Resistance to malaria through structural variation of red blood cell invasion receptors
| Autor: | Kate Rowlands, Eleanor M. Riley, David Modiano, David Kachala, Nicole Thornton, Muminatou Jallow, Edith C. Bougouma, Anna E. Jeffreys, Carolyne M. Ndila, Jim Stalker, Tobias O. Apinjoh, Eleanor Drury, Malcolm E. Molyneux, Alphaxard Manjurano, Ellen M. Leffler, Chris Drakeley, Shane Grimsley, Louise Tilley, George B.J. Busby, Victoria Cornelius, Kevin Marsh, Vysaul Nyirongo, Thomas N. Williams, Geraldine M. Clarke, Terrie Taylor, Fatoumatta Sisay-Joof, Christina Hubbart, Valentina D. Mangano, Kalifa Bojang, Sodiomon B. Sirima, David J. Conway, Katja Kivinen, Hugh Reyburn, Dominic P. Kwiatkowski, Norbert Peshu, Quang Si Le, Eric A. Achidi, Kirk A. Rockett, Chris C. A. Spencer, Gavin Band |
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| Přispěvatelé: | Wellcome Trust, Commission of the European Communities |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Erythrocytes Protein Structure Secondary 0302 clinical medicine Gene Frequency Glycophorins Copy-number variation Malaria Falciparum Child Disease Resistance Genetics 0303 health sciences Multidisciplinary GYPA biology GYPB Research Support Non-U.S. Gov't Medicine (all) 3. Good health Multidisciplinary Sciences medicine.anatomical_structure 030220 oncology & carcinogenesis Science & Technology - Other Topics Malaria Genomic Epidemiology Network Glycophorin Adult multidisciplinary antigens cells rbcs DNA Copy Number Variations General Science & Technology Locus (genetics) Receptors Cell Surface Host-Parasite Interactions Structural variation 03 medical and health sciences Research Support N.I.H. Extramural parasitic diseases Journal Article medicine Humans 1000 Genomes Project Gene Africa South of the Sahara 030304 developmental biology Science & Technology Genome Human Haplotype Plasmodium falciparum biology.organism_classification medicine.disease Red blood cell 030104 developmental biology biology.protein Malaria |
| Zdroj: | 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, Peshu, N, Williams, T N, 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, A E, Rowlands, K, Rockett, K A & Spencer, C C A & Kwiatkowski, D P 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 |
| ISSN: | 0036-8075 |
| DOI: | 10.1101/083634 |
| Popis: | INTRODUCTION Malaria parasites cause human disease by invading and replicating inside red blood cells. In the case of Plasmodium falciparum , this can lead to severe forms of malaria that are a major cause of childhood mortality in Africa. This species of parasite enters the red blood cell through interactions with surface proteins including the glycophorins GYPA and GYPB, which determine the polymorphic MNS blood group system. In a recent genome-wide association study, we identified alleles associated with protection against severe malaria near the cluster of genes encoding these invasion receptors. RATIONALE Investigation of genetic variants at this locus and their relation to severe malaria is challenging because of the high sequence similarity between the neighboring glycophorin genes and the relative lack of available sequence data capturing the genetic diversity of sub-Saharan Africa. To better assess whether variation in the glycophorin genes could explain the signal of association, we generated additional sequence data from sub-Saharan African populations and developed an analytical approach to characterize structural variation at this complex locus. RESULTS Using 765 newly sequenced human genomes from 10 African ethnic groups along with data from the 1000 Genomes Project, we generated a reference panel of haplotypes across the glycophorin region. In addition to single-nucleotide polymorphisms and short indels, we assayed large copy number variants (CNVs) using sequencing read depth and uncovered extensive structural diversity. By imputing from this reference panel into 4579 severe malaria cases and 5310 controls from three African populations, we found that a complex CNV, here called DUP4, is associated with resistance to severe malaria and fully explains the previously reported signal of association. In our sample, DUP4 is present only in east Africa, and this localization, as well as the extent of similarity between DUP4 haplotypes, suggests that it has recently increased in frequency, presumably under natural selection due to malaria. To evaluate the potential functional consequences of this structural variant, we analyzed high-coverage sequence-read data from multiple individuals to generate a model of the DUP4 chromosome structure. The DUP4 haplotype contains five glycophorin genes, including two hybrid genes that juxtapose the extracellular domain of GYPB with the transmembrane and intracellular domains of GYPA. Noting that these predicted hybrids are characteristic of the Dantu antigen in the MNS blood group system, we sequenced a Dantu positive individual and confirmed that DUP4 is the molecular basis of the Dantu NE blood group variant. CONCLUSION Although a role for GYPA and GYPB in parasite invasion is well known, a direct link between glycophorin polymorphisms and clinical susceptibility to malaria has been elusive. Here we have provided a systematic catalog of CNVs, describing structural diversity that may have functional importance at this locus. Our results identify a specific variant that encodes hybrid glycophorin proteins and is associated with protection against severe malaria. This discovery calls for further work to determine how this particular molecular rearrangement affects parasite invasion and the red blood cell response and may lead us toward new parasite vulnerabilities that can be utilized in future interventions against this deadly disease. |
| Databáze: | OpenAIRE |
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