JAX® Mice: the Gold Standard Just Got Better
One of the most important reasons why biomedical researchers use JAX® Mice is that they are the most well-characterized laboratory mice in the world. The JAX® Mice Database is renown for its wealth of genotypic and phenotypic information. The C57BL/6J strain was selected by the Mouse Genome Sequencing Initiative to be the first mouse strain to be sequenced. A set of 40 genetically-diverse and widely-used JAX® Mice strains were selected to be comprehensively characterized by the Mouse Phenome Project. More recently, with the construction of two new mouse bioinformatics resources, the characterization and utility of JAX® Mice has expanded substantially. The National Institute of Environmental Health Sciences (NIEHS) recently announced the completion of their Resequencing Project involving 15 JAX® Mice strains, and a group of scientists (Shifman et al. 2006) used JAX® Mice strains and strains derived from JAX® Mice to construct the most detailed genetic map of any mammal except humans. This article reviews these two recent events and explains why the Jackson Laboratory's Genetic Stability Program helps ensure the enduring value of JAX® Mice and the research tools derived from them.
The Completion of the NIEHS Resequencing Project
The NIEHS recently announced the completion of the Resequencing and SNP Discovery Project (NIH News 2006). This project involved identifying the single nucleotide polymorphisms (SNPs) among the following 15 JAX® Mice strains:
- 129S1/SvImJ (002448)
- C3H/HeJ (000659)
- MOLF/EiJ (000550)
- A/J (000646)
- CAST/EiJ (000928)
- NOD/LtJ (001976)
- AKR/J (000648)
- DBA/2J (000671)
- NZW/LacJ (001058)
- BALB/cByJ (001026)
- FVB/NJ (001800)
- PWD/PhJ (004660)
- BTBR T+ tf/J (002282)
- KK/HlJ (002106)
- WSB/EiJ (001145)
The Project members selected these strains because of their genetic diversity and routine use as research models (NIH News 2006). The SNPs were identified with the same high-density oligonucleotide array technology used to discover common DNA variation in the human genome.
The publication of the Resequencing Project data was greatly anticipated. More than 8.3 million SNPs were discovered among the resequenced strains. The polymorphisms will help researchers better understand the factors that affect susceptibility to and development of some 200 complex human diseases, including Parkinson's, cancer, diabetes, heart and lung diseases, reproductive diseases, and asthma. Says David A. Schwartz, M.D., NIEHS director (NIH News 2006): "Making this wealth of data freely available to the research community is a significant milestone. Each mouse strain is genetically unique. Now that we know the DNA variations for these mouse strains, we can compare the genetic makeup of one strain that acquires a certain disease to another strain that does not get the same disease. In this way researchers gain insight into the same processes that may cause one human to get a disease while another human in the same environment remains disease-free."
The SNP and other Resequencing Project data are publicly available at the National Center for Biotechnology Information Web site, the Mouse Genome Informatics (MGI) Web site, and the Mouse Phenome Database (MPD) Web site. The MGI Web site, maintained at The Jackson Laboratory, is an indispensable storehouse of mouse genetic information. The MPD, also maintained at The Jackson Laboratory, is a repository for phenotypic and genotypic data on 40 commonly used and genetically diverse inbred JAX® Mice strains and a platform for data analysis and in silico hypothesis testing. It enables investigators to choose optimal strains for their research, including physiological studies, drug and toxicology testing, and modeling disease processes. The new SNP information in these two databases will greatly enhance their value as tools for genetic analysis.
New Genetic Maps of the Mouse Genome
Although the sequencing of the mouse genome and the discovery of millions of SNPs in the mouse genome have permitted the construction of high-resolution physical maps, these maps cannot be used to construct high- resolution genetic maps because recombination rates across the mouse genome are not constant. The genetic maps of the mouse genome recently constructed by Shifman et al. (2006) will give scientists some very powerful and much anticipated tools. Shifman and his colleagues used more than 10,000 single nucleotide polymorphisms (SNPs) evenly spaced across the mouse genome to construct two high-resolution sex-specific genetic maps of the mouse genome. One map was constructed using eight recombinant inbred (RI) lines, AXB, BXA, CXB, BXD, BXH, AKXD, LXS, and SWXJ (all JAX® Mice strains except LXS); the second was constructed using genetically heterogeneous stocks descended from eight JAX® Mice inbred progenitors: A/J (000646), AKR/J (000648), BALB/cJ (000651), C3H/HeJ (000659), C57BL/6J (000664), CBA/J (000656), DBA/2J (000671), and LP/J (000676).
