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

Abstract

The human DARC (Duffy antigen receptor for chemokines) gene encodes a membranebound 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 at near fixation in sub-Saharan Africa, while FY*B and FY*A are common in Europe and Asia, respectively. Due to the combination of strong geographic differentiation and association with malaria resistance, DARC is considered a canonical example of positive selection in humans. Despite this, details of the timing and mode of selection at DARC remain poorly understood. Here, we use sequencing data from over 1,000 individuals in twenty-one human populations, as well as ancient human genomes, to perform a fine-scale investigation of the evolutionary history of DARC. We estimate the time to most recent common ancestor (T MRCA ) of the most common FY*O haplotype 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 human genome. We estimate the T MRCA of the FY*A mutation in non-Africans 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 6 ¼Khomani 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.

Soft sweeps and beyond: understanding the patterns and probabilities of selection footprints under rapid adaptation

“…Two haplotypes with LD across the selected site are found at intermediate frequency in sub‐Saharan Africa (Hamblin & Di Rienzo ; McManus et al . ). One further independent origin has been described in Papua New Guinea (Zimmerman et al .…”

How well do we understand the basis of classic selective sweeps in humans?

“…The derived C allele of the selected variant is almost fixed in most African populations (e.g. ~ 96% frequency in The 1000 Genomes Project African samples ), and shows strong signatures of positive selection, although on more than one haplotype . It has been picked up as one of the strongest selection candidates in almost all genome‐wide or targeted selection scan studies .…”

Ethnic benign neutropenia: A phenomenon finds an explanation

“…As for most other blood groups, these variants were discovered because individuals of the Fy(a+b−) phenotype can mount alloantibodies against Fy b if they are transfused with Fy(a+b+) or Fy(a−b+) blood, and vice versa. Fy b is the primordial allele from which the Fy a SNP emerged approximately 57,000 years ago . The Fy a variant seems to bind Pl.…”