Did you know that even minor changes to a mouse strain could have serious implications for your research?
Without the appropriate genetic quality control measures,
your studies may be susceptible to variability from unexpected phenotypes and strain contamination.
These issues not only produce invalid research results and present challenges to study reproducibility, but they also lead to a waste of valuable resources – including time, research dollars, and, most importantly, the lives of research animals.
Originally piloted in 2018, the Animal Care & Use Program's My Strain initiative aims to promote interdisciplinary research collaboration through the responsible** sharing of information about transgenic mouse strains.
As part of this initiative, we are pleased to offer the following resources to assist you with conducting responsible, rigorous research involving the use of transgenic mice:
About My Strain and How to Get Involved
Have you ever wished you could talk to a colleague about their experience(s) using a certain type of strain before conducting your research? Or maybe you've wondered how you could discover what transgenic mouse strains other researchers are using across campus?
The My Strain collaboration tool, available to University of Michigan (U-M) PIs and PI Proxies via eRAM , is a unique way to help foster cross-unit collaboration through the provision of a secure platform for researchers across campus to responsibly share information about their transgenic mouse strains.
The tool may be used to identify specific transgenic mouse strains being used at the University, or to connect with colleagues to inquire about potential collaborations, the performance of a specific strain, and/or best practices in breeding a strain.
U-M PIs and PI Proxies can opt-in to My Strain via eRAM to have their strains included in the cross-campus list. Step-by-step instructions for opting in are available on the eRAM Reference Materials webpage.
Upon opt-in, strains you purchase will automatically populate via the Rodent Strains tab in eRAM. You will also be able to view strains purchased by other participating labs on campus.
Strains are automatically removed after three years or may be voluntarily removed at any time.
Participation in this initiative is completely voluntary. All information contained within the platform is accessible only via valid Level-1 U-M login credentials and after agreeing to abide by specific terms and conditions of use.
Questions or concerns about including your strain data should be directed to your ULAM Faculty Veterinarian. Questions can also be submitted to project lead Tara Martin, DVM, at email@example.com.
**Please note that this tool has been developed for the sole purpose(s) of facilitating researcher connections and the responsible sharing of information. It is NOT to be used for any action that may violate Material Transfer Agreements (MTAs) or any other agreements that individual researchers and/or the institution have with outside vendors.
Genetic quality control is one of many animal-related factors that can have wide-ranging, unexpected effects on your research.
Ever wonder what exactly makes a strain a strain? Is there a difference between a C57BL/6 mouse bred at a vendor versus one bred in your lab? Why do strains have such long names? Read on for a primer!
- A strain is made by breeding brother and sister mice to one another for at least 20 generations. Mice in the same strain are considered genetically identical to each other, though residual heterozygosity can remain until the 60th filial generation.
- Substrains are branches within a strain created by breeding separate lines for at least 20 generations. Substrains can also occur if genetic differences arise within a strain. Even if they are the same strain, animals of different substrains are not genetically or phenotypically identical.
- Note that generations are additive – if you and a colleague separately breed the same strain for 10 generations, your mice have been separated for 20 total generations and are considered substrains.
- The background strain is the strain on which a mutation was induced. Backcrossing may be used to transfer a mutation from one background strain to a new strain. The new mutant strain will never be fully genetically identical to the background strain because the mutant locus is surrounded by flanking DNA. Flanking DNA can have unexpected and significant effects on phenotype.
The most common reasons for strain divergence are human error and genetic drift.
- Human error is the most significant cause of divergence. Common sources of error include mismarking cage cards, misrecording identification numbers, or accidentally pairing the wrong animals. Careful recordkeeping and training can minimize this.
- Genetic drift occurs when random mutations occur during cell division, are passed on to offspring, and accumulate in the population. These changes can have unexpected effects on phenotype even if they are not obvious. Good breeding practices can minimize genetic drift.
Inbred animals should be as genetically homogenous as possible to minimize variability caused by unexpected phenotypes. Poor genetic quality control leads to the contamination of strains. There are many published reports in the literature of contamination causing unexpected or invalid research results.
For example, Jackson Laboratories reports that 12.5% of newly imported strains are not in the background described by the investigators importing them (Kelmenson, 2016).
This leads to wasted time, money, and animal lives.
A good genetic quality control program uses a combination of factors. These may include the following:
- Consistent phenotypes: any change in phenotype should be investigated and mice exhibiting changes should be removed from the breeding colony. Changes may be noted on physical examination (body size, coat color, skeletal structure) or as part of your research (unexpected behavioral responses, changes in tumor susceptibility)
- Using this method alone may cause you to miss contamination that is not phenotypically obvious. One example of this is Nitzki, 2006 where contamination was not noted for years until the lab began working with F1 cross mice that yielded an unexpected coat color.
- Single nucleotide polymorphisms (SNP): SNP panels may be performed by commercial vendors or within your lab. SNP analysis is especially helpful to ensure the integrity of newly created or acquired strains, check that congenic strains have been appropriately back-crossed, and evaluate founder mice before you start a breeding colony.
