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Synthetic Lethality

A. A. a D. a D. X. X. B. B. b D. b D. Wild-type. Viable. Viable. Lethal. Synthetic Lethality. Synthetic Lethality Identifies Functional Relationships Large-Scale Synthetic Lethality Analysis Should Generate a Global Map of Functional Relationships between Genes

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Synthetic Lethality

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  1. A A aD aD X X B B bD bD Wild-type Viable Viable Lethal Synthetic Lethality • Synthetic Lethality Identifies Functional Relationships • Large-Scale Synthetic Lethality Analysis Should Generate a • Global Map of Functional Relationships between Genes • and Pathways • Gene Conservation = Genetic Network Conservation

  2. A A A A X X X X B B B B Y Y Y Y C C C C Z Z Z Z Essential Product Essential Product Essential Product Essential Product Similar Patterns of Genetic Interactions Identify Pathways or Complexes X X X X X X Dead Dead Dead Genetic Interaction Network

  3. MATa MATa X bni1 xxx Mating D a/a wild-type Sporulation MATa Haploid Selection (MFA1pr-HIS3) Double Mutant Selection

  4. Cell Polarity BEM1 BEM2 BEM4 BUD6 SLA1 CLA4 ELM1 GIN4 NAP1 SWE1 Cell Wall Maintenance BCK1 SLT2 BNI4 CHS3 SKT5/CHS4 CHS5 CHS7 FAB1 SMI1 Cell Polarity 20% Cytokinesis 6% Unknown 22% Cell Wall Maintenance 18% Mitosis 16% Cell Structure 6% Vesicular Transport SNC2 VPS28 YPT6 Mitosis ARP1 ASE1 DYN1 DYN2 JNM1 PAC1 NIP100 NUM1 Unknown BBC1/YJL020c NBP2 TUS1 YBL051c YBL062w YDR149c YHR111w YKR047w YLR190w YMR299c YNL119w Cytokinesis BNR1 CYK3 SHS1 Others PCL1 ELP2 ELP3 Cell Structure ATS1 PAC11 YKE2/GIM1 bni1D: Genome-Wide Synthetic Lethality Screen

  5. Cell Polarity BEM1 BEM2 BEM4 BUD6 SLA1 CLA4 ELM1 GIN4 NAP1 SWE1 Cell Wall Maintenance BCK1 SLT2 SMI1 CHS3 SKT5/CHS4 CHS5 CHS7 BNI4 SMI1 Cell Polarity 20% Cytokinesis 6% Unknown 22% Cell Wall Maintenance 18% Mitosis 16% Cell Structure 6% Vesicular Transport SNC2 VPS28 YPT6 Mitosis ASE1 ARP1 DYN1 DYN2 JNM1 PAC1 PAC11 NIP100 NUM1 Unknown BBC1/YJL020c NBP2 TUS1 YBL051c YBL062w YDR149c YHR111w YKR047w YLR190w YMR299c YNL119w Cytokinesis BNR1 CYK3 SHS1 Others PCL1 ELP2 ELP3 Cell Structure ATS1 PAC11 YKE2/GIM1 bni1D: Genome-Wide Synthetic Lethality Screen

  6. DNA Repair 46% Unknown 4% Cell Polarity 4% Chromatin Structure 13% DNA Synthesis 13% Meiosis 4% sgs1D : Genome-Wide Synthetic Lethality Screen (24 Interactions) DNA Repair ASF1 HPR5 POL32 RAD27 RAD50 SAE2 SLX1 MMS4/SLX2 MUS81/SLX3 SLX4 WSS1 Meiosis CSM3 Others PUB1 RPL24A SWE1 SIS2 SOD1 Unknown YBR094w Chromatin Structure ESC2 ESC4 TOP1 DNA Synthesis RNR1 RRM3 YNL218w

  7. Gary Bader & Chris Hogue SLRI Protein-Protein Interaction Map via Pajek Program

  8. Cell Polarity Cell Wall Maintenance Cell Structure Mitosis Chromosome Structure DNA Synthesis DNA Repair Unknown Others 8 SGA Screens: 291 Interactions 204 Genes

  9. SGA Expansion / Application • Essential genes, e.g. arrays of ts alleles • GAL1-ORF arrays, e.g. GAL1-GST-ORF (Mike Snyder) • Synthetic Chemical Genetics • Genetic Mapping e.g. suppressors of ts alleles • Backcrossing gene deletions into other genetic backgrounds • e.g. sigma for analysis of filamentous growth.

  10. Deletion Mutants Sensitive to a Particular Drug Should be Synthetically Lethal with the Drug Target Synthetic Lethal Interactions Synthetic Chemical Interactions Alive Alive Drug Alive Alive Drug Dead Dead

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