Genomics from the Perspective of the Laboratory Mouse
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Comparative Medicine Vol 52, No 3 Copyright 2002 June 2002 by the American Association for Laboratory Animal Science Pages 206-223 Overview “Muromics”: Genomics from the Perspective of the Laboratory Mouse Stephen W. Barthold, DVM, PhD The laboratory mouse has emerged as the preeminent model though mice are genetically well characterized, they also add an system for mammalian genomics research, and it continues its additional depth of complexity because of their genetic back- importance as a valuable model system for hypothesis-driven re- ground. By various counts, there are approximately 3,000 inbred, search. As scientific enterprise moves from the genomics era to the congenic, coisogenic, consomic, recombinant inbred, mutant, and post-genomics era, a rich lexicon of “-omics” has arisen, including other strains of mice. Genetically altered mice are swelling these phenomics, physiomics, proteomics, glycomics, dramanomics, numbers to unprecedented levels. The following overview illus- metabolomics, pharmacogenomics, and toxicogenomics. What is trates how the inherent value of these incredibly powerful re- missing is “muromics,” a rhetorical term used here to emphasize search models is diluted by genetic mismanagement or naivete. the focus of this review: understanding genomics and phenomics in the context of the complex biology of the laboratory mouse (the What is a laboratory mouse? murome). A proper definition of the modern laboratory mouse requires The inbred nature of laboratory mice is their greatest quality, an understanding of its history and origins. What is known as allowing control of important genetic variables and precise in- the laboratory mouse evolved at the beginning of the past cen- vestigation of specific gene alterations or gene function. Despite tury, during the American scientific movement through the im- this ability to control these variables, the mouse is a complex portation of “fancy mice” into the laboratory. Long before that biologic organism with complex biologic responses. When we time, mice had been selectively bred for coat color and other (the human species) attempt to explain gene function, we tend “phenotypes” for thousands of years. The first historical record to simplify and think in terms of linear, predictable outcomes. In of color-variant mice goes back to 1100 B.C. in China. Waltzing fact, biological systems, including mouse phenotypes, are non- mice were described in Japan in 80 B.C. (1, 2). The mouse was linear and complex, but not random. Nearly half of gene alter- brought into the laboratory with the rediscovery of Mendel’s ations result in no detectable phenotype, and nearly half of gene laws of heredity, and application of those principles to mamma- alterations result in unexpected phenotypes. These statistics lian inheritance. Early work by Castle (who coined the term “ge- are only roughly accurate, as few mice are examined compre- netics”) focused principally on inheritance of coat color and hensively. Furthermore, “forward genomics,” in which an out- other external characteristics because of the plethora of visible come (phenotype) is predicted from the alteration of a known variants among fancy mice, but interest rapidly turned to the gene, is fraught with investigator bias due to wishful thinking genetics of cancer. for a desired phenotype. “Reverse genomics,” such as that which Because of the complexity of inheritance, Little started in- involves random chemical mutagenesis, overcomes this bias, breeding mice to obtain “homogeneity of genetic constitution” to but requires screening processes that can be seriously disrupted effectively investigate the genetic basis of cancer (1). His first by misinterpretation of phenotype or comprehensiveness of the inbred mouse was the dilute brown non-agouti (DBA), which screening battery. was created in the early 1900s. This strain was nearly wiped out A glimpse at the “Trans-NIH Mouse Initiative” web site from an outbreak of “paratyphoid” while at Cold Spring Harbor (www.nih.gov/science/models/mouse/), which depicts an image Laboratory, portending the continuing threat of infectious dis- of laboratory rats rather than mice, illustrates the naivete con- ease among mice with uniform genetic susceptibility. This cata- cerning phenotype at the highest levels of the scientific commu- strophic event had the beneficial effect of stimulating creation nity. More than a few mouse pathologists must face scientists of other inbred strains of mice. During the 1920s and 1930s, the with the stark reality of abscesses, rather than transplantable efforts of Little, Strong, MacDowell, Dunn, Furth, Bagg, and tumors; lymph nodes, rather than mammary neoplasms; or several others resulted in the