006genetic shared Process 0.19 0.041physical 0.31 0.008genetic shared Function 0.15 0.061physical 0.29 0.012genetic shared Component 0.08 0.048

TAP matrix 104409

HMS-PCI spoke 168114

HMS-PCI matrix 168114

Y2H 566423

SSL vs protein interaction

Protein intxns are more accurate.SSL intxns are more sensitive.

Page 76: IPAM WorkshopJan 2006

Common regulatorGene co-occurenceGene fusionGene neighborhoodHomologymRNA coexpressionChromosomal distanceSame localizationSame phenotypeMany ‘2-hop’ relationships

SSL vs protein interaction: combining with other relationships

Page 77: IPAM WorkshopJan 2006

0

0.2

0.4

0.6

0.8

1

0 0.2 0.4 0.6 0.8 1

all characteristicsno Pno Gno P, G

P onlyG onlyP, G onlyrandom

Tru

e P

os

itiv

e R

ate

(S

ens

itiv

ity

)

False Positive Rate (1 – Specificity)

0

0.03

0.06

0 0.01 0.02

SSL vs protein interaction:combining with other relationships

Page 78: IPAM WorkshopJan 2006

Summary, Part II

SSL other biological relationships

Motifs in an integrated S. cerevisiae network

Map of compensatory complexes

Predicting synthetic lethality

Transcriptional compensation plays a minor role in robustness to gene loss

SSL vs. protein interaction in predicting function: SSL wins but is complementary

Page 79: IPAM WorkshopJan 2006

Acknowledgments, Part II

Roth Lab Sharyl Wong Lan Zhang Oliver King Debra Goldberg Gabriel Berriz Frank Gibbons Others

Data Sources SGD MIPS YPD

Canadian Synthetic Lethal Team

Charlie Boone Amy Tong Guillaume Lesage Howard Bussey Brenda Andrews Xiaofeng Xin Gary Bader Zhijian Li Others

Marc Vidal

Page 80: IPAM WorkshopJan 2006

Probabilistic Decision Trees

Models conditional probability of one variable given a combination of others.

Capable of integrating many variables (built-in feature selection).

Provides intuition about why predictions are made.