Synthetic Lethality

A

B

a

B

XA

bViable Lethal

a

bWild-type Viable

X

• 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

A

B

C

EssentialProduct

X

Y

Z

A

B

C

EssentialProduct

X

Y

Z

A

B

C

EssentialProduct

X

Y

Z

A

B

C

EssentialProduct

X

Y

Z

X

Dead

X

DeadDead

X

X X

X

GeneticInteractionNetwork

Similar Patterns of Genetic Interactions Identify Pathways or Complexes

xxxbni1 XMating

MAT MATa

a/wild-type

Sporulation

MATa Haploid Selection(MFA1pr-HIS3)

Double Mutant Selection

Cell Polarity 20%

Cytokinesis 6%

Cell Wall Maintenance18%Cell Structure

6%

Mitosis16%

Unknown22%

OthersPCL1ELP2ELP3

Vesicular TransportSNC2VPS28YPT6

UnknownBBC1/YJL020c NBP2 TUS1YBL051cYBL062wYDR149cYHR111wYKR047wYLR190wYMR299cYNL119w

MitosisARP1ASE1DYN1DYN2JNM1PAC1NIP100NUM1

Cell Wall MaintenanceBCK1SLT2BNI4CHS3SKT5/CHS4CHS5CHS7FAB1SMI1

Cell StructureATS1PAC11YKE2/GIM1

Cell PolarityBEM1BEM2BEM4BUD6SLA1CLA4ELM1GIN4NAP1SWE1

CytokinesisBNR1CYK3SHS1

bni1: Genome-Wide Synthetic Lethality Screen

Cell Polarity 20%

Cytokinesis 6%

Cell Wall Maintenance18%Cell Structure

6%

Mitosis16%

Unknown22%

OthersPCL1ELP2ELP3

Vesicular TransportSNC2VPS28YPT6

UnknownBBC1/YJL020c NBP2 TUS1YBL051cYBL062wYDR149cYHR111wYKR047wYLR190wYMR299cYNL119w

MitosisASE1ARP1DYN1DYN2JNM1PAC1PAC11NIP100NUM1

Cell Wall MaintenanceBCK1SLT2SMI1CHS3SKT5/CHS4CHS5CHS7BNI4SMI1

Cell StructureATS1PAC11YKE2/GIM1

Cell PolarityBEM1BEM2BEM4BUD6SLA1CLA4ELM1GIN4NAP1SWE1

CytokinesisBNR1CYK3SHS1

bni1: Genome-Wide Synthetic Lethality Screen

DNA RepairASF1HPR5POL32RAD27RAD50SAE2SLX1MMS4/SLX2MUS81/SLX3SLX4WSS1

DNA SynthesisRNR1RRM3YNL218w

MeiosisCSM3

UnknownYBR094w

OthersPUB1RPL24ASWE1SIS2SOD1

sgs1 : Genome-Wide Synthetic Lethality Screen

(24 Interactions)

Chromatin StructureESC2ESC4TOP1

DNA Repair 46%

DNA Synthesis13%

Meiosis4%

Chromatin Structure13%

Cell Polarity4%

Unknown4%

Gary Bader & Chris Hogue SLRIProtein-Protein Interaction Map via Pajek Program

Cell PolarityCell Wall Maintenance Cell StructureMitosisChromosome StructureDNA Synthesis DNA RepairUnknownOthers

8 SGA Screens:291 Interactions204 Genes

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.

Alive

Alive

Dead

Alive

Alive

Dead

Synthetic Lethal Interactions Synthetic Chemical Interactions

Deletion Mutants Sensitive to a Particular Drug Shouldbe Synthetically Lethal with the Drug Target

Drug

Drug