THE MAJOR MODEL ANIMALS FOR GENETIC ANALYSIS

The four genetically tractable model animals, C. elegans, Drosophila, zebrafish, and mouse, are useful for somewhat different reasons. Relevant characteristics of each are described briefly below, along with some of their experimental advantages and disadvantages (see also Tables 7-1 and 7-3). The potential utility of each animal for identifying and investigating mechanisms of developmental toxicants is discussed later in this chapter.

The Nematode Caenorhabditis elegans

History, Biology, and Genetics

Caenorhabditis elegans is a roundworm found commonly in soils all over the world. It has become widely exploited as a model animal largely because of the early efforts of Brenner (1974), who recognized its experimental advantages and pioneered its genetic analysis. The adult is about 1-mm long, just visible to the naked eye. It feeds on bacteria, such as the common bacterium E. coli, and is easy to grow and breed on agar plates in the laboratory. C. elegans is one of the simplest animals known, with a small fixed number of somatic cells: 959 in the adult hermaphrodite and 1,031 in the adult male. It is transparent throughout the life cycle, so that its entire development can be analyzed in living animals with the light microscope. Its generation time is only 3 days, and development is rapid (Figure 7-1). Embryogenesis is complete by 14 hours after fertilization. The first-stage (L1) larva hatches from the egg, growing and molting through three larval stages (L2, L3, and L4) as its reproductive system develops before the final molt to adulthood. Adult males make sperm and can mate with hermaphrodites, making genetic crosses possible. The hermaphrodites are essentially females but produce some sperm during late larval development and can self-fertilize, which simplifies genetic analysis. C. elegans has a genome size of about 100 megabases (Mb) packaged into six small chromosomes, including five autosomes and a sex (X) chromosome (hermaphrodites have two and males one). Extensive genetic and physical maps have been constructed, and its genome has recently become the first in a metazoan to be completely sequenced under the auspices of the Human Genome Model Organisms Project (C. elegans Sequencing Consortium 1998). The genome includes about 19,000 genes.

Because of its transparency and the invariance of cell-division patterns throughout C. elegans development, it has been possible to describe embryonic and larval development completely at the cellular level. By observation of developing animals using Nomarski microscopy, Sulston and coworkers were able to define all the larval cell lineages (Sulston and Horvitz 1977) and later the entire embryonic cell lineage (Sulston et al. 1983), so that the ancestry of every cell in the adult organism is now known. Perturbation of normal development by laser



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