Common host variation drives malaria parasite fitness in healthy human red cells

The replication ofPlasmodium falciparumparasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. The influence of host RBC variation on parasite replication is largely uncharted, aside from a handful of deleterious alleles like sickle cell. Here, we integrated analyses of exome sequencing, RBC phenotyping, and parasite fitness assays on blood from 122 individuals, most with African ancestry. In donors lacking alleles for hemoglobinopathies or G6PD deficiency, RBC phenotypes including size, deformability, and hydration status explained 21-38% of the variation in parasite growth rate. With the addition of non-pathogenic polymorphisms in 14 RBC proteins includingSPTA1, PIEZO1, andATP2B4, our model explained 73-82% of the variation in parasite growth rate. Interestingly, we observed little evidence for divergent selection on this variation between Africans and Europeans. These findings suggest a model in which widespread, non-pathogenic variation in a moderate number of genes strongly modulatesP. falciparumfitness in RBCs.