Читать книгу Pathology of Genetically Engineered and Other Mutant Mice - Группа авторов - Страница 61

Wild mouse populations are generally not inbred, and some populations have great genetic diversity between individuals. Exceptions occur when there is severe geographical isolation in which gene diversity is mixed but less so than in large free‐ranging populations. The result of outbreeding is various degrees of genetic and therefore phenotypic variability between individuals (Table 3.10). Since human populations, in general, are outbred, properly maintained outbred mouse stocks can, in many ways, be better models for the general human population for identifying population outliers/rare susceptibility in toxicology and other types of studies. One big advantage of outbred stocks is that fecundity, reproductive efficiency, is usually quite high compared to inbred animals. This translates to lower costs to produce large numbers of animals in a short period of time. The major disadvantage is that because of the high phenotypic variability between individuals, large numbers need to be used to generate valid results, and the colony size and breeding schemes necessary to prevent inbreeding are large and more complex. This variability severely limits the ability to do highly refined research to ask very specific genetic and environmental questions about effects on disease or other phenotypes. But if the goal is to look for rare events, such as adverse drug reactions, these types of mice might better reflect the response in humans. This depends, of course, on breadth of alleles in the starting population and the rigor with which the outbred population is maintained. Defined outbred stocks are closed colonies, and inadvertent selection for fecundity, size, or health are selective pressures that reduce the genetic diversity of the population, as is any passage through a genetic bottleneck such as can occur during rederivation.

Table 3.10 Outbred mouse stocks.

AdvantagesHigh genetic and phenotypic variabilityCan be more reflective of the general outbred human populationRobust (high fecundity)Inexpensive

DisadvantagesLarge numbers needed for analysisHigh variability in results

UsesWidely used in all types of researchModels for human disease with variability between patients (population outliers)

One of the most commonly used outbred stocks is Crl:CD1 mice from Charles River Laboratories. This and other related “Swiss”‐derived stocks originated from seven females and two males were sent from a non‐inbred albino stock of Dr. Andre de Coulon at Centre Anticancereux Romand, Lausanne, Switzerland to Clara J. Lynch at Rockefeller University in the United States in 1926. These mice were further developed into the Hauschka Ha/ICR stock, which was initiated in 1948 at the Institute for Cancer Research (ICR) in Philadelphia. In 1959, a colony of mice, then maintained at Roswell Park Memorial Institute, were send to Charles River designated as HaM/ICR (https://www.criver.com/sites/default/files/resources/CD‐1IGSMouseModelInformationSheet.pdf). Today on the Charles River website you will find various trade names for different colonies of these mice including CD1‐Elite (SOPF) or CD1‐Elite Mouse. However, the correct formal nomenclature for the stock is Crl:CD1. While it is commonly used as an outbred stock, the genetic diversity from the small number of albino progenitors used and variability of sublines passed between institutions make this not the best example of an outbred stock.

Fzt:DU provides a better example of an outbred stock [33]. This population was generated by crossing four other outbred stocks and four disparate inbred strains together to produce eight founder populations of 15 litters and then a careful breeding rotation was followed to maximize the allele frequencies in the population.

Various breeding strategies have been reported in the literature for maintaining maximal genetic diversity in an outbred stock and all require a large population with a set rotation of breeding interactions. Random breeding places selective pressures on the population, most notably for a preference of increased fecundity, but has been used in some outbred stocks, and sibling breeding must be avoided. The nomenclature for outbred stocks begins with the laboratory code of the researcher who bred it followed by a colon followed by upper case stock name of two to four letters representing the population. Some outbred populations have been generated around a particular mutation in order to assess that phenotype in a diverse genetic setting. J:NU is an outbred stock bred around the nude (Foxn1^nu) mutation. Crl:SKH1‐Hr^hr is an outbred stock commonly used for UV light carcinogenesis studies because they have a high frequency for developing aggressive squamous cell carcinomas compared to other inbred strains carrying the hairless mutation [23]. The nomenclature (Crl:SKH1‐Hr^hr) again reflects the breeder (Crl), outbred strain (SKH1), and the specific allelic mutation Hr^hr.