guinea pig have long been standard systems for physiological and toxicological investigation. However, because of the power of genetic analysis, the four genetically tractable model animals (C. elegans, Drosophila, zebrafish, and mouse) have become mainstays of recent research in developmental biology and, for the same reason, are also likely to be particularly valuable in emerging approaches to developmental toxicology. These systems are described in more detail below, following a brief review of methods in genetic analysis.

Rationale and Strategy of the Genetic Approach

Genetic analysis has a powerful advantage in that it can “dissect” functionally and define the important components of any biological process without knowing anything about the process in advance—simply by isolating mutations that affect it, using those mutations to define the genes that control the process, and then cloning and characterizing those genes and their gene products, thereby revealing molecular mechanisms. Over the past two decades this approach has been successfully applied to many aspects of animal development, as indicated in Chapter 6. It can also be applied to elucidating the mechanisms of action of developmental toxicants. The general steps in the standard genetic approach, described below, are sometimes referred to as “forward genetics” (going from the mutant phenotype to the gene) in contrast to the more recently developed methods of “reverse genetics” (going from the gene back to a phenotype) made possible by molecular biology and genomics (see Chapter 5 for some of the genomic methods). Although the terms forward and reverse genetics are now generally accepted, it should be noted that the term “reverse genetics” has had a history of use in earlier medical genetics literature to describe the progression from mapping of a heritable disease state to cloning of the responsible gene (called “forward genetics” elsewhere).

Forward Genetics

The steps in this approach are as follows:

  1. Choose a defective phenotype of interest (e.g., failure to develop a particular structure or increased sensitivity to a toxicant) that is specific and selectable or easily recognizable.

  2. Using mutagenized populations, carry out a saturation screen for mutants with the defective phenotype (i.e., a screen large enough so that mutations are likely to be found in every gene required in development of the normal phenotype).

  3. Use classical genetic analysis of these mutations to define the genes they represent by genetic mapping and complementation tests and to determine their null phenotypes (i.e., the effects of complete loss of gene function). The incisive-

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