Article

Genetic reliability of commercially bred laboratory mice

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Abstract

An analysis of 20 mouse colonies from 10 different breeders sampled over a period of up to a year using the mandible-analysis technique revealed 3 major cases of lack of authenticity: supply of mice as a pure strain from a colony founded by an unidentified cross: blending of 2 or 3 stocks into a single colony the offspring of which were sold under 3 different names, none of which were authentic; differences between nominally identical stock from 2 sources. These findings are discussed in relation to previously published information using named strains, and a genetic monitoring scheme for commercial breeders is proposed.

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... There is now an urgent need for improved methods of checking the genetic identity ('authenticity') of the many inbred and congenic strains of mice and rats used in biomedical research. In the past, most research workers have taken the authenticity of such strains on trust, but sometimes this trust is misplaced (Festing, 1974; Krog, 1976; Groen, 1977). Moreover, eyen if strains do not become genetically contaminated, errors in labelling when animals are transported could result in research workers inadvertently using the wrong animals. ...
... Skin grafting is sensitive for discovering whether a strain is inbred, but is clumsy as a means of strain identification: it also takes far too long (12-100 days) to get an answer. Mandible shape (Festing, 1974) is a satisfactory method for routine screening, but needs to be backed up by other methods, as it sometimes produces false positive results. Moreover, it is too mathematical in approach for the average biomedical research worker. ...
Article
Strain-specific polyvalent anoantisera may be obtained by injecting lymphocytes pooled from several different strains into an inbred recipient. 6 sera of this type were produced in rats and 23 in mice. A dye-exclusion microcytotoxic test was used to evaluate the strain specificity of such sera. A total of 663 out of 713 (93·0%) of the tests conformed with expectation, but there were 48 (6·7%) false negative results in which the test failed to detect non-authentic animals. There were also 2 (0·3%) false positive results, in which authentic animals were shown as non-authentic. These were attributed to technical errors. Most false negative results occurred when serum and test cell suspensions matched at the major histocompatibility complex. It was concluded that the use of strain-specific polyvalent immune sera, coupled with a simple immunological test such as the microcytotoxic test, offers a sensitive and quick new method for routine genetic quality control.
... These were incubated overnight in a few ml tap water with a pinch of the proteolytic enzyme papain to clean off the remaining flesh, incisors were removed, and the mandibles were dried and stored in plastic bags. A series of 11 measurements were made as previously described (Festing, 1974 ), and these were used to compute 4 discriminant functions (DFs) describing the shape of the mandible. The coefficients used in calculating the DFs are given inTable 3. ...
... The mean and within-sample standard deviation for each of the 4 DFs was calculated for each sample. However, the standard deviation among sample means from the same colony was taken from a previous study (Festing, 1974) involving a total of 103 samples (Table 1). Sample means were used to calculate an overall mean for the colony or strain and these data were used to construct control charts as used in industrial quality control (Thirkettle, 1968 ). ...
Article
SUMMARY A method of analysing mandible samples using 4 discriminant functions to describe mandible shape, and plotting the samples on control charts, as used in industrial quality control, is described. Repeated samples from 3 different colonies gave consistent results, with only occasional sam- ples 'out of control'. 5 known 'illegitimate' samples were correctly rejected, and 3 out of 4 'legitimate' samples were accepted as belonging to stock LACA. In the 4th case lack of fit was attributed to subline-differentiation. This method of genetic analysis is practical for the large-scale genetic monitoring of laboratory mouse strains and stocks, and a Genetic Monitor- ing Scheme is being offered to commercial breeders. The Accreditation Scheme for breeders of laboratory animals was started in ) 950 with the aim of improving the quality of animals available to bio- medical research workers in the United Kingdom. In 1969 a microbiologicalgrading scheme was introduced in which each accredited colony was screened for the presence of specified pathogenic micro- organisms, and graded according to the findings (Townsend 1969). The need for a method of genetic quality control has already been emphasised (Festing, )974). The development of the 'mandible analysis' technique (Festing, 1972, 1973a, 1973b) in which strains and stocks of laboratory mice can be identified from the shape of their right mandible, has now made it possible to introduce 'genetic monitoring' of mice into the Accreditation Scheme. The genetic monitoring (GM) scheme is a voluntary one, open to all accred- ited breeders of mice and, in the future, other species. It makes provision for the monitoring of inbred strains, outbred stocks and F 1 hybrids. How- ever, breeders wishing to enter the scheme must agree to abide by a number of rules in addition to those required under the microbiological grading scheme (Laboratory Animals Centre, )974). For example, the breeder must satisfy
... Human mistakes and mismanagement, murine size and abilities, and the genetics of coat colors, have all led to the inadvertent mixing of murine genetic material that researchers were attempting to separate and define. In 1974, the importance of genetic monitoring in commercial strains was demonstrated by Festing using mandibular measurements to determine genetic background (Festing, 1974). Roderick et al., in 1971 proposed using isoenzyme alleles to genetically monitor animals. ...
