Included in malaria theme

Altmetric score 15.75 (top 6.8%)

Research area: genomics

Population Genetic Analysis of the DARC Locus (Duffy) Reveals Adaptation from Standing Variation Associated with Malaria Resistance in Humans

Created on 25th April 2016

Kimberly F. McManus; Angela Taravella; Brenna Henn; Carlos D. Bustamante; Martin Sikora; Omar E. Cornejo;

The human DARC (Duffy antigen receptor for chemokines) gene encodes a membrane-bound chemokine receptor crucial for the infection of red blood cells by Plasmodium vivax, a major causative agent of malaria. Of the three major allelic classes segregating in human populations, the FY*O allele has been shown to protect against P. vivax infection and is near fixation in sub-Saharan Africa, while FY*B and FY*A are common in Europe and Asia, respectively. Due to the combination of its strong geographic differentiation and association with malaria resistance, DARC is considered a canonical example of a locus under positive selection in humans. Here, we use sequencing data from over 1,000 individuals in twenty-one human populations, as well as ancient human and great ape genomes, to analyze the fine scale population structure of DARC. We estimate the time to most recent common ancestor (TMRCA) of the FY*O mutation to be 42 kya (95% CI: 34-49 kya). We infer the FY*O null mutation swept to fixation in Africa from standing variation with very low initial frequency (0.1%) and a selection coefficient of 0.043 (95% CI:0.011-0.18), which is among the strongest estimated in the genome. We estimate the TMRCA of the FY*A mutation to be 57 kya (95% CI: 48-65 kya) and infer that, prior to the sweep of FY*O, all three alleles were segregating in Africa, as highly diverged populations from Asia and Khomani San hunter-gatherers share the same FY*A haplotypes. We test multiple models of admixture that may account for this observation and reject recent Asian or European admixture as the cause.

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