Nomenclature of Inbred Mice

Definition and applications

An inbred strain is one that:

  • is produced using at least 20 consecutive generations of sister x brother or parent x offspring matings, or;
  • is traceable to a single ancestral pair in the 20th or subsequent generation.

All of the standard JAX® Mice inbred strains have far surpassed 20 generations of inbreeding. Except for the sex difference, mice of an inbred strain are as genetically alike as possible, being homozygous at virtually all of their loci. An inbred strain has a unique set of characteristics that sets it apart from all other inbred strains. Many traits do not vary from generation to generation. Other traits are easily influenced by diet and environmental conditions and therefore may vary from one generation to the next. Some inbred strains carry mutations that may or may not be indicated in the strain designation. For examples, C3H/HeJ mice are homozygous for the retinal degeneration 1 mutation (Pde6brd1) and a defective lipopolysaccharide response allele (Tlr4Lps–d), and many inbred strains carry recessive genes affecting coat color. Some of these mutations are cross-referenced in the strain data sheets.

JAX® Mice inbred strains are particularly well characterized:

  • The DNA of 16 JAX® Mice strains has been sequenced: strain C57BL/6J was sequenced by the publicly funded Mouse Genome Sequencing initiative, and strains 129S1/SvImJ, A/J, AKR/J, BALB/cByJ, BTBR T+ Itpr3tf/J, C3H/HeJ, CAST/EiJ, DBA/2J, FVB/NJ, MOLF/EiJ, KK/HlJ, NOD/ShiLtJ, NZW/LacJ, PWD/PhJ, and WSB/EiJ were resequenced by the National Institute of Health and Environmental Sciences (NIEHS) Resequencing Project.
  • SNP data for the 15 JAX® Mice strains included in the NIEHS Resequencing Project are publicly available at the NIEHS and Mouse Phenome Database websites;  additional SNP data for many JAX® Mice strains are publicly available at the Mouse SNP Database and the Mouse Phenome Database.
  • The majority of the data in the Mouse Phenome Database is for 40 genetically diverse and widely used JAX® Mice strains.

Substrains

Substrains are branches of an inbred strain that are either known or suspected to be genetically different from that inbred strain. They form under any of the following three conditions: 1) branches of a strain are separated from the parent colony before the 40th generation of inbreeding; 2) a branch of a strain is maintained separately from the parent colony for more than 20 generations of inbreeding (10 generations in the branch and 10 in the parent colony); and 3) genetic differences from the parent colony are discovered. Unfortunately, the degree of genetic diversity among substrains is often not well characterized.

Research applications

A limited number of research applications are listed in the strain detail for many of the inbred strains. Investigators are strongly encouraged to research the suitability of a mouse model before ordering. The Mouse Phenome Database, an international effort to collect phenotypic data on commonly used and genetically diverse inbred mouse strains, is a valuable resource. It contains detailed characterizations of a wide array of biochemical and behavioral phenotypes for 40 commonly used and genetically diverse inbred mouse strains; it includes hundreds of measurements for phenotypes relevant to human health, including atherosclerosis, gallstones, alcoholism, hypertension, osteoporosis, airway hyperreactivity, pain responses, blood, neurological, behavioral, and sensory disorders, and toxicity to environmental pollutants; it is continually updated with data generated by contributing scientists.

Helpful hints for understanding inbred strain and gene nomenclature 

The parent strain designation of an inbred strain name may consist of capital letters, combinations of letters and numbers, or numbers only (e.g., DBA, C57BL, and 129). Related inbred strains, strains that have a common origin and separated before F20, are given symbols that indicate this relationship (e.g., NZB and NZW; NOD and NON). Substrains are designated by the name of the parent strain followed by a forward slash and a substrain symbol that may be a number and/or the Laboratory Registration Code of the individual or institution that maintains or generated the substrain. For example, DBA/1J, DBA/1LacJ, and DBA/2J are substrains of DBA: the numbers 1 and 2 identify the substrains, Lac is the laboratory code for Laboratory Animal Center at Carshalton, U.K., and J is the laboratory code for The Jackson Laboratory. Because genetic differences in successive substrains accumulate, so do the substrain symbols: A/HeJ is a substrain held first by Heston (He) and now maintained at The Jackson Laboratory (J).

