Bulk segregant analysis reveals environment x genotype interactions determining malaria parasite growth

Abstract

What genes determine growth and nutrient utilization in asexual blood-stage malaria parasites? Competition experiments between a lab-adapted African parasite (NF54), and a recently isolated Asian parasite (NHP4026) reveal contrasting outcomes in different media: NF54 outcompetes NHP4026 in media containing human serum, while NHP4026 outcompetes NF54 in media containing AlbuMAX, a lipid-rich bovine serum formulation. We conducted parasite genetic crosses and compared genome-wide allele frequency changes in progeny populations cultured in media containing serum or AlbuMAX: this bulk segregant analysis (BSA) reveals three quantitative trait loci (QTL) underlying differential growth. The strongest QTL (chromosome 13) contains EBA-140: competition experiments between EBA-140-knockout and isogenic wildtype parasites showed fitness reversals in the two media types, validating this locus as the causative gene. These results (i) demonstrate the effectiveness of BSA for dissecting fitness traits in Plasmodium falciparum, and (ii) reveal an intimate link between red blood cell invasion and nutrient composition of growth media.