129X1/SvJ genetically contaminated. What does that really mean?

In a series of strain name changes, strain 129/SvJ (Stock No. 000691) became 129X1/SvJ (Festing et al., 1999). The name change reflects a genetic contamination that occurred early in its history (Simpson et al., 1997; Threadgill et al., 1997).

What is the nature of this contamination, and how does it affect the model’s use?

129X1/SvJ mice were transferred from the laboratory of Dr. Roy Stevens (Sv) at The Jackson Laboratory to the production colonies in 1982. Historical data and genetic analysis indicate that an accidental outcrossing of 129X1/Sv occurred prior to that transfer, sometime between 1977 and 1978.

In 1979 Dr. Stevens reported a mutation in coat color from A^w to a (white-bellied agouti to nonagouti) in his 129/Sv substrain. This change at the agouti locus would only be apparent when outcrossing the strain. This is because 129X1/SvJ are carrying both the pink-eyed dilution and tyrosinase recessive mutations (p Tyr^c-ch/p Tyr^c), making their coat color either albino or light chinchilla. A mutation from A^w to a now seems improbable given the molecular structure and postulated evolution of agouti alleles (Bultman et al., 1994). Skin graft rejection and SSLP (simple sequence length polymorphism) data analysis comparing 129X1/SvJ mice to other 129 strains support the genetic contamination hypothesis; however the contaminating strain could not be determined by genetic analysis (Simpson et al., 1997).

Unfortunately, the genetic differences present in 129X1/Sv mice and other genetically diverse 129 strains did not result in changes in the protein markers normally used to ensure genetic integrity (see Simpson et al., 1997 for a complete list). Although all 129 strains tested had a major histocompatibility complex haplotype of b (H2^b), dramatic skin graft rejection occurred between some 129 strains (Simpson et al., 1997).

Since their transfer to the production colonies of The Jackson Laboratory, 129X1/SvJ mice have been strictly inbred and have not been subject to any accidental or intentional outcrossings. All data analysis (including a genome wide scan with SSLP DNA markers) indicates that the strain is currently completely inbred and is not segregating for any detectable loci (except the forced heterozygosity of alleles at the tyrosinase locus that is characteristic of both 129X1/SvJ and 129P3/J).

Despite its early history, 129X1/SvJ has been widely used in a large number of experiments and is the strain of choice when using certain embryonic stem (ES) cell lines. No differences have been detected between the 129X1/SvJ and the RW-4 ES cell line derived from it. In addition, the R1 ES cell line was derived from a cross between 129X1/SvJ and 129S1/Sv-+^p+^Tyr-c Kitl^Sl-J/+ strains. It is important to note that both of these ES cell lines were created in the early 1990s, and analysis confirms the absence of genetic heterogeneity between the ES cell lines and the parental strains (Simpson et al., 1997).

The Jackson Laboratory regularly distributes seven different 129 strains, most of which have been used in creating genetically targeted mutant mice (see Table 1).

For more information about the revised nomenclature of 129 mice please refer to JAX Bulletin No. 1 (June 30, 1999).

Table 1: Origins of ES cell lines

References

Authors in bold indicate Jackson Laboratory scientists

• Bultman SJ, Klebig ML, Michaud EJ, Sweet HO, Davisson MT, Woychik RP. 1994. Molecular analysis of reverse mutations from nonagouti (a) to black-and-tan (a(t)) and white-bellied agouti (Aw) reveals alternative forms of agouti transcripts. Genes Dev 8:481-490.
• Festing MF, Simpson EM, Davisson MT, Mobraaten LE. 1999. Revised nomenclature for strain 129 mice. Mamm Genome 10:836.
• Simpson EM, Linder CC, Sargent EE, Davisson MT, Mobraaten LE, Sharp J. 1997. Genetic variation among 129 substrains and its importance for 'targeted mutagenesis' in mice. Nat Genet 16:19-27.
• Stevens LC.1979. Mouse News Lett (companion issue Inbred Strains of Mice) 61:38-39.
• Threadgill DW, Yee D, Matin A, Nadeau JH, Magnuson T. 1997. Genealogy of the 129 inbred strains: 129/SvJ is a contaminated inbred strain. Mamm Genome 8:390-393.