@article {Leffler083634, author = {Ellen M. Leffler and Gavin Band and George B.J. Busby and Katja Kivinen and Quang Si Le and Geraldine M. Clarke and Kalifa A. Bojang and David J. Conway and Muminatou Jallow and Fatoumatta Sisay-Joof and Edith C. Bougouma and Valentina D. Mangano and David Modiano and Sodiomon B. Sirima and Eric Achidi and Tobias O. Apinjoh and Kevin Marsh and Carolyne M. Ndila and Norbert Peshu and Thomas N. Williams and Chris Drakeley and Alphaxard Manjurano and Hugh Reyburn and Eleanor Riley and David Kachala and Malcolm Molyneux and Vysaul Nyirongo and Terrie Taylor and Nicole Thornton and Louise Tilley and Shane Grimsley and Eleanor Drury and Jim Stalker and Victoria Cornelius and Christina Hubbart and Anna E. Jeffreys and Kate Rowlands and Kirk A. Rockett and Chris C.A. Spencer and Dominic P. Kwiatkowski and Malaria Genomic Epidemiology Network}, title = {Resistance to malaria through structural variation of red blood cell invasion receptors}, elocation-id = {083634}, year = {2017}, doi = {10.1101/083634}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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.}, URL = {https://www.biorxiv.org/content/early/2017/02/10/083634}, eprint = {https://www.biorxiv.org/content/early/2017/02/10/083634.full.pdf}, journal = {bioRxiv} }