Mouse Strains and Genetic Nomenclature
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Abstract
In this article we describe the main characteristics and peculiarities of the different strains and stocks of laboratory animals from the genetic point of view. We explain how they are produced and maintained as well as their advantages and disadvantages in the context of animal experiments. We also provide some guidance to make the best possible choice when establishing an experimental protocol. Curr. Protoc. Mouse Biol. 1:213?238. © 2011 by John Wiley & Sons, Inc.
Keywords: inbred strains; congenic strains; recombinant inbred strains; recombinant congenic strains; outbred stocks
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PDF or HTML at Wiley Online LibraryTable of Contents
- The Different Categories of Laboratory Strains and Stocks
- Inbred Strains and Their Derivatives
- Outbred and Randombred Stocks
- Nomenclature Rules for Mouse and Rat Strains
- Conclusions
- Warning!
- Literature Cited
- Figures
- Tables
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Figure 1. This drawing schematically represents the breeding system that is commonly used to produce an inbred strain: mating a male and a female from the same litter (brother × sister) in successive generations. Theoretical computation would indicate that exceptional matings between parent and offspring would not affect the progress towards homozygosity provided that the parent that is selected for mating is always the youngest. A male, for example, can be used for mating with one of its daughters but not with a female offspring born from this cross. Each generation of inbreeding is symbolized by the uppercase letter F, followed by the number of generations. When this number is not known, a question mark is often used; for example, F ? + 27 would indicate that the number of brother × sister matings was not known when the strain was acquired but 27 generations of unrelaxed inbreeding have been added since this time. B, brother; S, sister. View Image -
Figure 2. The curve was drawn based on the Fibonacci's series and represents faithfully the cumulated percentage of genes that have become fixed in the homozygous state as inbreeding proceeds. From generation F5 onwards, this percentage is incremented by 19.6% at each generation. View Image -
Figure 3. This table was captured from a window from the Mouse Phenome Database. It represents the complete set of data for blood cholesterol performed on both male and female mice of 43 different inbred strains in Dr. B. Paigen's laboratory at the Jackson Laboratory. These data (in mg/deciliter) correspond to baseline data from mice aged 7 to 9 weeks. Checking these data before embarking on a research project related to cholesterol metabolism is definitely of great help (http://phenome.jax.org/db/qp?rtn=views/measplot&brieflook=9904). Arrowheads indicate exceptionally high or low values. View Image -
Figure 4. Historical data, confirmed by sequence data, indicate that modern laboratory inbred strains derive from a small number of ancestors belonging to several different subspecies of the genus Mus . Today's classical laboratory inbred strains should be regarded as recombinant strains derived (in unequal percentages) from three parental components: Mus musculus domesticus , Mus musculus musculus , and Mus musculus castaneus . For this reason it would probably be more appropriate to designate them as Mus “ laboratorius ”! This heterogeneous and unnatural genetic constitution is detectable at the genomic/sequence level by variations in the density of polymorphisms (in particular SNPs), with sharp edges, as represented on the picture by color differences for some chromosomal regions. The pattern of DNA polymorphisms distribution along the different chromosomal regions varies according to the strain and can be used for the purpose of mapping complex (QTL) traits. View Image -
Figure 5. (A ) This picture represents a mouse family tree. The 102 inbred strains represented on this picture have been genotyped for a set of 1,638 informative SNP markers, evenly distributed over the whole genome (spaced on average <1.5 Mb). Applying a neighbor‐joining method to the data, the authors constructed a mouse strain family tree that could be organized into seven groups. The length and angle of the branches have been optimized for printing and do not reflect the actual evolutionary distances between strains. This family tree is in good agreement with most other existing genealogies. Adapted from Petkov et al. (). (B ) This picture represents a phylogenetic family tree of 93 rat inbred strains. It was developed with the same technique as above (heuristic search for maximum parsimony). Adapted from Mashimo et al. (). View Image -
Figure 6. This picture schematically represents the different breeding schemes that can be used for keeping an inbred strain with three cages. (A ) The first schemes consist of mating one male and one female in each of the three cages, at each generation, with the breeders being brother (B) and sister (S) born in the same cage. This system cannot be recommended because in case of infertility or death one line will be lost, and in case of full success (unlikely!), one would end up with three loosely related substrains instead of one single strain. (B ) This breeding scheme is the most reliable. It consists of selecting the progeny at generation F, which would allow making the largest number of pairs of breeders at generation F+1. It is very safe, but, unfortunately, it is not always applicable. (C ) This system is an intermediate between A and B, and is the most popular in practice. View Image -
Figure 7. This picture represents the successive steps in the establishment of a congenic strain. At each generation, a breeder carrying the targeted character ( marked with a dot ) is back‐crossed to a partner of the recipient (B) strain. View Image -
Figure 8. After each back‐cross generation, an average of 50% of the genomic DNA of the donor strain is replaced by the equivalent proportion of genomic DNA of the background strain. However, selecting at each back‐cross generation, the breeder with the lowest percentage of introgressed (donor) DNA greatly accelerates the establishment of a congenic strain. This picture represents the breeder (boxed) that was recognized as the most interesting (“best breeder”) after genotyping because of the lowest percentage of donor genome (shown in red). The mutation or region of interest is indicated by an arrowhead. View Image -
