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4.3: Genetic screening for mutations: Forward genetics

One way to identify genes that affect a particular biological process is to induce random mutations in a large population, and then look for mutants with phenotypes that might be caused by a disruption of a particular biochemical pathway.  This strategy of mutant screening has been used very effectively to identify and understand the molecular components of hundreds of different biological processes.  For example, to find the basic biological processes of memory and learning, researchers have screened mutagenized populations of Drosophila to recover flies (or larvae) that lack the normal ability to learn. They lack the ability to associate a particular odor with an electric shock.  Because of the similarity of biology among all organisms, some of the genes identified by this mutant screen of a model organism may be relevant to learning and memory in humans, including conditions such as Alzheimer’s disease.

4.3.1 – Genetic Screens

In a typical mutant screen, researchers treat a parental population with a mutagen. This may involve soaking seeds in EMS, or mixing a mutagen with the food fed to flies.  Usually, no phenotypes are visible among the individuals that are directly exposed to the mutagen because in all the cells every strand of DNA will be affected independently.  Thus the induced mutations will be heterozygous and limited to single cells.  However, what is most important to geneticists are the mutations in the germline of the mutagenized individuals.  The germline is defined as the gametes and any of their developmental precursors, and is therefore distinct from the somatic cells (i.e. non-reproductive cells) of the body.  Because most induced mutations are recessive, the progeny of mutagenized individuals must be mated in a way that allows the new mutations to become homozygous (or hemizygous).   Strategies for doing this vary between organisms.   In any case, the generation in which induced mutations are expected to occur can be examined for the presence of novel phenotypes. Once a relevant mutant has been identified, geneticists can begin to make inferences about what the normal function of the mutated gene is, based on its mutant phenotype.  This can then be investigated further with molecular genetic techniques.

Exposure of an organism to a mutagen causes mutations in essentially random positions along the chromosomes. Most of the mutant phenotypes recovered from a genetic screen are caused by loss-of-function mutations. These alleles are due to changes in the DNA sequence that cause it to no longer produce the same level of active protein as the wild-type allele. Loss-of-function alleles tend to be recessive because the wild-type allele is haplosufficient (see Chapter 3). A loss-of-function allele that produces no active protein is called an amorph, or null. On the other hand, alleles with only a partial loss-of-function are called hypomorphic. More rarely, a mutant allele may have a gain-of-function, producing either more of the active protein (hypermorph) or producing an active protein with a new function (neomorph). Finally, antimorph alleles have an activity that is dominant and opposite to the wild-type function; antimorphs are also known as dominant negative mutations.