- Allele-specific genotyping: this method is used for identifying mutant alleles within a strain and is especially useful for checking breeders.
In some situations, such as differentiating between closely related strains, more specialized techniques may be necessary to monitor your strains.
For all strains:
- Use brother x sister mating schemes.
- SNP analyze breeders prior to use.
- Periodically refresh inbred lines. You should use pedigreed animals from a high-quality vendor or cryopreserved founders to refresh lines.
For mutant strains (including those created with programmable endonucleases such as CRISPR), the following tips are especially important:
- Back-cross to the parent strain every 10 generations to minimize drift.
- Confirm the presence of mutant alleles with phenotyping and genetic testing.
- Genetically test newly created lines.
- Periodically monitor transgene copy number and expression.
For newly acquired strains (whether purchased, donated, or self-created):
- Validate both the background and mutations prior to beginning experiments.
Because there are so many strains, stocks, and mutant mice available, the International Committee on the Standardized Genetic Nomenclature for Mice and Rats developed a systematic naming scheme to reduce confusion.
Under this system, every strain name will tell you the following information:
- Background strain
- Originating laboratory
- Where the strain is maintained
- How a mutant strain was created
- Whether a congenic strain has been fully back-crossed
Learning about, and using, proper nomenclature can, therefore, tell you a lot of information about the mouse strains you encounter. Using standardized naming and abbreviations reduces confusion when animals are shared between labs or when scientists from outside of the university read papers you have published.
Failure to use these conventions can have effects on your research. Illustrations of this can be found in Fontaine and Davis, 2016.
Information about mouse nomenclature can be found at the following resources:
- Fahey JR, KAtoh H, Malcolm R, Perez AV. 2013. The case for genetic monitoring of mice and rats used in biomedical research. Mamm Genome 24(3 – 4): 89 – 94.
- Fontaine D and Davis BD. 2016. Attention to background strain is essential for metabolic research: C57BL/6 and the International Knockout Mouse Consortium. Diabetes 65(1): 25 – 33.
- Kelmenson P. “Maybe it’s not you – maybe it’s your mice!” JAX Blog, The Jackson Laboratories,
- Low-Marchelli, J. “Remember, only you can prevent genetic drift.” JAX Blog, The Jackson Laboratories, March 2018.
- Nitzki F, Kruger A, Reifenberg K, Wojnowski L, Hahn H. 2007. Identification of a genetic contamination in a commercial mouse strain using two panels of polymorphic markers. Laboratory Animals 41: 218 – 228.
- Petkov PM, Cassell MA, Sargent EE, Donnellly CJ, Robinson P, Crew, V, Asquith S, Vonder Haar R, Wiles MV. 2004. Development of a SNP genotyping panel for genetic monitoring of laboratory mice. Genomics 83(5): 902 – 911.
- Pritchett-Corning KR and Landel CP. “Genetically Modified Animals.” Laboratory Animal Medicine 3rd Edition. Eds: Fox JG, Anderson LC, Otto G, Pritchett-Corning KR, Whary MT. Boston: Elsevier, 2015.
1417 – 1440.
- Simon MM, Greenaway S, White JK, et al. 2013. A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains. Genome Biology. 14(7):R82. doi:10.1186/gb-2013-14-7-r82.
- Strobel MC, Reinholdt LG, Malcolm RD, Pritchett-Corning K. “Genetic Monitoring of Laboratory Rats and Mice.” Laboratory Animal Medicine 3rd Edition. Eds: Fox JG, Anderson LC, Otto G, Pritchett-Corning KR, Whary MT. Boston: Elsevier, 2015. 1403 - 1416.
- Taft RA, Davisson M, Wiles MV. 2006. Know thy mouse. Trends in Genetics 22(12):649 – 653.
- Jackson Laboratories – Founded in 1929, The Jackson Laboratory (JAX) is an independent, nonprofit biomedical research institution that serves as “a global resource for developing, distributing and analyzing innovative models of human disease. It offers an array of model creation, husbandry, and diagnostic and analytic services, ranging from custom breeding and strain preservation to drug efficacy studies and genome sequencing, all focused on empowering basic scientific research and drug discovery.”
- Mouse Genome Informatics (MGI) – MGI is an international database resource for the laboratory mouse, providing integrated genetic, genomic, and biological data to facilitate the study of human health and disease.
- Mutant Mouse Resource & Research Centers (MMRRC) – Supported by the National Institutes of Health, the MMRRC distributes and cryopreserves scientifically valuable, genetically engineered mouse strains and mouse ES cell lines with potential value for the genetics and biomedical research community.
- International Mouse Strain Resource (IMSR) – The IMSR is a searchable online database of mouse strains, stocks, and mutant ES cell lines available worldwide, including inbred, mutant, and genetically engineered strains.
Links marked with a lock icon can only be accessed using valid Level-1 U-M login credentials.
References and Resources
- If you have additional questions about transgenic mouse strains not addressed here, we recommend that you schedule a consultation with your ULAM Faculty Veterinarian.
- If you don't know your faculty veterinarian, send an email to firstname.lastname@example.org or call (734) 764-0277 and your question will be routed appropriately.