Chapter
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In the early days of research involving mice and rats, the importance of both genetic and health quality and monitoring of that quality was not recognized. The health quality of animals was quickly reflected in sick animals that could not be used for research, so immediate strides were made to ensure animal health in the research environment. Recognition of and efforts to maintain genetic quality lagged behind as laboratory animal genetics was initially only important to geneticists. As detailed investigations into genetics and immunology began, the inbred mouse and more recently, the rat, arose as genetic models of disease (Malakoff, 2000) and with those came the challenge of maintaining genetic homogeneity. Human error and genetic drift are ever-present sources of unwanted genetic heterogeneity, which ultimately lead to experimental irreproducibility. Genetic monitoring and colony maintenance quality control are necessary measures to detect and remove unwanted genetic heterogeneity. This chapter will discuss the rationale for genetic homogeneity and monitoring, the history of genetic monitoring from its inception to today, and current and historical means by which this may be accomplished. Also addressed in the chapter are current monitoring paradigms, or genetic quality control, for mice and rats, including inbred, congenic, outbred, and genetically engineered strains, as well as the role of breeders, vivaria, and end users in genetic quality control. Finally, the future of genetic monitoring and genetic quality control will be discussed.
... Almost in all laboratory animal houses, the breeding colony of outbred stock was founded with minimum number of males and females and was subjected to closed colony mating for more than 45 years at the same institute. In the United Kingdom, Festing [5] reported several cases of deficiency in authenticity of inbred and non-inbred mouse stocks. In India outbred stock are not being monitored for their population genetic structure using molecular markers. ...
Article
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Molecular genetic analysis was performed using random amplified polymorphic DNA (RAPD) on three commonly used laboratory bred rodent genera viz. mouse (Mus musculus), rat (Rattus norvegicus) and guinea pig (Cavia porcellus) as sampled from the breeding colony maintained at the Animal Facility, CSIR-Indian Institute of Toxicology Research, Lucknow. In this study, 60 samples, 20 from each genus, were analyzed for evaluation of genetic structure of rodent stocks based on polymorphic bands using RAPD markers. Thirty five random primers were assessed for RAPD analysis. Out of 35, only 20 primers generated a total of 56.88 % polymorphic bands among mice, rats and guinea pigs. The results revealed significantly variant and distinct fingerprint patterns specific to each of the genus. Within-genera analysis, the highest (89.0 %) amount of genetic homogeneity was observed in mice samples and the least (79.3 %) were observed in guinea pig samples. The amount of genetic homogeneity was observed very high within all genera. The average genetic diversity index observed was low (0.045) for mice and high (0.094) for guinea pigs. The inter-generic distances were maximum (0.8775) between mice and guinea pigs; and the minimum (0.5143) between rats and mice. The study proved that the RAPD markers are useful as genetic markers for assessment of genetic structure as well as inter-generic variability assessments.
... In some cases, we found that all was not well. Several of the outbred stocks had become genetically contaminated (13), and, although every inbred strain and each colony of outbred stock had a unique shape to their mandibles, there was no clear distinction between Wistar and Sprague-Dawley rats, because individual colonies within these two stocks differed (14,15). For many years, I was puzzled as to why bone shape is so strongly inherited, although the actual shape of the mandible, and other bones, does not seem to matter very much. ...
Article
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Everybody's career depends on many chance factors: the people one meets, the opportunities which are available, or the state of a scientific discipline. Mine is no exception. I started out in agriculture, obtained a PhD in quantitative genetics, and spent most of my career concerned with the use of animals in biomedical research. Soon after I joined the Medical Research Council Laboratory Animals Centre in 1966, as their geneticist in charge of many species and strains of laboratory animals, I was introduced to Russell and Burch's book, The Principles of Humane Experimental Technique. It had a significant effect on my future, which has encompassed two related themes: the need for better experimental design, and the conviction that, in most research, inbred strains of rats and mice should normally be used in preference to genetically undefined outbred stocks. The establishment of the FRAME Reduction Committee has helped me to pursue both of these, although toxicologists continue to ignore basic design principles, by using outbred stocks.
