Resistance to malaria through structural variation of red blood cell invasion receptors.

Leffler, EMORCID logo; Band, GORCID logo; Busby, GBORCID logo; Kivinen, K; Le, QS; Clarke, GMORCID logo; Bojang, KAORCID logo; Conway, DJORCID logo; Jallow, M; Sisay-Joof, F; +31 more...Bougouma, EC; Mangano, VD; Modiano, D; Sirima, SB; Achidi, E; Apinjoh, TO; Marsh, KORCID logo; Ndila, CMORCID logo; Peshu, N; Williams, TNORCID logo; Drakeley, CORCID logo; Manjurano, A; Reyburn, H; Riley, E; Kachala, D; Molyneux, M; Nyirongo, V; Taylor, TORCID logo; Thornton, NORCID logo; Tilley, L; Grimsley, S; Drury, EORCID logo; Stalker, JORCID logo; Cornelius, V; Hubbart, CORCID logo; Jeffreys, AEORCID logo; Rowlands, KORCID logo; Rockett, KAORCID logo; Spencer, CCORCID logo; Kwiatkowski, DPORCID logo; Malaria Genomic Epidemiology Network and (2017) Resistance to malaria through structural variation of red blood cell invasion receptors. Science (New York, NY), 356 (6343). eaam6393-eaam6393. ISSN 0036-8075 DOI: 10.1126/science.aam6393
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The malaria parasite Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genes GYPA and GYPB We find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss of GYPB and gain of two GYPB-A hybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria.


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