Resistance to malaria through structural variation of red blood cell invasion receptors
Author:
Leffler Ellen M.ORCID, Band Gavin, Busby George B.J.ORCID, Kivinen Katja, Si Le Quang, Clarke Geraldine M.ORCID, Bojang Kalifa A., Conway David J., Jallow Muminatou, Sisay-Joof Fatoumatta, Bougouma Edith C., Mangano Valentina D., Modiano David, Sirima Sodiomon B., Achidi Eric, Apinjoh Tobias O., Marsh Kevin, Ndila Carolyne M., Peshu Norbert, Williams Thomas N., Drakeley Chris, Manjurano Alphaxard, Reyburn Hugh, Riley Eleanor, Kachala David, Molyneux Malcolm, Nyirongo Vysaul, Taylor Terrie, Thornton Nicole, Tilley Louise, Grimsley Shane, Drury Eleanor, Stalker Jim, Cornelius Victoria, Hubbart ChristinaORCID, Jeffreys Anna E.ORCID, Rowlands Kate, Rockett Kirk A.ORCID, Spencer Chris C.A., Kwiatkowski Dominic P.,
Abstract
AbstractPlasmodium falciparuminvades 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 genesGYPAandGYPB. We find that a nearby reported association with severe malaria is explained by a complex structural variant that involves the loss ofGYPBand 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 toP. falciparummalaria.
Publisher
Cold Spring Harbor Laboratory
|
|