For more detailed information on mouse strain nomenclature, consult the following:

Revised nomenclature for strain 129 mice

A large degree of genetic diversity among 129 substrains was recently identified by scientists at The Jackson Laboratory (Simpson et al., Nat Genetics 16:19-27, 1997), and subsequently by investigators at Case Western Reserve University (Threadgill et al., Mamm Genome 8:390-393, 1997). Because of the importance of 129 mice in creating "knockout" and other targeted mutant mice, the International Committee on Standardized Genetic Nomenclature for Mice introduced a new nomenclature to distinguish different 129 parental lines and related 129 strains.

The overall result is a nomenclature that specifies groups of strains related by their common parental lineage. The major parental lineages include:

  • 129 strains derived from the original parent strain (designated by the letter P)
  • 129 strains derived from a congenic strain made by outcrossing to introduce the steel mutation (designated by the letter S)
  • 129 strains derived from the 129 congenic that originally carried the teratoma mutation (designated by the letter T).

The numbers following the letters (e.g., P3) distinguish the different 129 parent strains within each lineage.

These nomenclature changes affect the strain names for inbred 129 mice and all mice carrying transgenes, or spontaneous or targeted mutations on a 129 background.

Many targeted mutations (e.g., "knockouts") are maintained on a mixture of C57BL/6 and a particular 129 strain. This mixed genetic background was previously designated simply B6,129 and subsequently B6;129. Strain names have been revised, e.g., B6;129P or B6;129S, distinguishing between 129 strains of the parental (P) or steel (S) lineages.

The exact origin and breeding history of some spontaneous and targeted mutations maintained on either a 129 background or mixed B6;129 is unknown. Therefore, substrain information has been eliminated from some strain names, and they are designated simply 129 or B6;129.

Two papers (Simpson et al., 1997; Threadgill et al., 1997) have shown that there is substantial genetic variation among substrains of this important inbred strain. Some of this has apparently arisen as a result of genetic contamination, and the rest appears to be due to residual heterozygosity and/or "contaminant" alleles introduced during various backcrossing programs such as in the production of congenic strains carrying steel and susceptibility to teratomas.

Correct identification and designation of substrains is essential if the genotype of the mouse strain is to be matched accurately with an appropriate embryonic stem cell line in the development of "knockout" strains. Unfortunately, current nomenclature makes this difficult. Thus substrains 129/SvJ and 129/SvJae are very different, but this is not immediately obvious even to someone with a good understanding of nomenclature rules. Moreover, some substrains can only be accurately identified using nomenclature involving quite complex gene symbols. Thus, in view of the widespread use of these strains by people with little understanding of genetic nomenclature, it seems sensible to introduce new, simpler, nomenclature which will minimize future misunderstandings particularly as investigators have sometimes referred to different substrains as simply "129," adding further confusion.

The new nomenclature

The following new nomenclature has been approved by the Committee on Standardized Genetic Nomenclature for Mice. The aim is to provide short symbols that distinguish different substrains when they are abbreviated from the frequently long and complicated substrain symbols, either in common usage or in manuscripts. The new nomenclature is based on the substrains identified and defined in terms of microsatellite markers by Simpson et al., (1997). A letter and a number have been introduced in front of the slash that will unequivocally identify each of the substrains. The letter is either P, S, T or X indicating whether it is a "Parental," "Steel," "Ter" (i.e. susceptible to teratomas) or a genetically contaminated "X" substrain [See JAX® Notes No. 481, Feb. 2001], respectively. A number will be used to differentiate between substrains within each grouping, working from left to right in Fig. 2 of Simpson et al., (1997).

All existing substrain symbols and gene symbols will be retained. The only change is the introduction of a letter and a number in front of the slash. A genuine congenic strain such as 129/ReJ-Lama2 dy will take the strain designation of its partner, i.e. it will be designated 129P1/ReJ-Lama2 dy. This nomenclature change is equivalent to that used to distinguish between RIII and RIIIS, where the latter differs substantially from the former. Table 1 shows the approved new nomenclature for each substrain. Note that 129/Sv (000094), which exists as frozen embryos and has been discovered to be heterozygous at many loci, has not been included on this list as it is clearly not an inbred strain.

