title: Susceptibility to lethal cerebral malaria is regulated by epistatic interaction between chromosome 4 (Berr6) and chromosome 1 (Berr7) loci in mice.
abstract: In humans, cerebral malaria is a rare but often lethal complication of infection with Plasmodium parasites, the occurrence of which is influenced by complex genetic factors of the host. We used a mouse model of experimental cerebral malaria (ECM) with Plasmodium berghei ANKA to study genetic factors regulating appearance of neurological symptoms and associated lethality. In a genome-wide screen of N-ethyl-N-nitrosourea-mutagenized mice derived from C57BL/6J (B6) and 129S1/SvImJ (129) mouse strains, we detected a strong interaction between the genetic backgrounds of these strains, which modulates ECM resistance. We have mapped a major gene locus to central chromosome 4 (log of the odds (LOD) 6.7; 79.6-97.3 Mb), which we designate Berr8. [corrected]. B6 alleles at Berr6 are associated with resistance, and are inherited in a co-dominant fashion. In mice heterozygous for Berr6 B6/129 alleles, resistance to ECM is strongly modulated by a second locus, Berr7, that maps to the proximal portion of chromosome 1 (LOD 4.03; 41.4 Mb). 129 alleles at Berr7 are associated with ECM resistance in a dosage-dependent fashion. Results are discussed in view of the possible role of this two-locus system in susceptibility to unrelated inflammatory conditions in mice and humans.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Torre
authors.forename: R
authors.initials: R
authors.lastname: van Bruggen
authors.forename: J M
authors.initials: JM
authors.lastname: Kennedy
authors.forename: J
authors.initials: J
authors.lastname: Berghout
authors.forename: S E
authors.initials: SE
authors.lastname: Bongfen
authors.forename: P
authors.initials: P
authors.lastname: Langat
authors.forename: M
authors.initials: M
authors.lastname: Lathrop
authors.forename: S M
authors.initials: SM
authors.lastname: Vidal
authors.forename: P
authors.initials: P
authors.lastname: Gros
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics*; D060467:Disease Resistance / Q000235:genetics; D004843:Epistasis, Genetic; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D016779:Malaria, Cerebral / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D040641:Quantitative Trait Loci