Driving a protective allele of the mosquito FREP1 gene to combat malaria

Malaria remains a substantial global health challenge, causing approximately half a million deaths each year¹. The mosquito fibrinogen-related protein 1 (FREP1) is required for malaria parasites to infect the midgut epithelium². The naturally occurring FREP1^Q allele has been reported to prevent parasite infection, while supporting essential physiological functions in the mosquito³. Here we generate congenic strains of Anopheles stephensi, edited to carry either the parasite-susceptible FREP1^L224 or the putative-refractory FREP1^Q224 alleles. The FREP1^Q224 allele confers robust resistance to infection by both human and rodent malaria parasites, with negligible fitness costs. The protective FREP1^Q224 allele can be efficiently driven into FREP1^L224 mosquito populations using a novel linked allelic-drive system that selectively replaces the L224 codon with the parasite-refractory Q224 allele, thereby rendering populations refractory to parasite infection. This antimalaria drive system provides a novel genetic approach to aid in malaria elimination efforts.