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Susceptibility to lethal cerebral malaria is regulated by epistatic interaction between chromosome 4 (Berr6) and chromosome 1 (Berr7) loci in mice

A Corrigendum to this article was published on 24 October 2013

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 Berr6. 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.

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Acknowledgements

This work was supported by a Team Grant to PG and SMV from the Canadian Institutes of Health Research (CIHR Team in ENU mutagenesis and infectious diseases). PG is supported by a James McGill Professorship award. SMV is supported by the Canada Chairs Research Program. RvB is supported by a Neuroinflammation CIHR Strategic Training Program. The authors are indebted to Patricia D’Arcy, Geneviève Perreault, Nadia Prud’homme, Adam Li, Jean-Daniel Castonguay and Susan Gauthier for expert technical assistance.

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Torre, S., van Bruggen, R., Kennedy, J. 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 14, 249–257 (2013). https://doi.org/10.1038/gene.2013.16

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