have been isolated as ones affected in the projection of retinal nerves to the tectum of the brain.
Large-scale efforts are under way in many laboratories to clone the mutant genes. Genetic and physical maps, crucial for positional cloning, are being constructed. Additionally, a large-scale EST project is under way, along with development of methodologies to map the ESTs. Because there is extensive synteny (conservation of chromosomal gene order over short distances) even between zebrafish and mammals, the dense EST maps of mouse and human should suggest candidate genes once the map position of an EST is established. The large insert libraries needed for positional cloning are now available. One important advantage of zebrafish for positional cloning, compared with the mouse, is the ease and thrift of scoring thousands of embryos in mapping crosses. The large numbers greatly enhance genetic resolution, thereby delimiting the chromosomal region in which to search for a mutant gene. With current maps, and some guess-work, more than 30 zebrafish mutant genes have been located and identified as of late 1999. One mutant gene had not been previously described in any other species and is critical to normal endoderm (gut) differentiation. Other mutant genes are related to known genes in other organisms and have refined the understanding of how signaling pathways pattern the early vertebrate embryo.
Although lower vertebrate and nonvertebrate organisms are valid model systems for studying many aspects of cell and molecular processes that are shared by widely disparate organisms, certain characteristics are restricted to mammals. These characteristics include placentation, intrauterine development, lactation, and aspects of immunology and carcinogenesis. To study these characteristics, only a mammalian model is ultimately appropriate. The laboratory mouse provides a small, tractable, and genetically well-characterized model, in spite of minor differences among mammals in the details of development and metabolism.
Many different mammalian models have been used for different aspects of biomedical research, but among mammals, the mouse is perhaps the most versatile and best studied. Among the advantages, mice are among the smallest mammals and have a short generation time of around 10 weeks. They are prolific breeders and their reproductive cycles are easily monitored for the timing of pregnancies. They have been bred in captivity for biomedical research for nearly a century and are docile animals. All these features add up to a great practical benefit in cost efficiency when large numbers of animals are required for research (e.g., in genetic and toxicological studies). As many as 3,000 pups (and up to 5 generations per year) can be raised per year per square meter of area in an approved animal facility, assuming cage racks are 5-6 shelves high (Silver 1995).