(nematode) Caenorhabditis elegans, the fruit fly Drosophila melanogaster, the frog Xenopus laevis, the zebrafish Danio rerio, the chick, and the laboratory mouse. Also particularly useful for certain investigations are sea urchin, sea slug (Aplysia), puffer fish, and a few mammals, including the rat. This set of model animals is somewhat different from those most widely used in the 1950s. Why have these species been chosen for recent intensive study? For four of them, the principal answer is genetics.

The genetic approach has become established in the last three decades as one of the most powerful tools for elucidating biological mechanisms. It allows researchers to compare wild type with a mutant phenotype and to identify new genes involved in controlling a biological process and to determine their functions in the organism. Genes that control important functions are identified by mutations that cause defects in those functions. These genes are then mapped, cloned, and identified at the molecular level so that the proteins they encode can be studied using methods of biochemistry and cell biology. This approach has proved to be extremely powerful, not only for basic research in model organisms but also for medical research on heritable human diseases. The approach was followed, for example, in the mapping, cloning, and subsequent study of the cystic fibrosis gene, the breast cancer susceptibility gene, and many others.

The four model animals chosen primarily on the basis of their convenience for genetic analysis are C. elegans, Drosophila, zebrafish, and mice. All are relatively small, easy to maintain in large populations in the laboratory, and have short generation times, which allow for rapid analysis of breeding experiments. The remaining animals are not well suited for classical genetic analysis, primarily because of much longer generation times, but have compensating advantages of convenience and manipulability or simplicity. Sea urchins, because of their reproductive properties, have been particularly valuable in studies of fertilization and gene regulation in early embryos. Aplysia are used in nerve growth and development studies. Puffer fish are useful for genomics because of their remarkably small genome size (400 megabases (Mb)) compared with most other vertebrates (about 3,500 Mb, including humans). The frog Xenopus has eggs and embryos that can be obtained in quantity and are relatively large (about 1 millimeter (mm) in diameter). The eggs and embryos are convenient for biochemical analysis as well as microsurgery and can easily be microinjected with cloned genes, RNAs, proteins, drugs, and so forth to study the developmental effects of those molecules. The embryos have been used in toxicant tests, such as the frog embryo teratogenesis assay–Xenopus (FETAX). FETAX is currently under consideration for validation (Bantle et al. 1996; NIEHS 1998). Chick embryos, more closely related to mammalian embryos, are readily accessible for observation and microsurgery (unlike those of mice, which develop in the uterus) and are convenient for tissue transplantation experiments. Putative developmental toxicants can be added directly to the embryo, thereby bypassing the modifying effects of maternal metabolism and selective transfer by the placenta. Rat, rabbit, and



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