129/SvEmsJ (002065) and 129/SvEms (002064) are presumed to be genetically identical. [129S1/SvImJ (002448) was derived from 000090, 129S1/Sv-+p + Tyr-c Kitl Sl-J/+ (formerly Mgf Sl-J/+; see JAX® Notes No. 481, Feb. 2001) in 1995 by selectively breeding out the steel Jackson mutation. Therefore, except for the region surrounding Kitl on Chr 10, these two strains are genetically identical. Designated 129S3/SvImJ in 1999 (Festing et al. 1999), 002448 was renamed in February, 2001 to emphasize its relationship to 129S1/Sv-+p + Tyr-c Kitl Sl-J /+.]

Table 1. New nomenclature for strain 129 mice [modified to incorporate 129S3 to 129S1 change]

Abbreviated
designation
Full designation Former designation Jackson
Laboratory
stock
number

129P1-Lama2dy

129P1/ReJ-Lama2dy

129/ReJ-Lama2dy

000641

129P1

129P1/ReJ

129/ReJ

001137

129P2

129P2/OlaHsd

129/OlaHsd

na

129P3

129P3/J

129/J

000690

129X1

129X1/SvJ

129/SvJ

000691

129S1

129S1/Sv-+p+Tyr-cKitlSl-J/+

129/Sv-+p+Tyr-c+MgfSl-J/+

000090

129S1

129S1/SvImJ

129S3/SvImJ (formerly 129/SvImJ, 129/Sv-+p+Tyr-c+Mgf-Sl/J)

002448

129S2

129S2/SvPas

129/SvPas

na

129S4

129S4/SvJae

129/SvJae

na

129S5

129S5/SvEvBrd

129/SvEvBrd

na

129S6

129S6/SvEvTac

129/SvEvTac

na

129S7

129S7/SvEvBrd-Hprtb-m2

129/SvEvBrd-Hprtb-m2

na

129S8

129S8/SvEv@J-Gpi1c Hprtb-m2

129/SvEv-Gpi1c Hprtb-m2 @J (formerly 129/SvEv -Hprtb-m2)

002027

129T1

129T1/Sv-+p Tyrc-ch Ter/+@Na

129/Sv-+p Tyrc-ch Ter/+@Na

na

129T2

129T2/SvEms

129/SvEms (formerly 129/SvEms-+Ter?)

002064

129T2

129T2/SvEmsJ

129/SvEmsJ (formerly 129/SvEms-+Ter?/J)

002065

References

[Festing MFW. Inbred strains of mice. Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, Maine. World Wide Web (URL: http://www.informatics.jax.org/). (March, 1999).]

Simpson E. M., Linder C. C., Sargent E. E., Davisson M. T., Mobraaten L. E., and Sharp J. J. (1997) Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice. Nature Genet. 16, 19-27.

Threadgill D. W., Yee D., Matin A., Nadeau J. H., and Magnuson T. (1997) Genealogy of the 129 inbred strains: 129/SvJ is a contaminated inbred strain. Mamm. Genome 8:390-393.

Nnt mutation and function

Nnt mutation

  • Mice with Nnt mutations, such as C57BL6/J (B6J), have a normal, healthy lifespan with no overt abnormalities.
  • The Nnt mutation was detected in 2006 when QTL analysis revealed it correlated with robust weight gain and impaired glucose tolerance in B6J mice fed a high-fat (60 kcal%) diet in a diet-induced-obesity (DIO) study (Freeman et al. Diabetes 2006). 
  • Mutations in Nnt have not been linked to human disease. Given the increased weight gain of B6J in response to a high-fat diet, Nnt mutations may be correlated to abnormalities in glucose homeostasis in humans.

Nnt function

The nicotinamide nucleotide transhydrogenase (Nnt) gene encodes a mitochondrial protein that catalyzes production of NADPH, which participates in ATP synthesis. The normal lifespan of the B6J suggests that Nnt is not critical for normal cellular function.

