Synthetic Lethality Explorer — DNA-Repair Gene Network

Double-Knockout

Gene A

Gene B

Genetic-background stringency 60%

Fitness Readout

Select a pair to test

Expected fitness E = f_A·f_B

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Observed fitness

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Epistasis score ε (observed − expected)

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Pathways

Homologous recombination (HR) Base-excision / SSB repair (BER) Core-essential (lethal alone) Unrelated housekeeping (control)

How it works

Each gene has a measured single-knockout fitness f (fraction of wild-type growth after removing just that gene). For a double knockout of genes A and B, the standard multiplicative null model predicts:

E(A,B) = f_A · f_B          (expected, no interaction)
Observed = E(A,B) · (1 − r(A,B) · s)
ε = Observed − E(A,B)        (epistasis score)

r(A,B) is the network's redundancy coefficient — how much B backs up A's job — read off the edges drawn between nodes: strong (0.9) between paired HR↔BER genes, mild (0.35) between two genes in the same pathway, zero for unconnected genes. s is the stringency slider (0–1), standing in for drug dose or genetic-background pressure that forces cells to depend on the redundant backup.

ε ≈ 0 — the genes act independently; losing both is no worse than expected.
ε moderately negative — aggravating interaction: both genes contribute to the same process.
Observed fitness → 0 — synthetic lethality: neither knockout alone is lethal, but together they are, because each was quietly covering for the other.

This is exactly the logic behind PARP-inhibitor therapy: healthy cells tolerate losing either homologous recombination (BRCA1/BRCA2) or base-excision repair (PARP1) alone because the other pathway backs it up. A BRCA-mutant tumour cell has already lost HR — adding a PARP inhibitor removes the backup too, and only the cancer cell, not the patient's healthy tissue, dies. Try Gene A = BRCA1, Gene B = PARP1 at high stringency to see it.

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