ping functions provides a basis for generating diversity without losing essential functionality.

The Drosophila Breakthrough

The recent molecular understanding of developmental processes and components was gained from the experimental analysis of a few model organisms such as Drosophila melanogaster (the fruit fly), Caenorhabditis elegans (a free-living nematode), Danio rerio (the zebrafish), Xenopus laevis (a frog), the chick, and the mouse (see Chapter 7 for proposals about their use in the assessment of developmental toxicities). D. melanogaster and C. elegans were chosen by researchers for their amenability to genetic analysis, afforded by their small size (hence, large populations) and short life cycle (hence, many generations). Nüsslein-Volhard and Wieschaus (1980) began a systematic search for developmental mutants of Drosophila in the mid-1970s. They submitted adults to high-frequency chemical mutagenesis and then inspected large populations of offspring for mutant individuals with strong and early developmental defects (before hatching) at discrete locations and discrete stages in the embryo. They discarded mutants with weak or pleiotropic effects as ones too difficult to analyze at their start. They examined mutagenized flies until the same kinds of mutants began to appear repeatedly in their collections. The recurrence was evidence that they had obtained all the different kinds of zygotic mutants (those affected in genes transcribed after fertilization) that mutagenized flies could yield under the conditions of inspection. This procedure is called “saturation mutagenesis,” in which all the susceptible genes whose encoded products are important in development are thought to be revealed. Several laboratories, including those of Nüsslein-Volhard and Wieschaus, were also collecting maternal-effect mutants (those affected in genes transcribed in female germ cells before fertilization) and pursued this search to saturation.

The Drosophila mutants were categorized by phenotype and complementation behavior (putting two mutations together in a heterozygote to see whether they are alike or different) to establish the number of different genes whose mutations give the same phenotypic defect of development. Their categories included those embryos failing to develop the anterior or posterior end, odd or even segments, dorsal or ventral parts, mesoderm, endoderm, or nervous system. Further mutant combinations were made to establish epistasis (the interaction of different gene products, reflected in the dominance of one mutant defect over another) and to deduce plausible developmental pathways in which the actions of the encoded gene products could be related and ordered. By the late 1980s, a solid base of observations of Drosophila mutant phenotypes and gene locations had been built, and ordered pathways of function based on the mutant interactions had been proposed. This information served as the foundation for future molecular genetic analysis. The research was the first systematic and exhaustive approach to under-



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