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

Ellen M Leffler, Gavin Band, George B J Busby, Katja Kivinen, Quang Si Le, Geraldine M Clarke, Kalifa A Bojang, David J Conway, Muminatou Jallow, Fatoumatta Sisay-Joof, Edith C Bougouma, Valentina D Mangano, David Modiano, Sodiomon B Sirima, Eric Achidi, Tobias O Apinjoh, Kevin Marsh, Carolyne M Ndila, Norbert Peshu, Thomas N WilliamsChris Drakeley, Alphaxard Manjurano, Hugh Reyburn, Eleanor Riley, David Kachala, Malcolm Molyneux, Vysaul Nyirongo, Terrie Taylor, Nicole Thornton, Louise Tilley, Shane Grimsley, Eleanor Drury, Jim Stalker, Victoria Cornelius, Christina Hubbart, Anna E Jeffreys, Kate Rowlands, Kirk A Rockett, Chris C A Spencer, Dominic P Kwiatkowski, Malaria Genomic Epidemiology Network

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalScience
Volume356
Issue number6343
DOIs
Publication statusPublished - 18 May 2017

Keywords

  • Adult
  • Africa South of the Sahara
  • Child
  • DNA Copy Number Variations
  • Disease Resistance
  • Erythrocytes
  • Gene Frequency
  • Genome, Human
  • Glycophorin
  • Host-Parasite Interactions
  • Humans
  • Malaria, Falciparum
  • Models, Molecular
  • Protein Structure, Secondary
  • Receptors, Cell Surface
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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