Figure 9. Selecting the best breeders at each back‐cross generation can save a lot of time when establishing a congenic strain. It is important to note that genotyping requires many polymorphic DNA markers only for the first back‐cross progenies. Once a marker is characterized homozygous, it is no longer necessary to type it in the forthcoming generations. The y axis represents the number of mice with a percentage of homozygous loci lower or equal to the value indicated on the x axis. Adapted from Wakeland et al. (). View Image -
Figure 10. The genomic DNA flanking the target (introgressed) gene or transgene can be estimated very precisely with a battery of molecular markers, generation after generation. When, by chance, a cross‐over reduces the flanking DNA on one side or the other, the mouse then becomes a privileged breeder. The genotyping of the flanking regions with the aim of selecting the “best breeder” can be integrated in the overall genotyping protocol. Briefly, it is recommended to select and type many more markers in the flanking regions than in other regions of the genome. The probability of finding a mouse with one crossing‐over on each side of the flanking region is extremely low. For this reason it is recommended to proceed in two discrete steps, sequentially breeding mice with cross‐overs in a flanking region of the targeted gene. If we consider a locus A, which is c Morgans distant from the selected (or targeted) locus T, on the same chromosome, the probability that there has been no recombination between the two loci A and T is e − c per generation and therefore e − nc after n generations (Johnson, ). After 10 generations of back‐crossing, there is a 37% chance that no recombination occurred between loci A and T if they are distant 10 centimorgans (cM). This will rise to 61% if A and T are 5 cM apart and up to 90% if the two loci are 1 cM apart. If we consider that there are approximately 27,000 genes in the mouse genome and that the genetic map in this species spans ∼1,520 cM on average, this would mean that in 90% of the cases two congenic strains differ by ∼17 genes on both sides of the introgressed locus T. Of course, this is far from being negligible even if it should be weighted by the fact that no more than 20% of the genes are polymorphic between any two inbred strains. View Image -
Figure 11. Reciprocal congenics allow making comparisons with a high degree of standardization because epistatic interactions may be detected by this procedure. For example, if a given allele in the background of a congenic strain interferes with the expression of the target gene, this might be detected when comparing the two reciprocal congenic strains but would presumably be corrected when comparing the two congenic F1s. View Image -
Figure 12. This picture represents a set of four consomic strains flanked by the parental strains A and B. In each strain, a complete chromosome pair has been replaced by the homologous chromosome of the other inbred strain via a series of marker‐assisted back‐crosses. A complete panel of consomic strains consists of 21 strains, each derived from the same donor and host but having a different chromosome (Chr 1‐19, X or Y) of the host replaced by its counterpart from the donor. A reciprocal panel can be produced by inverting the donor and host strains, respectively. View Image -
Figure 13. This diagram represents a set of four recombinant inbred (R.I.) strains flanked by the parental strains A and B. Individual RI strains have a unique combination of loci derived by recombination of the alleles present in the original parental strains. Since RI strains are inbred and each strain has a unique genotype, RI strains have a number of advantages over F2 or back‐cross mouse populations as tools for mapping genes or quantitative trait loci (QTL). View Image -
Figure 14. (A ) The Collaborative Cross is a randomized cross of eight unrelated mouse inbred strains designed by members of the Complex Trait Consortium. The lines are first crossed pair‐wise to make all 56 possible G1 parents. A set of possible 4‐way crosses is performed, keeping Y‐chromosome and mitochondrial balance. Finally, all 8 genomes are brought together in G2:F1 and the offspring of this cross are inbred. The Collaborative Cross is a community resource that was initially designed for the purpose of mapping complex traits. (B ) The initial previsions were to breed around 1000 inbred strains where all the alleles of the initial inbred strains would be associated in a wide and unique variety of combinations. Only one strain is represented in this illustration; other strains would be similar but with a different pattern of parental strain distribution. View Image
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| INTERNET RESOURCES | |
| http://www.informatics.jax.org/mgihome/nomen/strains.shtml | |
| In 2001, the International Committee on Standardized Nomenclature for Mice (Chairperson: Dr. Janan T. Eppig) and the Rat Genome and Nomenclature Committee (Chairperson: Dr. Göran Levan) agreed to establish a joint set of rules for strain nomenclature, applicable to strains of both species. These guidelines are updated annually by the international nomenclature committees. The official Web site for these guidelines may be found at the above URL. | |
| http://phenome.jax.org/ | |
| Official Web site of The Mouse Phenome Project, an international collaboration representing five countries in both the academic and corporate sectors. Its aim is to establish a collection of baseline phenotypic data on commonly used and genetically diverse inbred mouse strains through a coordinated effort. | |
| http://www.informatics.jax.org/external/festing/search_form.cgi | |
| An annotated list of mouse and rat inbred strain. | |
| http://www.isogenic.info/html/animal_models_in_research.html | |
| Dr. M. F. W. Festing's Web site about the best use of animal models. | |
| http://www.informatics.jax.org/morsebook/ | |
| Electronic version of the book by Herbert C. Morse III, Origins of Inbred Mice, Academic Press. 1978. | |
| http://www.informatics.jax.org/silverbook/ | |
| Electronic version of the book by Lee M. Silver. 1995. Mouse Genetics: Concepts and Applications, Oxford University Press. |
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