Conditional Lethal Mutations

 Mutations that cause lethality under one condition (the restrictive or nonpermissive condition) but not another (the permissive condition) are called conditional lethal mutations, or loosely, conditional lethals. Conditional lethal mutations have an honored position in molecular biology. The recognition that a gene is not indivisible, the determination of the triplet nature of the genetic code, and the discovery of nonsense codons, all resulted from studies of a particular class of conditional lethal mutants of bacteriophage T4. T4 rII mutants grow on Escherichia coli strain B (the permissive host) but not on E. coli strain K-12 when it is lysogenic for bacteriophage lambda (the nonpermissive host). Interestingly, the function of the proteins encoded by the two rII genes remains unknown. The conditional lethality of the rII mutants allowed geneticists to grow the phage, to perform genetic crosses on the permissive host, and then to analyze the results on the nonpermissive host.

Conditional lethal mutations are the only genetic way to identify essential genes in haploid organisms or cells. By definition, a mutant with a null mutation in an essential gene cannot be isolated in the haploid state (in diploid organisms, recessive lethal mutations on autosomes are complemented by the other functional allele). Conditional lethal mutations are usually identified by screening mutant clones for growth under permissive conditions but not under restrictive conditions. Lethal in this case does not always mean conveying death. For example, auxotrophies are considered a class of conditional lethals because the auxotrophic cells grow only in the presence of the required growth factor, although they do not necessarily die in its absence. The more typical classes of conditional lethals are host-range mutants, temperature-sensitive mutants, and cold-sensitive mutants. Nonsense mutations are considered conditionally lethal because the mutation is suppressed when a suppressor transfer RNA is present.

Conditional lethal mutations are a powerful way to identify protein–protein interactions. A mutation that renders a protein inactive at high or low temperature, for example, may be suppressed by a compensating mutation in the gene encoding a protein that interacts with it. To conclude that the two proteins interact, the suppression must be allele-specific, ie, not caused by general suppression (as in the case of tRNA nonsense suppressors). In addition, other events, such as gene duplication, suppress conditional lethals. Interacting proteins are also identified by synthetic lethal mutations, which are mutations in each of two genes, neither of which is lethal alone but which are lethal when together in the same cell.