Without question, the mouse is and will continue to be an important animal model for performing functional genomics. However, there are circumstances in which mouse models are limited. The great majority of common human diseases remain un-modeled in the mouse. Published knockouts exist for approximately 10% of mouse genes. Although efforts are now underway to create publicly available genome-wide collections of mouse knockouts, it will take many years to achieve this goal, and it seems unlikely that every gene in the mouse will be amenable to disruption [44
]. Furthermore, there are many instances in which disrupting a gene in the mouse leads to no observable phenotype. Rat models are an alternative to mice that may enable the creation of new gene disruptions that are unavailable in the mouse, and that can complement existing transgenic mouse models. The evolutionary distance between rats and mice, some 12 to 24 million years [46
], is about the same as that between humans and new world monkeys [48
]. Comparing mouse and rat models with known human diseases can allow the distinction between rodent specific phenotypes and those that may be general to all mammals.
In many applications the rat is a better animal model for human disease. Although mice have been the animal model of choice for most geneticists, the rat has traditionally been favored by physiologists and pathologists. Their larger size make rats more conducive to study by instrumentation, and facilitates manipulations such as blood sampling, studying nerve conduction, or performing surgery. In many ways, rats are physiologically more similar to humans than are mice. For example, rats have a heart rate similar to that of humans, whereas mice have a heart rate nearly ten times as fast [28
]. Rats have been used as important models for human cardiovascular disease, diabetes, arthritis, and many other autoimmune and behavioral disorders [28
]. Rat models are superior to mouse models for testing the pharmacodynamics and toxicity of potential therapeutic compounds, partially because the number and type of many of their detoxifying enzymes are very similar to those in humans [49
Most techniques for genetic manipulation, including random mutagenesis with a gene trap (both retrovirus-based and non-retrovirus-based), gene knockouts, gene knockins, and conditional mutations, depend upon embryonic stem (ES) cells [50
]. However, for unknown technical reasons, rat ES cells cannot be isolated and used to create a viable organism [51
]. Consequently, many genetic manipulation techniques widely used in the mouse have not been possible in the rat. There are currently only two technologies that can be used to produce rat models of human disease: cloning and chemical mutagenesis using ENU. Although cloning could be used to create rats with specific genetic modifications, by first creating mutations in mitotic cells and then using the mutated cells to clone a rat, this approach is extremely inefficient. The first published attempt at cloning a rat had a success rate of less than 1% [52
]. Alternatively, ENU mutagenesis is a common random mutagenesis gene knockout strategy in the mouse that can also be used in the rat. However, only a very small number of the total mutations created by ENU mutagenesis have an observable phenotype [53
], and mapping mutations responsible for interesting phenotypes is typically difficult and time consuming.
There is a need for new techniques that can rapidly create and map gene knockouts in rats for the creation of new models of human disease. Mutagenesis using transposable elements is an attractive option. Indeed, a recent report demonstrated the feasibility of using SB for mutagenesis in rats [54
]. We recently showed the feasibility of using L1 for mutagenesis in the rat (Sprague-Dawley strain) and demonstrated a high level of somatic retrotransposition with occasional germline transmission of de novo
insertions (Kano H, Ostertag EM, Kazazian HH Jr, unpublished data).