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Serial backcross analysis of genetic resistance to mousepox, using marker loci for Rmp-2 and Rmp-3
D G Brownstein1, P N Bhatt, L Gras
1Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Abstract:
At least three genes from C57BL/6 mice that mediate dominant resistance to lethal mousepox were isolated and transferred onto a susceptible DBA/2 background. Three [(C57BL/6 x DBA/2)F1 x DBA/2] male mice that survived infection were selected as founders on the basis of different complements of marker loci for two resistance genes, Rmp-2r (Hc1) and Rmp-3r (H-2Db). They were crossed with DBA/2 mice, male progeny were infected with ectromelia virus, and the cycle was repeated with surviving male progeny through seven backcross generations. Two founders carried a marker locus for Rmp-2r or Rmp-3r, and the third carried neither marker locus. Resistance pedigrees were analyzed for passage of marker loci. From the three founders, resistance was passaged through multiple generations, producing backcross lines with intermediate-male-resistance phenotypes (20% resistant). Females of backcross lines with intermediate male resistance had high resistance (> 50%). High-resistance backcross lines (40% male resistance) also developed from the founders that carried marker loci for Rmp-2r and Rmp-3r, and marker loci were passaged through all generations of high resistance but not intermediate-resistance lines. About one-third of all resistant mice in high-resistance lines sired by mice that carried marker loci for Rmp-2r and Rmp-3r did not carry the respective marker locus. In lines that carried Rmp-2r, this was apparently not the result of recombination between Rmp-2r and Hc1, because Rmp-2 was not in the predicted location on chromosome 2 and because mice that did not inherit Hc1 transmitted significantly less male resistance than Hc1-positive mice, although female resistance remained high. These results confirmed that C57BL/6 mice have redundant resistance mechanisms, two of which are controlled at least in part by Rmp-2r and Rmp-3r, and provided evidence for a fourth resistance gene, herein presumptively named Rmp-4, which protects females more than males and which may be epistatic to Rmp-2.
Insights
Researchers identified mouse genes conferring resistance to lethal mousepox. They found that resistance mechanisms are redundant, with specific genes (Rmp-2r, Rmp-3r) and a potential new gene (Rmp-4) playing key roles.
Area of Science:
- Immunology
- Genetics
- Virology
Background:
- Mousepox, a lethal viral infection, poses a significant threat to mouse populations.
- Understanding the genetic basis of resistance is crucial for developing effective countermeasures.
- C57BL/6 mice exhibit resistance to mousepox, while DBA/2 mice are susceptible.
Purpose of the Study:
- To isolate and transfer dominant resistance genes from C57BL/6 mice to DBA/2 mice.
- To investigate the genetic mechanisms underlying resistance to lethal mousepox.
- To identify and characterize novel resistance genes.
Main Methods:
- Genes mediating dominant resistance to mousepox were isolated from C57BL/6 mice.
- These genes were transferred to a susceptible DBA/2 background using selective backcrossing over seven generations.
- Resistance pedigrees were analyzed for the passage of marker loci associated with resistance genes Rmp-2r (Hc1) and Rmp-3r (H-2Db).
Main Results:
- Backcross lines with intermediate male resistance (20% resistant) and high female resistance (>50%) were generated.
- High-resistance backcross lines (40% male resistance) developed from founders carrying Rmp-2r and Rmp-3r marker loci.
- Evidence for a fourth resistance gene (Rmp-4) was found, showing greater protection in females and potential epistasis with Rmp-2.
Conclusions:
- C57BL/6 mice possess redundant resistance mechanisms against mousepox.
- Rmp-2r and Rmp-3r partially control two of these resistance mechanisms.
- A novel gene, Rmp-4, contributes to resistance, particularly in females.