Synthetic lethality

Synthetic lethality arises when a combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes does not, and by itself is said to be viable 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.

The importance of synthetic lethality as a type of genetic screen is reflected in the tendency of organisms to maintain buffering schemes that allows phenotypic stability despite genetic variation, environmental changes and random events such as mutations. 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. By exploring these relationships, a synthetic lethal screen may help illuminate questions about how cellular processes work when the protein products expressed by two different genes have an effect together but not separately.

Synthetic lethality may be explored in a variety of model organisms, including Drosophila melanogaster and Saccharomyces cerevisiae. Since synthetic lethal mutations are inherently inviable, common approaches are to employ temperature sensitive mutations or put mutations under the control of a regulated promoter to allow exploration of the phenotype without leading to death.

A synthetic lethal approach to cancer therapy is currently being explored as a means to developed targeted therapies to reduce off-target effects in chemotherapies and chemopreventative drugs. These typically target tumour suppressor genes.