was mapped by crossing the parental strain with five other inbred strains, in the process of creating five new congenic strains, a large variation in phenotypes was evident [9]. Skin fragility (blister formation) was a feature on all backgrounds, characteristic of junctional epidermolysis bullosa. However, on one background, nail abnormalities were observed. Mapping for these quantitative differences revealed the collagen 17A1 (Col17a1) was a major modifier gene that resulted in the mice having nail dystrophy, a feature of one subtype of the human disease [10]. A second gene was later identified that explained the musculoskeletal weakness in another subtype of this human disease (Sproule and Sundberg, unpublished work). Figure 4.4 illustrates how using websites that define specific features of subtypes of a human disease can facilitate phenotyping mouse models to understand the underlying genetics behind these variations.
Figure 4.1 Nonhuman (including mouse) models were historically compared empirically to human diseases. Diseases present a variety of phenotypes and severity levels in a mixed population, as it does with a human population as illustrated by the Gaussian curve. Where the lesions (phenotypes) overlapped was where they were considered to be potentially useful as models. Many did not hold up over time.
Figure 4.2 Human population response to disease is often highly variable between individuals. By contrast, inbred mice carrying the same genetic mutation are more monomorphic and can present as a specific subtype of the human disease.
Figure 4.3 Effect of strain on phenotype for a single gene mutation. A classic example of the effect of an inbred strain background on phenotype was when the epidermal growth factor receptor null mutation (Egfrtm1Dwt) was transferred by breeding onto different hybrid genetic backgrounds.
Sources: Based on Threadgill et al. [7] and Sibilia and Wagner [8].
Basic Concepts of Defining a Mouse Model for a Human Disease
There are numerous criteria needed to make an animal model for a human disease, many of which were standardized in a fascicle series edited by George Migaki during the 1970s–1990s (Table 4.1) [11]. Models can be built on spontaneous or induced mutations, or those experimentally generated by various methods (including chemicals, infectious and physical agents, surgery, etc.). Simply finding a case or case series is a start but, ideally, the model should be reproducible either by breeding or by using some type of manipulation [12]. Sometimes a model may combine an underlying genetic lesion with an additional challenge such as infection, aging, or high fat diet to manifest its full range of phenotypes. An example of this would be the feeding of high‐fat diets to mice to understand the genetics of atherosclerosis [13]. Furthermore, the model should be readily available for other scientists to validate and utilize. Single gene mutations in mice, which result in a genetically reproducible disease, have been the cornerstone of mouse genetics and models for more than a century. However, the locus or allele heterogeneity in human genetic disorders also makes a specific gene mutation mouse model useful for perhaps that human equivalent but not necessarily for all human forms of a monogenic disease.
Mouse models, as well as other species used as models, should have some or many of the clinical and pathological features of the human disease to which they are compared. Where these features overlap were historically considered to be where the models were useful (Figure 4.1).
An informative example of the complexity of phenotype‐genotype relationships in both mice and humans, and the consequent difficulty in establishing a model, can be found in CHARGE syndrome [14]. CHARGE syndrome is an extremely phenotypically diverse syndrome with coloboma, heart defects, choanal atresia, retardation (of growth or development), genitourinary malformation, and ear abnormalities, being the most common phenotypes. The phenotypic variability raises the question as to whether this is indeed a genetic or a clinical definition of the syndrome, suggesting that the phenotypic clusters could be due to multiple genetic origins. As it turned out, the identification of the CHD7 gene in humans lead to huge simplification of the understanding of the syndrome and identified at least some allelic:phenotypic spectrum relationships [15]. This stimulated the investigation of mouse N‐ethyl‐N‐nitrosourea (ENU) mutations showing related phenotypes in balance function, and the identification of mouse mutants in Chd7 but which nonetheless did not model all of the phenotypes seem in humans [16]. The building of mouse models since that initial discovery has generated very valuable and useful strains for the understanding of both genotype/phenotype relationships, together with the mechanisms underlying them, but there still does not exist a single mutation on a single background that completely recapitulates all of the phenotypes expressed in CHARGE allelic series [17]. This example illustrates how identification of models through phenotype similarity can be extremely difficult, but that modeling of a restricted set of phenotypes can be scientifically extremely useful [18].
Figure 4.4 Mouse models identify subtypes of junctional epidermolysis bullosa. A spontaneous hypomorphic allele of Lamc2jeb had different phenotypes when moved to different congenic backgrounds. Using this observation the underlying gene for each variation was identified. The range of phenotypes of junctional epidermolysis bullosa were gathered from the literature by text mining using disease labels from the DERMO ontology and accessed through the Aber OWL skin disease phenotypes database.
Source: http://aber‐owl.net/aber‐owl/diseasephenotypes.
Table 4.1 Criteria for accurately defining an animal model, regardless of how it was created, for a human disease.
Source: Based on Scarpelli et al. [11].
| Accurately recapitulates the clinical and pathological features of the human disease (responds to similar drugs in both species).Primary molecular defect similar (ideally similar or identical mutation in the same).Readily available to other investigators:Genetic, breed mice to produce more as needed.Repository for archiving model for public distribution.Experimental induction easily done if not a genetic‐based model.Reproducibility (stability of model, inbred strains).Genetic manipulability (arsenal of genetic tools). |