Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain

Abstract

Malaria is a complex infectious disease in which the host͞parasite interaction is strongly influenced by host genetic factors. The consequences of plasmodial infections range from asymptomatic to severe complications like the neurological syndrome cerebral malaria induced by Plasmodium falciparum in humans and Plasmodium berghei ANKA in rodents. Mice infected with P. berghei ANKA show marked differences in disease manifestation and either die from experimental cerebral malaria (ECM) or from hemolytic anemia caused by hyperparasitemia (HP). A majority of laboratory mouse strains so far investigated are susceptible to ECM; however, a number of wild-derived inbred strains show resistance. To evaluate the genetic basis of this difference, we crossed a uniquely ECM-resistant, wild-derived inbred strain (WLA) with an ECM susceptible laboratory strain (C57BL͞6J). All of the (WLA ؋ C57BL͞6J) F 1 and 97% of the F2 progeny displayed ECM resistance similar to the WLA strain. To screen for loci contributing to ECM resistance, we analyzed a cohort of mice backcrossed to the C57BL͞6J parental strain. A genome wide screening of this cohort provided significant linkage of ECM resistance to marker loci in two genetic regions on chromosome 1 ( 2 ‫؍‬ 18.98, P ‫؍‬ 1.3 ؋ 10 ؊5 ) and on chromosome 11 ( 2 ‫؍‬ 16.51, P ‫؍‬ 4.8 ؋ 10 ؊5 ), being designated Berr1 and Berr2, respectively. These data provide the first evidence of loci associated with resistance to murine cerebral malaria, which may have important implications for the search for genetic factors controlling cerebral malaria in humans.

Allelic penetrance approach as a tool to model two-locus interaction in complex binary traits

“…Finally, it is worth noting that the likelihoods of current and allelic penetrance models are not comparable, because the parameter number among these models is different. Bagot et al (2002) performed a genetic mapping study in mice for the susceptibility to experimental cerebral malaria (ECM) following Plasmodium berghei ANKA infection. A cross was performed between the ECM resistant strain WLA and the ECM susceptible strain C57BL/6J, where F 1 progeny was ECM resistant and was backcrossed with the susceptible parental strain.…”

“…This is a consequence of modeling internal penetrance of recessive alleles at each locus by two allelic penetrances, one for the dominant allele and another for the recessive allele (see Equation (4)). Since the WLA strain was 100% resistant to the disease, while the other strain was not fully susceptible (Bagot et al, 2002), we could avoid overparameterization by assuming that the internal component of penetrance of a recessive phenotype-conferring (or inhibiting) allele follows Equation (4) with p A ¼ 1. In this case, penetrances for all models add up to three parameters: one allelic penetrance for each locus and the external penetrance p ext .…”

“…Despite showing that some current models could fit the data, both Cordell et al (2001) and Bagot et al (2002) were unable to unravel which kind of genetic interaction actually underlies those traits.…”

“…Bagot et al (2002) experienced the same difficulties in a study of the interaction between Berr1 and Berr2 loci in the resistance to experimental cerebral malaria in mice.…”

“…We illustrate the advantage of using the allelic penetrance models with data from an intercross and a backcross experiment on the genetic control of susceptibility of mice following infections with Listeria monocytogenes (Boyartchuk et al, 2001) and Plasmodium berghei (Bagot et al, 2002), respectively. We further show by simulation that allelic penetrance models can generate data that cannot be fitted by current models, and therefore cover at least a different range of genetic interaction.…”