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Chromosome mapping of Rmp-4, a gonad-dependent gene encoding host resistance to mousepox
1Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Abstract:
DBA/2 (D2) mice are susceptible and C57BL/6 (B6) mice are resistant to lethal mousepox. A congenic resistant strain, D2.B6-Rmp-4r (D2.R4), was developed by serially backcrossing male mice that survived ectromelia virus infection with D2 mice, beginning with (B6 x D2)F1 mice. Male D2.R4 mice were at least 300-fold more resistant to lethal mousepox than male D2 mice. Female D2.R4 mice were 100-fold more resistant than male D2.R4 mice and 500-fold more resistant than female D2 mice. Neonatal gonadectomy prevented development of resistance in D2.R4 mice of both sexes. Differences in resistance between strains and between sexes correlated with restriction of virus replication in spleen and liver, but gender differences were less evident in liver than in spleen. High-resolution interval mapping of the 19 autosomes of D2.R4 mice using dispersed informative microsatellites as marker loci revealed a segment of distal chromosome 1 to be of B6 origin. Haplotypes for a marker locus, D1Mit57, from the differential segment were determined in (D2.R4 x D2)F1 x D2 backcross mice, which were then infected with ectromelia virus. Significantly more heterozygotes than homozygotes survived ectromelia virus infection in both sexes. Whereas nearly all surviving males were heterozygotes, 44% of surviving females were homozygotes. These results indicate that resistance in D2.R4 mice is determined by a gonad-dependent gene on distal chromosome 1, provisionally named Rmp-4, and by an ovary-dependent factor that is not genetically linked to Rmp-4.
Insights
Mousepox resistance in DBA/2 mice is linked to a gonad-dependent gene on chromosome 1, named Rmp-4. An additional ovary-dependent factor also contributes to resistance, independent of Rmp-4.
Area of Science:
- Immunology
- Genetics
- Virology
Background:
- DBA/2 (D2) mice are susceptible to lethal mousepox, while C57BL/6 (B6) mice are resistant.
- A congenic resistant strain, D2.B6-Rmp-4r (D2.R4), was developed to study mousepox resistance mechanisms.
Purpose of the Study:
- To identify the genetic basis of mousepox resistance in the D2.R4 congenic strain.
- To investigate the role of sex hormones and genetic factors in conferring resistance to ectromelia virus.
Main Methods:
- Development of a congenic resistant mouse strain (D2.R4) through serial backcrossing.
- High-resolution interval mapping of mouse autosomes using microsatellite markers.
- Analysis of ectromelia virus infection survival rates in different mouse genotypes and sexes, including neonatally gonadectomized mice.
Main Results:
- D2.R4 mice exhibited significantly higher resistance to lethal mousepox compared to D2 mice (300-fold in males, 500-fold in females).
- Neonatal gonadectomy abolished resistance in D2.R4 mice of both sexes, indicating a gonad-dependent mechanism.
- A major resistance locus, provisionally named Rmp-4, was mapped to distal chromosome 1.
- Survival analysis revealed heterozygotes for the D1Mit57 marker had significantly higher survival rates than homozygotes, with sex-specific differences observed.
Conclusions:
- Mousepox resistance in D2.R4 mice is primarily determined by a gonad-dependent gene (Rmp-4) located on distal chromosome 1.
- An additional, unlinked ovary-dependent factor contributes to resistance, particularly in females.
- These findings highlight the complex interplay of genetics and sex hormones in viral immunity.