creation of nearly all of the inbred seminal vesicles, rather than uterine horns. Few scientists, and strains of mice that are used in contemporary biomedical re- in particular, few molecular biologists are fully cognizant of the search. The AKR mouse strain was developed by Furth because complexity of the multi-systemic mammalian organism, and al- MacDowell was unwilling to share his cancer-prone C58 mice, which were the key to his research funding by private benefac- Received: 12/11/01. Revision requested: 1/24/02. Accepted: 3/15/02. Professor and Director, Center for Comparative Medicine, University of Califor- tors. This early example of proprietary control of mouse strains nia at Davis, One Shields Avenue, Davis, California 95616. pales in comparison with today’s legal constraints placed on ge- Supported by grant RR-14905 “University of California Davis Mutant Mouse Regional Resource Center” from the National Center for Research Resources, netically engineered mice with perceived commercial value, National Institutes of Health. such as Onco-mice and Cre-Lox mice. 206 “Muromics” Most of the breeding stock for these early lines of mice were velop amyloidosis (except for tumor-related amyloid, which is derived from fancy mouse stocks, and often from common common). Most BALB/c mice do not have a corpus callosum, and sources, such as Miss Abbie Lathrop’s Granby Mouse Farm in have progressive hearing loss associated with a recessive gene Massachusetts. The alphabet soup of letters and numbers that that differs from that of B6 mice (6). BALB/c mice also develop represent many inbred strains of mice are derived from various high prevalence of pulmonary adenomas, salivary myoepithelio- line and subline laboratory designations of these early efforts to mas, mammary tumors, generalized lymphoproliferative disease inbreed. There are exceptions, such as mice developed by Lynch, (lymphoma), and glomerulonephritis. The C3H strain was origi- who imported her own mice directly from Switzerland, giving nally derived by Strong for its susceptibility to mammary cancer, rise to “Swiss” mice and their inbred and outbred derivatives. but this strain also is prone to hepatocellular cancer. They are a Another is BALB/c (Bagg albino) mice, whose progenitors origi- notably docile mouse, because they are totally blind at weaning nated from a dealer in Ohio (1). A recent geneology chart of in- age due to retinal degeneration. Because these three strains of bred mouse strains, which is based on historical data and recent mice have been commonly used in toxicology and aging research, new data, has been compiled (2). the pathologist is fortunate to benefit from a large body of litera- Fancy mice have been traded throughout Asia, Europe, and ture involving their background pathology (phenotype) (7-9). North America for centuries. Thus, the progenitors of the labora- Genomics research has also increased the use of 129 and FVB tory mouse strains that are used today are a hybrid of various spe- mice, and a potpourri of other strains. The 129 strain of mice is cies or subspecies of the Mus musculus genospecies complex. Most extensively used in genomics research as a source of embryonic inbred strains of mice have an undefined mix of European and stem (ES) cells. This strain did not enjoy much prominence as Asian genes/alleles contributed by M. musculus, M. domesticus, M. research animals except for its tendency to develop testicular ter- castaneus, M. molossinus (which is a natural mix of M. castaneus atomas (a.k.a. teratocarcinomas, embryonal carcinomas). These and M. musculus), and possibly other members of the M. musculus mice were developed by Dunn from English fancy mice and chin- genospecies complex, including M. spretus (3, 4). chilla stock provided by Castle. The derivation of stem cells from Various inbred strains of mice, because of their diverse back- embryos was a natural extension of considerable earlier effort grounds, are genetic apples and oranges, and therefore, each based on teratocarcinoma stem cells (which were of 129 strain with their own distinct strain characteristics. A valuable re- origin). Substrains of 129 mice (formerly named 129/Sv and 129/ source for information on general inbred mouse strain charac- Sv-ter), with enhanced rates of teratoma development, were thus teristics that is periodically updated is available from Festing: produced (10). Although ES cells can be derived from other (http://www.informatics.jax.org/external/festing/mouse/ mouse strains, most targeted mutations are created from well STRAINS.shtml). established 129 ES cell lines, and often backcrossed onto a more desirable or better standardized strain, such as B6 mice. Like The big five and a sprinkling of others BALB/c mice, many 129 mice (and therefore, mice derived from Among the numerous mouse