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

View ORCID ProfileEllen M. Leffler, Gavin Band, View ORCID ProfileGeorge B.J. Busby, Katja Kivinen, Quang Si Le, View ORCID ProfileGeraldine 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. Williams, Chris 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, View ORCID ProfileChristina Hubbart, View ORCID ProfileAnna E. Jeffreys, Kate Rowlands, View ORCID ProfileKirk A. Rockett, Chris C.A. Spencer, Dominic P. Kwiatkowski, Malaria Genomic Epidemiology Network
doi: https://doi.org/10.1101/083634
Ellen M. Leffler
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
2Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
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  • ORCID record for Ellen M. Leffler
Gavin Band
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
2Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
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George B.J. Busby
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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Katja Kivinen
2Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
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Quang Si Le
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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Geraldine M. Clarke
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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  • ORCID record for Geraldine M. Clarke
Kalifa A. Bojang
3Medical Research Council Unit, Atlantic Boulevard, Fajara, PO Box 273, The Gambia
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David J. Conway
3Medical Research Council Unit, Atlantic Boulevard, Fajara, PO Box 273, The Gambia
4Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
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Muminatou Jallow
3Medical Research Council Unit, Atlantic Boulevard, Fajara, PO Box 273, The Gambia
5Royal Victoria Teaching Hospital, Independence Drive, PO Box 1515, Banjul, The Gambia
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Fatoumatta Sisay-Joof
3Medical Research Council Unit, Atlantic Boulevard, Fajara, PO Box 273, The Gambia
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Edith C. Bougouma
6Centre National de Recherche et de Formation sur le Paludisme (CNRFP), 01 BP 2208 Ouagadougou 01, Burkina Faso
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Valentina D. Mangano
7University of Rome La Sapienza, Piazzale Aldo Moro 5, 00185 Rome, Italy
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David Modiano
7University of Rome La Sapienza, Piazzale Aldo Moro 5, 00185 Rome, Italy
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Sodiomon B. Sirima
6Centre National de Recherche et de Formation sur le Paludisme (CNRFP), 01 BP 2208 Ouagadougou 01, Burkina Faso
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Eric Achidi
8Department of Medical Laboratory Sciences, University of Buea, PO Box 63, Buea, South West Region, Cameroon
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Tobias O. Apinjoh
9Department of Biochemistry & Molecular Biology, University of Buea, PO Box 63, Buea, South West Region, Cameroon
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Kevin Marsh
10KEMRI-Wellcome Trust Research Programme, PO Box 230-80108, Kilifi, Kenya
11Nuffield Department of Medicine, NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, UK
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Carolyne M. Ndila
10KEMRI-Wellcome Trust Research Programme, PO Box 230-80108, Kilifi, Kenya
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Norbert Peshu
10KEMRI-Wellcome Trust Research Programme, PO Box 230-80108, Kilifi, Kenya
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Thomas N. Williams
10KEMRI-Wellcome Trust Research Programme, PO Box 230-80108, Kilifi, Kenya
12Faculty of Medicine, Department of Medicine, Imperial College, Exhibition Road, London SW7 2AZ, UK
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Chris Drakeley
13Joint Malaria Programme, Kilimanjaro Christian Medical Centre, PO box 2228, Moshi, Tanzania.
14Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
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Alphaxard Manjurano
13Joint Malaria Programme, Kilimanjaro Christian Medical Centre, PO box 2228, Moshi, Tanzania.
14Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
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Hugh Reyburn
13Joint Malaria Programme, Kilimanjaro Christian Medical Centre, PO box 2228, Moshi, Tanzania.
14Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
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Eleanor Riley
14Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
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David Kachala
15Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital, College of Medicine, PO Box 30096, Chichiri, Blantyre 3, Malawi
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Malcolm Molyneux
15Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital, College of Medicine, PO Box 30096, Chichiri, Blantyre 3, Malawi
16Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
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Vysaul Nyirongo
15Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital, College of Medicine, PO Box 30096, Chichiri, Blantyre 3, Malawi
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Terrie Taylor
17Blantyre Malaria Project, Queen Elizabeth Central Hospital, College of Medicine, PO Box 30096, Chichiri, Blantyre 3, Malawi.
18College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA
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Nicole Thornton
19International Blood Group Reference Laboratory, NHS Blood and Transplant, 500 North Bristol Park, Filton, Bristol BS34 7QH, UK
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Louise Tilley
19International Blood Group Reference Laboratory, NHS Blood and Transplant, 500 North Bristol Park, Filton, Bristol BS34 7QH, UK
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Shane Grimsley
19International Blood Group Reference Laboratory, NHS Blood and Transplant, 500 North Bristol Park, Filton, Bristol BS34 7QH, UK
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Eleanor Drury
2Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
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Jim Stalker
2Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
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Victoria Cornelius
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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Christina Hubbart
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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  • ORCID record for Christina Hubbart
Anna E. Jeffreys
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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Kate Rowlands
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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Kirk A. Rockett
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
2Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
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Chris C.A. Spencer
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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  • For correspondence: spencer@well.ox.ac.uk dominic.kwiatkowski@sanger.ac.uk
Dominic P. Kwiatkowski
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
2Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
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  • For correspondence: spencer@well.ox.ac.uk dominic.kwiatkowski@sanger.ac.uk
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
2Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
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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.

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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. Williams, Chris 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
bioRxiv 083634; doi: https://doi.org/10.1101/083634
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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. Williams, Chris 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
bioRxiv 083634; doi: https://doi.org/10.1101/083634

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