Berr8^129S1/SvImJ
QTL Variant Detail

Summary

• QTL variant: Berr8^129S1/SvImJ
• Name: berghei resistance locus 8; 129S1/SvImJ
• MGI ID: MGI:5883301
• QTL: Berr8 Location: Chr4:81222460-81222460 bp Genetic Position: Chr4, Syntenic

Variant origin

• Strain of Specimen: 129S1/SvImJ

Variant description

• Allele Type: QTL

Notes

Mapping and Phenotype information for this QTL, its variants and associated markers

J:220661

The current study reports the chromosomal mapping of a new two-locus system that shows epistatic interaction in controlling resistance to experimental cerebral malaria (ECM).

The breeding scheme to screen for recessive mutations involved crossing mutagenized C57BL/6J (G0) male mice with 129S1/SvImJ (129) or C57BL/10J (B10) (data not shown) female mice. The G1 males were crossed with 129 and the G2 progeny were backcrossed to G1 males generating G3 progeny with several G0 mutations fixed to homozygosity.

In parallel, G1 males were crossed with 129 females and the resulting G2 mice were intercrossed to produce F2S. Infection with parasitized PbA (P.berghei ANKA) erythrocytes was lethal for B6, B10, and 129 by day 8 post infection, and for F1 and F2 animals derived from them.

The appearance of PbA-resistant animals in successive F2S and G3 pedigrees derived from the same G1 male suggested transmission of a novel ECM-protective mutation.

Twenty four ECM-resistant and 42-susceptible mice derived from a subset of Carmelo-derived F2S pedigrees showing segregation of resistant animals were genotyped for 245 informative SNPs capable of distinguishing the B6-129 strains. Analysis of genotyping data by R/qtl software detected highly significant linkage on the distal portion of Chromosome 4.

MGI curators have named the Chr 4 QTL Berr8, berghei resistance locus 8. (Berr6 was previously mapped J:160892 using multiple inbred strains in 2010.) Berr8 mapped to Chr 4 with a LOD score of 6.7 at peak marker rs3708061 (79.6 Mb) in an interval spanning 58-114 Mb. Eighty percent of mice homozygous with the B6 allele were resistant to PbA infection. ECM resistance in Carmelo-derived pedigrees appeared to be determined by a major locus with B6-associated resistance alleles being inherited in a co-dominant fashion. In addition, recombinant haplotypes detected in mice F2-52.42R and F2S-55.29R from the resistant F2S cohort suggested a minimimum physical interval of 18Mb for Berr8, which was defined by markers rs3708061 (79.6Mb) and rs3705454 (97.3 Mb).

A test for the possibility that additional genetic effects might further modulate penetrance and expressivity of the Berr8 genetic effect was investigated using a two-dimensional genome scan. The aim of the scan was to assess the genome-wide contribution of any additional loci on survival in the 3 allelic classes when controlled for Berr8 (AA, AB, BB) as defined by the peak marker rs3708061.

A significant linkage peak was detected on Chromosome 1 with a LOD score of 4.03 at peak marker gnf01.037.906 (41.4 Mb). This QTL was designed Berr7, berghei resistance locus 7.

Combined haplotype analysis in Carmelo F2S mice demonstrated a strong genetic interaction regulating survival of PbA infected mice. In Berr8 heterozygotes, the presence of 129 alleles at Berr7 increased resistance in a dosage dependent fashion, with homozygosity for 129 alleles at Berr7 linked to resistance and homozygosity for B6 alleles linked to susceptibility. The Berr7 genetic effect detected in the Carmelo pedigree was validated in additional unrelated G3 pedigrees that showed linkage of CM resistance to Chr 4.

References

• Original: J:220661 Torre S, et al., Susceptibility to lethal cerebral malaria is regulated by epistatic interaction between chromosome 4 (Berr6) and chromosome 1 (Berr7) loci in mice. Genes Immun. 2013 Jun;14(4):249-57
• All: 1 reference(s)