Berr4^WLA/Pas
QTL Variant Detail

Summary

• QTL variant: Berr4^WLA/Pas
• Name: berghei resistance locus 4; WLA/Pas
• MGI ID: MGI:5883258
• QTL: Berr4 Location: Chr4:88982069-88982216 bp Genetic Position: Chr4, Syntenic

Variant origin

• Strain of Specimen: WLA/Pas

Variant description

• Allele Type: QTL

Notes

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

J:220880

The focus of the current study was to further analyze the genetic basis for the control of resistance to Plasmodium berghei ANKA (P. berghei). Plasmodium falciparum is the leading cause of death and is responsible for the more severe forms of malaria, including the neurological syndrome cerebral malaria (CM).

All laboratory and wild-derived inbred strains of mice tested thus far for P. berghei ANKA infection die of experimental cerebral malaria (ECM) or hyperparasitaemia (HP), including the C57BL/6 and the WLA strains used in this study (2005). The C57BL/6 strain is commonly used as a prototype of an ECM susceptible strain. WAL and (WAL x C57BL/6)F1 mice do not show ECM symptoms but invariably die later with high levels of parasitized red blood cells.

219 (WAL/Pas x C57BL/6JRj)F2 mice at 8-12 weeks of age were infected with parasitized erythrocytes (P.berghei ANKA clone 1.49L) by intraperitoneal injection. Neurological symptoms and survival were recorded daily. ECM was diagnosed by clinical signs followed by death. Parasitaemia progression was determined on day 3, day 5,and every day until day 30 post infection using flow cytometry analysis. DNA from the F2 animals was genotyped for 113 microsatellite markers from the WHitehead MIT Center for Genome Research. Evidence for significant genetic linkage to peak parasitaemia and survival time was considered for p-values less than 0.00005. QTL were analyzed using R/QTL software. LOD thresholds were estimated by performing 1000 permutation tests.

The analysis of peak parasitaemia and survival time revealed that the response to malaria in the F2 mice segregated in 3 different phenotypic groups. The majority (159 F2 mice) died between days 11 and 33 due to high levels of parasitaemia similar to WLA and F1 mice.

A second group of 38 F2 mice showed a severe form of disease and died early with low parasitaemia. Eight mice in this second group displayed clear signs of ECM resembling the parental C57BL/6 strain.

A third group of 22 F2 mice survived the infection, representing a new phenotype not observed in either parental strain or any other inbred strain tested. The mice reached limited parasitaemia peaks between days 10 and 14 but were able to clear parasitaemia and cure. The same mice were reinfected one year later and survived the reinfection showing significantly lower peak parasitaemia levels.

QTL analysis revealed that the time of survival in the F2 progeny was associated with 2 loci on Chromosomes 1 and 9.

QTL Berr3, berghei resistance locus 3, mapped to Chromosome 9 with a LOD score of 4.9 at marker D9Mit18. The C57BL/6J allele at this locus appeared to confer increased probability to survival following infection. 26.1% of C57BL/6 homozygotes at D9Mit18 were found to cure from the infection; whereas mice homozygous for the WAL allele died within 35 days postinfection.

The mapping of a QTL on distal Chromosome 1 appeared to confirm a previously reported locus, Berr1 mapped in J:78027 (also mapped using WAL/Pas and C57BL/6JRj mice). In the current study Berr1 mapped with a LOD score of 6.4 at marker D1Mit221. 55% of the F2 mice that died early (before day 13) were homozygous for the C57BL/6J allele at D1Mit221, suggesting that WLA alleles confer resistance to early death post infection.

QTL analysis of the group of mice that died due to hyperparasitaemia (HP) revealed a novel locus controlling survival time on Chromosome 4. QTL Berr4, berghei resistance locus 4, mapped with a LOD score of 3.42 at marker D4Mit27. WLA alleles at this locus appearded to confer extended resistance to HP.

References

• Original: J:220880 Campino S, et al., Genetic control of parasite clearance leads to resistance to Plasmodium berghei ANKA infection and confers immunity. Genes Immun. 2005 Aug;6(5):416-21
• All: 1 reference(s)