Identification of a malaria new susceptibility locus (Char4) in recombinant congenic strains of mice

The genetic component of susceptibility to malaria is complex, both in huma ns and in the mouse model of infection. Two murine loci on chromosomes 8 (P chr/Char2) and 9 (Char1) have previously been mapped in F-2 crosses, and pl ay an important role in regulating blood parasitemia and survival to infect ion with Plasmodium chabaudi. These loci explain only part of the interstra in phenotypic variance, and their penetrance and expressivity vary in diffe rent inbred strains. Novel loci regulating response to P. chabaudi infectio n were investigated by using an alternative strategy based on a newly deriv ed set of AcB/BcA recombinant congenic strains bred from malaria-susceptibl e A/J (A) and resistant C57BL/6J (B6). One of the AcB strains, AcB55, is sh own to be highly resistant to infection despite 83% susceptible A genomic c omposition, including susceptibility alleles at Char1 and Pchr/Char2. Early onset of parasite clearance in AcB55 is associated with lower peak parasit emia and absence of mortality. Linkage analysis in an informative (AcB55 x A)F-2 population, using peak parasitemia as a quantitative trait, located a new B6-derived resistance focus on chromosome 3 (lod score = 6.57) that we designate Char4. A second, suggestive linkage on chromosome 10 (lod score = 2.53) shows additive effect with Char4 on peak parasitemia. Char4 maps to a Small congenic B6 fragment in AcB55 that should facilitate the search fo r candidate genes. Our findings provide an entry point for parallel associa tion studies in humans between the syntenic 4q21-4q25 region and susceptibi lity to disease in endemic areas of malaria.