TY - JOUR T1 - A structural variant encoding hybrid glycophorins is associated with resistance to severe malaria JF - bioRxiv DO - 10.1101/083634 SP - 083634 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 Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/10/26/083634.abstract N2 - Human genetic variation in the region between FREM3 and GYPE was recently reported as associated with resistance to severe malaria in sub-Saharan Africa. By constructing a new imputation reference panel from sequence data with an increased representation of African populations, we show that the signal of association extends across the nearby genes GYPA and GYPB, which encode receptors for erythrocyte invasion by Plasmodium falciparum. Detailed analysis of large copy number variation reveals that the association can be explained by a complex structural variant that has lost GYPB but gained two hybrid genes, each with a GYPB extracellular domain and GYPA intracellular domain. This rearrangement, which is globally rare but carried by one in six children in parts of Kenya, encodes the Dantu blood group antigen, and reduces the risk of severe malaria by up to 40%. These findings provide the first direct evidence of the role malaria has played in shaping the landscape of variation at this polymorphic locus. ER -