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

Malaria Genomic Epidemiology Network; 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

doi:10.1126/science.aam6393

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

Malaria Genomic Epidemiology Network, 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 PeshuThomas 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

Research output: Contribution to journal › Article › peer-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 language	English
Journal	Science
Volume	356
Issue number	6343
DOIs	https://doi.org/10.1126/science.aam6393
Publication status	Published - 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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10.1126/science.aam6393

Resistance to malaria through structural variation
This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on 16 Jun 2017: Vol. 356, Issue 6343, eaam6393 DOI: 10.1126/science.aam6393
Accepted author manuscript, 3.3 MB

Cite this

Malaria Genomic Epidemiology Network, Leffler, E. M., Band, G., Busby, G. B. J., Kivinen, K., Le, Q. S., Clarke, G. M., Bojang, K. A., Conway, D. J., Jallow, M., Sisay-Joof, F., Bougouma, E. C., Mangano, V. D., Modiano, D., Sirima, S. B., Achidi, E., Apinjoh, T. O., Marsh, K., Ndila, C. M., ... Kwiatkowski, D. P. (2017). Resistance to malaria through structural variation of red blood cell invasion receptors. Science, 356(6343). https://doi.org/10.1126/science.aam6393

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title = "Resistance to malaria through structural variation of red blood cell invasion receptors",

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.",

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",

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

note = "Copyright {\textcopyright} 2017, American Association for the Advancement of Science.",

year = "2017",

month = may,

day = "18",

doi = "10.1126/science.aam6393",

language = "English",

volume = "356",

journal = "Science",

issn = "0036-8075",

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Malaria Genomic Epidemiology Network, Leffler, EM, Band, G, Busby, GBJ, Kivinen, K, Le, QS, Clarke, GM, Bojang, KA, Conway, DJ, Jallow, M, Sisay-Joof, F, Bougouma, EC, Mangano, VD, Modiano, D, Sirima, SB, Achidi, E, Apinjoh, TO, Marsh, K, Ndila, CM, Peshu, N, Williams, TN, Drakeley, C, Manjurano, A, Reyburn, H, Riley, E, Kachala, D, Molyneux, M, Nyirongo, V, Taylor, T, Thornton, N, Tilley, L, Grimsley, S, Drury, E, Stalker, J, Cornelius, V, Hubbart, C, Jeffreys, AE, Rowlands, K, Rockett, KA, Spencer, CCA & Kwiatkowski, DP 2017, 'Resistance to malaria through structural variation of red blood cell invasion receptors', Science, vol. 356, no. 6343. https://doi.org/10.1126/science.aam6393

TY - JOUR

T1 - Resistance to malaria through structural variation of red blood cell invasion receptors

AU - Malaria Genomic Epidemiology Network

AU - Leffler, Ellen M

AU - Band, Gavin

AU - Busby, George B J

AU - Kivinen, Katja

AU - Le, Quang Si

AU - Clarke, Geraldine M

AU - Bojang, Kalifa A

AU - Conway, David J

AU - Jallow, Muminatou

AU - Sisay-Joof, Fatoumatta

AU - Bougouma, Edith C

AU - Mangano, Valentina D

AU - Modiano, David

AU - Sirima, Sodiomon B

AU - Achidi, Eric

AU - Apinjoh, Tobias O

AU - Marsh, Kevin

AU - Ndila, Carolyne M

AU - Peshu, Norbert

AU - Williams, Thomas N

AU - Drakeley, Chris

AU - Manjurano, Alphaxard

AU - Reyburn, Hugh

AU - Riley, Eleanor

AU - Kachala, David

AU - Molyneux, Malcolm

AU - Nyirongo, Vysaul

AU - Taylor, Terrie

AU - Thornton, Nicole

AU - Tilley, Louise

AU - Grimsley, Shane

AU - Drury, Eleanor

AU - Stalker, Jim

AU - Cornelius, Victoria

AU - Hubbart, Christina

AU - Jeffreys, Anna E

AU - Rowlands, Kate

AU - Rockett, Kirk A

AU - Spencer, Chris C A

AU - Kwiatkowski, Dominic P

PY - 2017/5/18

Y1 - 2017/5/18

N2 - 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.

AB - 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.

KW - Adult

KW - Africa South of the Sahara

KW - Child

KW - DNA Copy Number Variations

KW - Disease Resistance

KW - Erythrocytes

KW - Gene Frequency

KW - Genome, Human

KW - Glycophorin

KW - Host-Parasite Interactions

KW - Humans

KW - Malaria, Falciparum

KW - Models, Molecular

KW - Protein Structure, Secondary

KW - Receptors, Cell Surface

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1126/science.aam6393

DO - 10.1126/science.aam6393

M3 - Article

C2 - 28522690

VL - 356

JO - Science

JF - Science

SN - 0036-8075

IS - 6343

ER -

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

Abstract

Keywords

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