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

Zhiqian Li, Yuemei Dong, Lang You, Rodrigo M. Corder, Jemariz Arzobal, Audrey Yeun, Lei Yang, John M. Marshall, George Dimopoulos () and Ethan Bier ()
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Zhiqian Li: University of California, San Diego
Yuemei Dong: Bloomberg School of Public Health
Lang You: University of California, San Diego
Rodrigo M. Corder: University of São Paulo
Jemariz Arzobal: University of California, San Diego
Audrey Yeun: University of California, San Diego
Lei Yang: University of California, San Diego
John M. Marshall: University of California
George Dimopoulos: Bloomberg School of Public Health
Ethan Bier: University of California, San Diego

Nature, 2025, vol. 645, issue 8081, 746-754

Abstract: Abstract 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 FREP1Q 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 FREP1L224 or the putative-refractory FREP1Q224 alleles. The FREP1Q224 allele confers robust resistance to infection by both human and rodent malaria parasites, with negligible fitness costs. The protective FREP1Q224 allele can be efficiently driven into FREP1L224 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.

Date: 2025
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DOI: 10.1038/s41586-025-09283-6

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