The importance of mutations in biomedical research

  • A mouse without mutations is not a model of human disease. A spectrum of mutations gives each strain its unique phenotypic profile. Nnt is one mutation that contributes to the unique genetic profile of the B6J, the most published and widely used mouse model in biomedical research.
  • The B6J and B6NJ are part of a unique genetic stability program (GSP) (Taft et al. 2006) to minimize genetic drift, maintain unique phenotypes, and ensure data reproducibility across generations of scientific researchers.

Frequently asked questions: The Nnt Mutation in C57BL/6J

The identification of the nicotinamide nucleotide transhydrogenase (Nnt) deletion in C57BL/6J (B6/J) has led many investigators to inquire about how this mutation may affect the phenotype of their mutant mice.

What is the Nnt mutation in the B6/J?

A spontaneous deletion eliminating exons 7-11 in the Nnt gene arose in B6/J sometime between 1976 and 1984.

What is the function of the Nnt gene?

The Nnt gene encodes a mitochondrial protein that catalyzes production of NADPH, which participates in ATP synthesis.

What effect does the Nnt mutation have in mice?

B6/J mice have a normal lifespan, and manifest no overt abnormalities indicating that Nnt is not critical for normal physiological function. The mutation has been linked to more robust weight gain on a high-fat diet.

Are B6/J mice diabetic as a consequence of the Nnt deletion?

No. B6/J mice show moderately impaired glucose clearance and resting glucose levels slightly higher then wildtype Nnt mice; however, glucose levels are below the diabetic threshold.

Does Nnt affect B6/J response to diet-induced obesity (DIO)?

B6/J males on a 60kcal % fat diet for 14 weeks, weighed more, had higher non-fasting plasma glucose levels, and were more severely glucose intolerant than C57BL/6NJ (B6/NJ) males, which are wild-type for the Nnt allele. 

Is the Nnt deletion required for a robust DIO response?

No. B6/J males do respond more robustly to DIO; however, B6/NJ mice develop DIO, and NON/ShiLtJ (also with a wild-type Nnt) males are even more DIO-responsive. View a DIO strain comparison article.

Which B6 strain is best for my studies, the B6/J strain or its substrain the B6/NJ?

Using a consistent strain background will promote generation of more consistent data. The B6/J is the most published, best characterized mouse model available and has been the background of choice for thousands of genetically engineered mice. Also consider that the genotypic and phenotypic profiles of the B6/J and B6/NJ are different and one may be advantageous over the other for some studies. The B6/J, for example, gains weight faster on a high-fat diet and is considered a desirable trait for many metabolic studies. Review the literature and consider what backgrounds have been used in your area of research or consider trying both strains if you are doing a pilot study. Both the B6/J and the B6/NJ are available from the Jackson Laboratory and are part of our unique Genetic Stability Program to drastically reduce genetic drift.

Do researchers need to test for the Nnt mutation in their mouse models?

Not unless you have specific scientific-based reasons for ensuring you have a functional Nnt gene. The Nnt mutation does not have adverse effects on the lifespan or integrity of the B6/J mouse. In fact, the B6/J is known for its longevity compared to other inbred strains. Every mouse model, including the B6/J and B6/NJ, is genetically distinct with known phenotypic characteristics that make it useful in a wide variety of research areas.

How does The Jackson Laboratory limit genetic drift in their most popular strains?

Our Genetic Stability Program (GSP) ensures genetic integrity and limits genetic drift of JAX® Mice. For details, see our Genetic Stability Program website.

References

Freeman HC, Hugill A, Dear NT, Ashcroft FM, Cox RD. 2006. Deletion of Nicotinamide Nucleotide Transhydrogenase: A New Quantitative Trait Locus Accounting for Glucose Intolerance in C57BL/6J Mice. Diabetes 55(7):2153-6. [PubMed: 16804088].

Taft RA, Davisson M and Wiles MV. 2006. Know thy mouse. Trends Genet 22(12):649-53. [PubMed: 17007958].