Synthetic lethality

Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The deficiencies can arise through mutations, epigenetic alterations or inhibitors of one of the genes. In a synthetic lethal genetic screen, it is necessary to begin with a mutation that does not kill the cell, although may confer a phenotype (for example, slow growth), and then systematically test other mutations at additional loci to determine which confer lethality. Synthetic lethality has utility for purposes of molecular targeted cancer therapy, with the first example of a molecular targeted therapeutic exploiting a synthetic lethal exposed by an inactivated tumor suppressor gene (BRCA1 and 2) receiving FDA approval in 2016 (PARP inhibitor). A sub-case of synthetic lethality, where vulnerabilities are exposed by the deletion of passenger genes rather than tumor suppressor is the so-called "collateral lethality".

The phenomenon of synthetic lethality was first described by Calvin Bridges in 1922, who noticed that some combinations of mutations in the model organism Drosophila melanogaster confer lethality. Theodore Dobzhansky coined the term "synthetic lethality" in 1946 to describe the same type of genetic interaction in wildtype populations of Drosophila. If the combination of genetic events results in a non-lethal reduction in fitness, the interaction is called synthetic sickness. Although in classical genetics the term synthetic lethality refers to the interaction between two genetic perturbations, synthetic lethality can also apply to cases in which the combination of a mutation and the action of a chemical compound causes lethality, whereas the mutation or compound alone are non-lethal.

Synthetic lethality is a consequence of the tendency of organisms to maintain buffering schemes that allow phenotypic stability despite genetic variation, environmental changes and random events such as mutations. This genetic robustness is the result of parallel redundant pathways and "capacitor" proteins that camouflage the effects of mutations so that important cellular processes do not depend on any individual component. Synthetic lethality can help identify these buffering relationships, and what type of disease or malfunction that may occur when these relationships break down, through the identification of gene interactions that function in either the same biochemical process or pathways that appear to be unrelated.

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