title: 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 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 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 (TMRCA) 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 TMRCA 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 ≠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.
authors.affiliation: Department of Biology, Stanford University, Stanford, California, United States of America.
authors.forename: Kimberly F
authors.identifier: 0000-0002-3970-8204
authors.initials: KF
authors.lastname: McManus
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Taravella
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Brenna M
authors.identifier: 0000-0003-4998-287X
authors.initials: BM
authors.lastname: Henn
authors.affiliation: Department of Biology, Stanford University, Stanford, California, United States of America.|Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, United States of America.|Centre for Geogenetics, Natural History Museum Denmark, Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Sikora
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, United States of America.|Department of Biological Sciences, Washington State University, Pullman, washington, United States of America.
authors.forename: Omar E
authors.identifier: 0000-0003-4076-4227
authors.initials: OE
authors.lastname: Cornejo
mesh_terms: D000349:Africa; D000483:Alleles; D000818:Animals; D001208:Asia; D060467:Disease Resistance / Q000235:genetics*; D004375:Duffy Blood-Group System / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency; D005828:Genetics, Population; D015894:Genome, Human; D005843:Geography; D006071:Gorilla gorilla; D006239:Haplotypes; D006801:Humans; D016780:Malaria, Vivax / Q000235:genetics*; D009154:Mutation; D019974:Pan paniscus; D002679:Pan troglodytes; D020641:Polymorphism, