MOUSE GENETICS AND GENOMICS
The laboratory mouse is an artificial creation, and there is no true “wild-type” laboratory mouse. Furthermore, there is no such thing as “normal” microflora, since laboratory mice are often maintained in microbially pristine environments devoid of pathogens and opportunistic pathogens, as well as other commensal flora/ fauna.
Laboratory mice are largely derived from domesticated “fancy mice” that arose from many years of trading mouse variants among fanciers in Europe, Asia, North America, and Australia. The laboratory mouse genome is, therefore, a mosaic derived from different subspecies of the Mus musculus (house mouse) complex, including M.m. domesticus, M.m. musculus, M.m. castaneus, M.m. molossinus (a natural hybrid of M.m. musculus and M.m. castaneus), and others. The genome of M.m. domesticus is the predominant contributor to most strains of mice, but many inbred strains share a common “Eve” with a mitochondrial genome of M.m. musculus origin and a common “Adam” that contributed their Y chromosome from M.m. castaneus. In addition, there is evidence that other Mus species, outside of the M. musculus complex, have contributed to the genome of some, but not all, laboratory mouse strains. For example, the C57BL mouse genome contains a contribution from M. spretus. Perhaps the only laboratory mouse that is derived from a single M.m. domesticus species (subspecies) is the “Swiss” mouse. Several Mus species that are outside of the M. musculus complex, such as M. spretus, have been inbred. Thus, the laboratory mouse genome is not uniform among strains and mouse strains are not entirely within the M. musculus clade.There are over 450 inbred strains of laboratory mice that have arisen during the last century, and these strains, which were selectively inbred to pan-genomic homozygosity for purposes entirely unrelated to modern research, are the foundation upon which literally thousands of spontaneous mutants and GEMs have been built.
Additional inbred strains have been developed from wild mice (M.m. castaneus, M. spretus, etc.). Furthermore, “outbred” mice (mostly Swiss mice) are highly homozygous and nearly inbred. In addition to historical inbreeding that may be intentional or the inadvertent result of maintaining small populations of mice, rederivation of a mouse population results in genetic bottlenecks as well. There is no such thing as a truly “outbred” laboratory mouse with a fully heterozygous genome representative of wild-type M. musculus, and there is no wild mouse genetic counterpart of the laboratory mouse. Recently, an octaparental Diversity Outbred (DO) mouse stock was developed from eight disparately related inbred strains of mice, but this stock is not extensively utilized. When working with mice, the pathologist must also become facile with strains, substrains, sub-substrains, hybrids, congenics, insipient congenics, coiso- genics, consomics, conplastics, recombinant inbreds, recombinant congenics, spontaneous mutants, random induced (radiation, chemical, retroviral, gene trap) mutants, transgenics (random insertions), and targeted mutant mice, each with relatively unique, predictable, and sometimes unpredictable phenotypes and patterns of disease whose expression is modified by environmental and microbial variables.The inherent value of the laboratory mouse is its inbred genome, but maintaining the genetic stability of inbred strains of mice is a challenge. Since the advent of GEMs, there has been widespread genetic mismanagement of mouse strains by investigators with considerable skill in mouse genomics but limited expertise in mouse genetics. Even with the best of intentions, continuous inbreeding leads to substrain divergence among different populations of the same parental origin due to spontaneous mutations, retrotransposon integrations, or residual heterozygosity. Genetic contamination is also a surprisingly frequent event in both commercial and academic breeding colonies of mice. Within a few generations, substrain divergence can result in significant differences in phenotype, including response to research variables. The variable genetic contributions of different origins of mice and selective inbreeding for strain characteristics, such as coat color or neoplasia, are especially important when considering retroele- ments, which make up 37% of the mouse genome. Retroelements are highly dynamic within the context of the inbred mouse genome. They are present in the genomes of all mammals but have become artificially important in the homozygous genome of the laboratory mouse, and in fact had much to do with development of original inbred strains of mice with unique phenotypes, especially coat color and neoplasia. It is difficult to ignore their impact on mouse pathology, and thus retroelements are discussed later in this chapter (see Section “ Retroelements and Retroviral Infections”).