ipam workshopjan 2006
DESCRIPTION
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 PresentationTRANSCRIPT
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
Outline
Human alternative-splicing motif search
Yeast synthetic-lethal network analysis
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
Adapted from Molecular Cell Biology, Lodish et al.
Brief review of canonical mRNA splicing
~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
From correlation to regulatory mechanism
Roth et al , 1998, Hughes et al, 2000 Tavazoie et al 1999, Slides adapted from S. Tavazoie
Sequence neighborhood of a splice junction
(Sorek & Ast, Gen. Research, 2003)
Conservation: constitutive vs. alternative
3’ acceptorneighborhood
5’ donor neighborhood
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)
• 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
Tissue-specific probes & data
splice junction usage data
Flowchart
original intensities
probes5’ 3’
tissues
NPTB
Tissue-specific splice junction expression
original intensities
probes5’ 3’
tissues rescaled intensities
NPTB
Tissue-specific splice junction expression
original intensities
probes5’ 3’
tissues relative splicing
rescaled intensities
NPTB
Tissue-specific splice junction expression
Synexin (ANXA7)
Tissue-specific splice junction expression
splice junction usage data cassette exons
alternative donors / acceptors
skipped cassette exons
Flowchart
Clustered splice junctions
allcassette exons
alternative
donors / acceptors
Probe set choice
Cassette exons skipped in heart & skeletal muscle
Results: heart & muscle
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
Sequence neighborhood of a splice junction
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
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
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
Cassette exons skipped in brain
26% of probes (9-fold enrichment)
Results: brain
76% (3-fold)
65% (15-fold)
Results: ileum
Results: jejunum, liver, pancreas Cluster
HNRPLClusterResults: jejunum, liver, pancreas
RRM1 RRM2 RRM3 RRM4
HNRPL
Results: jejunum, liver, pancreasHNRPLCluster
RRM1 RRM2 RRM3 RRM4
RRM1 RRM2 RRM3 RRM4
PTB
HNRPLProtein interaction
Results: jejunum, liver, pancreasHNRPLCluster
RRM1 RRM2 RRM3 RRM4
RRM1 RRM2 RRM3 RRM4
PTB
HNRPLProtein interaction
Results: jejunum, liver, pancreasHNRPLCluster
tissue-specificalternative
splicing
candidatecis-regulatory
motifs
Summary, Part I
validatedcis-regulatory
motifs
Map to trans-actingsplicing factors
candidatecis-regulatory
secondary strcture
Acknowledgments, Part I
Adnan Derti
George Church & Lab
Roth Lab
Rosetta/Merck Jason Johnson John Castle Lee Lim
Adrian Krainer
Outline
Human alternative-splicing motif search
Yeast synthetic-lethal network analysis
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
What is Synthetic Lethality?
Cells live
Cells live
Cells die
Gene XGene Y
Gene XGene Y
Gene XGene Y
What is Synthetic Sickness/Lethality (SSL)?
Cells live
Cells live
Cells dieor grow slowly
Gene XGene Y
Gene XGene Y
Gene XGene Y
An engine can run without one cylinder
(from http://www.cs.unc.edu/~geom/collide/videos.shtml)
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
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)
The known sub-network circa 2001
(Tong et al., Science, 2001)
The known SSL sub-network circa 2004160 query x 4500 nonessential ≈ 700,000 tested pairs (≈4% pairs)
(Tong et al., Science, 2004)
~3800 interactions
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
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”
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
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
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
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
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”
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
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% *
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
“Network Motifs: Simple Building Blocks of Complex Networks”
R. Milo, S. Shen-Orr, , , U. Alon, Science (2003).
The synthetic lethal network has many triangles
Xiaofeng Xin, Boone Lab
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
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
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
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
Thematic map ofsynthetic-lethal complexes
Mapping pairs ofsynthetic-lethal complexes
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
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.
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
Predicting Synthetic Lethality: Probabilistic decision trees
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!)
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
Upregulation of compensatory genes?
Gene MSSL
Gene G
Anecdotally, this is rare (Lesage et al, 2004)
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.)
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)]
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
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
Transcriptional compensation for gene loss.
exists for a few SSL pairs is extremely rare
Rationalization
Regulatory apparatus to detect gene loss… Provides only a weak benefit if gene loss is rare Large mutational target
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
Tested forProtein intxnTested
for genetic intxn
Tested for both
data sets: 1 genetic, 5 protein
SSL vs protein interaction: The arena
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.
Common regulatorGene co-occurenceGene fusionGene neighborhoodHomologymRNA coexpressionChromosomal distanceSame localizationSame phenotypeMany ‘2-hop’ relationships
SSL vs protein interaction: combining with other relationships
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
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
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
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.