3.1: Forward Genetics

Imagine a biological process that you're interested in -- take "learning and memory" for example. How can we identify genes that are involved in this process? 

One way 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 is called forward genetics and 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 screened mutagenized populations of Drosophila to recover flies (or larvae) that lack the normal ability to learn: for example, 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.

Genetic Screens

What is involved in a typical mutant screen? The process might look something like this:

1. Treat a parental population with a mutagen. This may involve soaking seeds in a mutagen, 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. Mutations in the the somatic cells (i.e. non-reproductive cells) cannot be inherited by progeny, but mutations in the germline (i.e. gametes and gamete precursors) can be inherited.
2. Mate progeny of mutagenized organisms so that new mutations become homozygous. This is important because most induced mutations are recessive and only affect the phenotype when they are homozygous (or hemizygous -- ie, present only once in a haploid cell.)
3. Screen these progeny for relevant 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.

There are a number of kinds of mutants that are often recovered from a genetic screen. 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 (i.e., the cell continues to work just fine with only one functional allele). 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.