Journal article
A novel locus of resistance to severe malaria in a region of ancient balancing selection
- Abstract:
- The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies1,2,3. To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-threatening Plasmodium falciparum infection (severe malaria) in over 11,000 African children, with replication data in a further 14,000 individuals. Here we report a novel malaria resistance locus close to a cluster of genes encoding glycophorins that are receptors for erythrocyte invasion by P. falciparum. We identify a haplotype at this locus that provides 33% protection against severe malaria (odds ratio = 0.67, 95% confidence interval = 0.60–0.76, P value = 9.5 × 10−11) and is linked to polymorphisms that have previously been shown to have features of ancient balancing selection, on the basis of haplotype sharing between humans and chimpanzees4. Taken together with previous observations on the malaria-protective role of blood group O1,2,3,5, these data reveal that two of the strongest GWAS signals for severe malaria lie in or close to genes encoding the glycosylated surface coat of the erythrocyte cell membrane, both within regions of the genome where it appears that evolution has maintained diversity for millions of years. These findings provide new insights into the host–parasite interactions that are critical in determining the outcome of malaria infection.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Accepted manuscript, pdf, 5.9MB, Terms of use)
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- Publisher copy:
- 10.1038/nature15390
Authors
+ Medical Research Council
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- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- G0600718
- G0600230
- G9901439
- G19/9
- Funding agency for:
- Kwiatkowski, D
+ Wellcome Trust
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- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- WT077383/Z/05/Z
- 090770/Z/09/Z
- 090532/Z/09/Z
- 077012/Z/05/Z
- 075491/Z/04
- 087285
- 096527
- 098051
- 097364/Z/11/ Z
- Funding agency for:
- Spencer, C
+ Fogarty International Center
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- Funder identifier:
- https://ror.org/02xey9a22
- Grant:
- D43TW001589
+ National Institutes of Health
More from this funder
- Funder identifier:
- https://ror.org/01cwqze88
- Grant:
- 556
+ National Institute of Allergy and Infectious Diseases
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- Funder identifier:
- https://ror.org/043z4tv69
- Grant:
- U19AI065683
- N01AI85346
- Publisher:
- Nature Publishing Group
- Journal:
- Nature More from this journal
- Volume:
- 526
- Issue:
- 7572
- Pages:
- 253–257
- Publication date:
- 2015-09-30
- Acceptance date:
- 2015-08-10
- DOI:
- EISSN:
-
1476-4687
- ISSN:
-
0028-0836
- Language:
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English
- Keywords:
- Pubs id:
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pubs:571271
- UUID:
-
uuid:bd45bc19-47fd-49cf-b674-acc6e0df43f8
- Local pid:
-
pubs:571271
- Source identifiers:
-
571271
- Deposit date:
-
2015-12-16
Terms of use
- Copyright holder:
- Macmillan Publishers Limited
- Copyright date:
- 2015
- Rights statement:
- © 2015 Macmillan Publishers Limited. All rights reserved.
- Notes:
-
This is the accepted manuscript version of the article. The final version is available online from Nature Publishing Group at https://dx.doi.org/10.1038/nature15390
Malaria Genomic Epidemiology Network: Lists of participants and their affiliations appear at the end of the paper.
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