The replication of Plasmodium falciparum parasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. Deleterious alleles like hemoglobin S are well-known to confer strong resistance to malaria, but the effects of common RBC variation are largely undetermined. Here we collected fresh blood samples from 121 healthy donors, most with African ancestry, and performed exome sequencing, detailed RBC phenotyping, and parasite fitness assays. Over one third of healthy donors unknowingly carried alleles for G6PD deficiency or hemoglobinopathies, which were associated with characteristic RBC phenotypes. Among non-carriers alone, variation in RBC hydration, membrane deformability, and volume was strongly associated with P. falciparum growth rate. Common genetic variants in PIEZO1, SPTA1/SPTB, and several P. falciparum invasion receptors were also associated with parasite growth rate. Interestingly, we observed little or negative evidence for divergent selection on non-pathogenic RBC variation between Africans and Europeans. These findings suggest a model in which globally widespread variation in a moderate number of genes and phenotypes modulates P. falciparum fitness in RBCs.
All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 4, and 5 and other raw data and normalization scripts are available at https://github.com/emily-ebel/RBC
Exome Sequencing from Participants in RBC/Malaria StudySequence Read Archive PRJNA683732.
- Elizabeth S Egan
- Elizabeth S Egan
- Emily R Ebel
- Dmitri A Petrov
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: Written informed consent and consent to publish was obtained from each subject and/or their parent as part of a protocol approved by the Stanford University Institutional Review Board (#40479).
- Jenny Tung, Duke University, United States
© 2021, Ebel et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.