PT - JOURNAL ARTICLE AU - Ellen M. Leffler AU - Gavin Band AU - George B.J. Busby AU - Katja Kivinen AU - Quang Si Le AU - Geraldine M. Clarke AU - Kalifa A. Bojang AU - David J. Conway AU - Muminatou Jallow AU - Fatoumatta Sisay-Joof AU - Edith C. Bougouma AU - Valentina D. Mangano AU - David Modiano AU - Sodiomon B. Sirima AU - Eric Achidi AU - Tobias O. Apinjoh AU - Kevin Marsh AU - Carolyne M. Ndila AU - Norbert Peshu AU - Thomas N. Williams AU - Chris Drakeley AU - Alphaxard Manjurano AU - Hugh Reyburn AU - Eleanor Riley AU - David Kachala AU - Malcolm Molyneux AU - Vysaul Nyirongo AU - Terrie Taylor AU - Nicole Thornton AU - Louise Tilley AU - Shane Grimsley AU - Eleanor Drury AU - Jim Stalker AU - Victoria Cornelius AU - Christina Hubbart AU - Anna E. Jeffreys AU - Kate Rowlands AU - Kirk A. Rockett AU - Chris C.A. Spencer AU - Dominic P. Kwiatkowski AU - Malaria Genomic Epidemiology Network TI - Resistance to malaria through structural variation of red blood cell invasion receptors AID - 10.1101/083634 DP - 2017 Jan 01 TA - bioRxiv PG - 083634 4099 - http://biorxiv.org/content/early/2017/02/10/083634.short 4100 - http://biorxiv.org/content/early/2017/02/10/083634.full AB - Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. Here we analyse whole genome sequence data from worldwide human populations, including 765 new genomes from across sub-Saharan Africa, and identify a diverse array of large copy number variants affecting the host invasion receptor genes GYPA and GYPB. We find that a nearby reported association with severe malaria is explained by a complex structural variant that involves the loss of GYPB and gain of two hybrid genes, each with a GYPB extracellular domain and GYPA intracellular domain. This variant reduces the risk of severe malaria by 40% and has recently risen in frequency in parts of Kenya. We show that the structural variant encodes the Dantu blood group antigen, and therefore a serologically distinct red cell phenotype. These findings demonstrate that structural variation of red blood cell invasion receptors is associated with natural resistance to P. falciparum malaria.