The new genetic maps provide the high resolution needed to address many problems in biomedical research. For example, they will help researchers finely resolve quantitative trait loci (QTLs) to intervals of a few megabases, more easily identify QTL genes, investigate the effects of sex on recombination rates, determine why recombination rate constraints are seemingly different over long and short distances, explain why recombination hotspots rarely occur in the same positions in humans and chimpanzees, and define the features that induce and maintain recombination hotspots in mammals. The maps are available and as supporting information to the article by Shifman and his colleagues.
The Jackson Laboratory's Genetic Stability Program
Given the extensive characterization of JAX® Mice and the vast amount of public health research that depends on their genetic integrity, The Jackson Laboratory is taking a proactive approach to ensure that the JAX® Mice researchers use today will be the same tomorrow. In 2004, The Jackson Laboratory implemented an innovative Genetic Stability Program (GSP) (Fig. 1) designed to minimize genetic drift. Defined as a cumulative change in the genetic make-up of an organism over time (Silver 1995), genetic drift in inbred mouse colonies happens slowly, subtly, and can be difficult to detect and control. It is primarily due to three factors: 1) separation of a sub-colony from its parent colony for more than 20 generations (10 generations in the parent colony plus the 10 that simultaneously pass in the sub-colony); 2) undetected spontaneous mutations that become fixed in a colony; and 3) residual heterozygosity in or incomplete inbreeding of a colony before it is separated from its progenitors (Bailey 1977, 1982; Taft et al. 2006). To limit genetic drift, The Jackson Laboratory's GSP uses a three-pronged approach: 1) it minimizes the number of generations attained in its foundation and production stocks: 2) it uses highly skilled technicians to oversee breeding in those stocks, and 3) it uses a unique cryopreservation approach to nearly eliminate genetic drift in the most commonly used inbred strains.
The cryopreservation component entails cryopreserving 25-year supplies of embryos from widely-used strains and refreshing foundation stocks of those strains with frozen embryos about every five generations. Already, embryos from JAX® Mice strains 129S1/SvImJ (002448), C3H/HeJ (000659) C57BL/6J (000664), DBA/2J (000671), FVB/NJ (001800), NOD/LtJ (001976), and NOD.CB17-Prkdcscid/J (001303) have been cryopreserved to use in this program (Taft et al. 2006). Limiting genetic drift in these strains is particularly important because all except NOD.CB17-Prkdcscid/J were part of the Resequencing Project. Furthermore, some 300 congenic JAX® Mice strains constructed by backcrossing to these inbred strains are, by extension, included in the program. The Jackson Laboratory Genetic Stability Program ensures that the genotypic and phenotypic characterization of some key JAX® Mice strains will be reliable over space and time.
The "J" at the end of a JAX® Mice strain names indicates that the strain originates from The Jackson Laboratory. It represents over 75 years of expertise in mouse husbandry and mouse-based genetic research, a vast resource of mouse bioinformatics, and a comprehensive genetic quality monitoring and stability program. The use of JAX® Mice by many of the most published biomedical researchers and as the strains of choice for publically accessible bioinformatics tools are testaments to their importance and gold standard quality.
|Foundation stocks of several broadly-used strains are refreshed with cryo-recovered embryos about every five generations.|
Bailey DW. 1977. Genetic drift: the problem and its possible solution by frozen-embryo storage. Ciba Found Symp 291-303.
Bailey DW. 1982. How pure are inbred strains of mice? Immunology Today 3:210-14.
NIH News. 2006. Mouse DNA to Aid Biomedical Research. NIEHS PR #06-17, October 25.
Shifman S, Bell JT, Copley RR, Taylor MS, Williams RW, Mott R, Flint J. 2006. A high-resolution single nucleotide polymorphism genetic map of the mouse genome. PloS Biol 4(12):e395.
Silver L. 1995. Mouse Genetics. Oxford.
Taft RA, Davisson M, Wiles MV. 2006. Know thy mouse. Trends Genet 22:649-53.
Learn more about The Jackson Laboratory's Genetic Integrity Program.