Environmental correlation analysis for genes associated with protection against malaria
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Genome-wide searches for loci involved in human resistance to malaria are currently being conducted on a large scale in Africa using case-control studies. Here, we explore the utility of an alternative approach – “environmental correlation analysis, ECA”, which tests for clines in allele frequencies across a gradient of an environmental selection pressure - to identify genes that have historically protected against death from malaria. We collected genotype data from 12,425 newborns on 57 candidate malaria resistance loci and 9,756 SNPs selected at random from across the genome, and examined their allele frequencies for geographic correlations with long-term malaria prevalence data based on 84,042 individuals living under different historical selection pressures from malaria in coastal Kenya. None of the 57 candidate SNPs showed significant (P < 0.05) correlations in allele frequency with local malaria transmission intensity after adjusting for population structure and multiple testing. By contrast, two of the random SNPs that had highly significant correlations (P < 0.01) were in genes previously linked to malaria resistance, namely, CDH13, encoding cadherin 13, and HS3ST3B1, encoding heparan sulphate 3-O-sulfotransferase 3B1. Both proteins play a role in glycoprotein-mediated cell-cell adhesion which has been widely implicated in cerebral malaria, the most life-threatening form of this disease. Other top genes, including CTNND2 which encodes δ-catenin, a molecular partner to cadherin, were significantly enriched in cadherin-mediated pathways affecting inflammation of the brain vascular endothelium. These results demonstrate the utility of ECA in the discovery of novel genes and pathways affecting infectious disease.
Date Issued
2016-01-06
Date Acceptance
2016-01-05
Citation
Molecular Biology and Evolution, 2016, 33 (5), pp.1188-1204
ISSN
1537-1719
Publisher
Oxford University Press (OUP)
Start Page
1188
End Page
1204
Journal / Book Title
Molecular Biology and Evolution
Volume
33
Issue
5
Copyright Statement
© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium,
provided the original work is properly cited.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium,
provided the original work is properly cited.
License URL
Sponsor
Wellcome Trust
Grant Number
091758/B/10/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Evolutionary Biology
Genetics & Heredity
environmental correlation analysis balancing selection malaria local adaptation
PLASMODIUM-FALCIPARUM MALARIA
GENOME-WIDE ASSOCIATION
HEPARAN-SULFATE PROTEOGLYCANS
RED-BLOOD-CELLS
AFRICAN POPULATIONS
ENDOTHELIAL-CELLS
INFECTED ERYTHROCYTES
HEMOGLOBIN-VARIANTS
ALPHA-THALASSEMIA
NATURAL-SELECTION
0604 Genetics
0603 Evolutionary Biology
0601 Biochemistry And Cell Biology
Publication Status
Published