Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis
Open accessAbstract
It has been 100 years since the first report of sickle haemoglobin (HbS). More than 50 years ago, it was suggested that the gene responsible for this disorder could reach high frequencies because of resistance conferred against malaria by the heterozygous carrier state. This traditional example of balancing selection is known as the 'malaria hypothesis'. However, the geographical relationship between the transmission intensity of malaria and associated HbS burden has never been formally investigated on a global scale. Here, we use a comprehensive data assembly of HbS allele frequencies to generate the first evidence-based map of the worldwide distribution of the gene in a Bayesian geostatistical framework. We compare this map with the pre-intervention distribution of malaria endemicity, using a novel geostatistical area-mean comparison. We find geographical support for the malaria hypothesis globally; the relationship is relatively strong in Africa but cannot be resolved in the Americas or in Asia. Sixty years ago it was suggested that the sickle cell disease mutation survives because the heterozygous genotype confers resistance to malaria, resulting in correlation of the two geographical distributions. The authors use a new global assembly of sickle allele frequencies to support this hypothesis at the global scale.
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Sickle cell anemia results from homozygosity for the βS allele, a single nucleotide polymorphism in the β-globin gene that substitutes valine for glutamic acid and produces hemoglobin S.
“Sickle cell anemia is caused by homozygosity of the beta-S (βS) allele (located on chromosome 11p15.5), which differs from the wild-type β-allele by a single nucleotide polymorphism dbSNP Rs334(T;T) in which GTG is substituted for GAG in the sixth codon of the β-globin gene (1, 3, 5, 6).”
From Pathophysiology of Sickle Cell Disease (2019) · cites this paper as [3]
The paper’s Abstract (page not provided) states that HbS has a β-globin Glu→Val substitution at position 6 and that a child inheriting HbS from both parents suffers from sickle cell anaemia. Our copy does not specify the single-nucleotide change, rs334 identifier, GTG/GAG codons, or chromosome location given in the citing sentence. (LLM, conf=0.88)
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- Authors
- Piel, F. B., Patil, A. P., Howes, R. E., Nyangiri, O. A., Gething, P. W., Williams, T. N., Weatherall, D. J., & Hay, S. I.
- Affiliations
- University of Oxford (GB)
- Kenya Medical Research Institute (KE)
- John Radcliffe Hospital (GB)
- Corresponding author
- Piel, Frédéric B.
- Hay, Simon I.
- ORCID
- Venue
- Nature Communications
- Published
- 2010-11-02
- Volume
- 1
- Issue
- 1
- Pages
- 104-104
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3060623
- OpenAlex
- W2128855640
- Cited by
- 629
- References
- 271
- Citations by year
- 2026: 36 · 2025: 39 · 2024: 47 · 2023: 62 · 2022: 52 · 2021: 52 · 2020: 61 · 2019: 45 · 2018: 36 · 2017: 41 · 2016: 41 · 2015: 29 · 2014: 25 · 2013: 22 · 2012: 21
- FWCI
- 19.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust (091758, 076934, 085406, 079080, 079091)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- sickle cell trait, hemoglobin S, balancing selection, malaria resistance, malaria endemicity, geostatistical mapping, Bayesian geostatistics, global distribution
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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