... In some cases, we found that all was not well. Several of the outbred stocks had become genetically contaminated (13), and, although every inbred strain and each colony of outbred stock had a unique shape to their mandibles, there was no clear distinction between Wistar and Sprague-Dawley rats, because individual colonies within these two stocks differed (14,15). For many years, I was puzzled as to why bone shape is so strongly inherited, although the actual shape of the mandible, and other bones, does not seem to matter very much. ...
Article
Full-text available
According to the US Food and Drugs Administration (Food and Drug Administration (2004) Challenge and opportunity on the critical path to new medical products.) “The inability to better assess and predict product safety leads to failures during clinical development and, occasionally, after marketing”. This increases the cost of new drugs as clinical trials are even more expensive than pre-clinical testing. One relatively easy way of improving toxicity testing is to improve the design of animal experiments. A fundamental principle when designing an experiment is to control all variables except the one of interest: the treatment. Toxicologist and pharmacologists have widely ignored this principle by using genetically heterogeneous “outbred” rats and mice, increasing the chance of false-negative results. By using isogenic (inbred or F1 hybrid, see Note 1) rats and mice instead of outbred stocks the signal/noise ratio and the power of the experiments can be increased at little extra cost whilst using no more animals. Moreover, the power of the experiment can be further increased by using more than one strain, as this reduces the chance of selecting one which is resistant to the test chemical. This can also be done without increasing the total number of animals by using a factorial experimental design, e.g. if the ten outbred animals per treatment group in a 28-day toxicity test were replaced by two animals of each of five strains (still ten animals per treatment group) selected to be as genetically diverse as possible, this would increase the signal/noise ratio and power of the experiment. This would allow safety to be assessed using the most sensitive strain. Toxicologists should also consider making more use of the mouse instead of the rat. They are less costly to maintain, use less test substance, there are many inbred and genetically modified strains, and it is easier to identify gene loci controlling variation in response to xenobiotics in this species. We demonstrate here the advantage of using several inbred strains in two parallel studies of the haematological response to chloramphenicol at six dose levels with CD-1 outbred, or using four inbred strains of mice. Toxicity to the white blood cell lineage was easily detected using the inbred strains but not using the outbred stock, clearly showing the advantage of using the multi-inbred strain approach.
... There is a need for a routine, cheap, sensItive and qualitative test for the authenticity of inbred strains of mice. The mandible-shape technique (Festing, 1974Festing, , 1979), is a sensitive, quantitative technique but it can give false positive results and so needs to be backed up by other methods. The recently devised polyvalent strain-specific alloantisera technique (Festing & Totman, 1980) is qualitative but not yet routinely available. ...
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The shape of the mandible in. nine sublines of C57BL/Gr, seven other strains of ‘C57 ancestry’ and four unrelated strains was studied by multivariate techniques. The generalized distance function was used to classify individuals in the groups which they most closely resembled. The degree of misclassification depended on the pedigree relationship between strains and sublines. The generalized distance between pairs of subline centeroids was also highly correlated (r = 0·60) with the number of generations between them. A canonical variate analysis was used to reduce the dimensionality so that a graphical display of the relationships between strains and sublines could be made. The results agreed closely with the classification analysis. It was concluded that the shape of the mandible could be used for subline identification though the accuracy of this technique depends on how closely the sublines are related.
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Data are presented on the life span and pathology of 15 inbred and 2 outbred strains of mice, and 1 inbred and 1 outbred strain of rats, maintained under specified-pathogen-free (SPF) conditions. Among the mice, longevity ranged from 312 to 802 days. Survival curves for each strain are given. Neoplasia was the most common pathological finding.
Biology of the laboratory mouse The grading of commercially-bred Record 85,225. analysis of subline divergence in the shape of the by mandible analysis Cancer laboratory animals
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Green, E. L. (1966). Biology of the laboratory mouse, 2nd ed. New York: Staats, J. (1972). Standardizednomenclature Research 32,1609. Townsend, G. T. (1969). The grading of commercially-bred Record 85,225. analysis of subline divergence in the shape of the by mandible analysis. In The laboratory Fischer. (MRC McGraw-HilI. for inbred strains of mice, 5th listing. Cancer laboratory animals.Veterinary