Functional Genomics and Rat Models

The 20th Century has seen a remarkable number of inventions and technological advances in virtually all aspects of human life and health care. Many areas of biomedical research have made great strides in unraveling the cause of human disease and in developing new therapies to counter, or at least improve, outcome from disease. However, the cause of the vast majority of common disease remains poorly defined. In the final year of the millennium, the release of the draft sequence of the human genome promises to bring in a new era for basic science research and, hopefully, unprecedented growth in our understanding of human disease. For this to occur there is a critical need to annotate the genomic sequence with gene function and basic biology. Typically, the view from the geneticist immediately turns to mouse, as the mammalian contributor. Yet, not all biologists are willing to convert to the mouse as their system of choice, in many cases because of the existence of better models. Although the mouse is undoubtedly going to play a major role in contributing to the annotation of gene function, other mammalian species will also make significant contributions. This Insight/Outlook piece focuses on the role the rat will play in annotating the genome in the functional genomics era. The laboratory rat, Rattus norvegicus, was the first mammalian species domesticated for scientific research, with work dating back to before 1850 (Lindsey 1979). From this auspicious beginning, the rat has become the most widely studied experimental animal model for biomedical research. Since 1966 (the earliest year covered by the Medline database), nearly 500,000 research articles reporting the use of rats have been published, most focused on evaluating the biology and/or the pathobiology of the rat. In contrast to its central role in the study of behavior, biochemistry, neurobiology, physiology, and pharmacology, the rat has lagged far behind the mouse as a genetic “model” organism, until recently. Historically, rat genetics had a surprisingly early start. The first genetic studies were carried out by Crampe from 1877 to 1885 and focused on the inheritance of coat color (Lindsey 1979). Hugo De Vries, Karl Correns, and Erich Tschermak rediscovered Mendel’s laws at the turn of the century, and Bateson used these concepts in 1903 to demonstrate that rat coat color is a Mendelian trait (Lindsey 1979). The first rat inbred strain, PA, was established by King in 1909—the same year that inbreeding began for the first inbred strain of mouse, DBA (Lindsey 1979). Despite this parallel start, the mouse soon became the model of choice for mammalian geneticists, whereas the rat became the model of choice for physiologists, nutritionists, and other biomedical researchers. Geneticists preferred the mouse because of its smaller size, which simplified housing requirements, and the availability of many coat color and other mutants exhibiting Mendelian patterns of inheritance, which had been collected by mouse fanciers (Nishioka 1995). Physiologists and other biomedical researchers favored the rat because its larger size facilitated experimental interventions. Over time a large number of rat strains were used to develop disease models by selective breeding, which “fixes” natural disease alleles in particular strains or colonies (Greenhouse et al. 1990). For example, there are inbred strains of rats used for research in the following areas: addiction, aging, anatomy, autoimmune diseases, behavior, blood diseases, breast cancer, cardiovascular diseases, cancer, comparative genomics, dental diseases, diseases of the skin and hair, endocrinology, eye disorders, growth and reproduction, hematologic disorders, histology, kidney diseases, metabolic disorders, neurological and neuromuscular diseases, nutrition, pathophysiology, pharmacology, pulmonary diseases, physiology, reproductive disorders, skeletal disorders, sleep apnea, transplantation and immunogenetics, toxicology, and urological disorders (Gill et al. 1989; Greenhouse et al. 1990; James and Lindpaintner 1997).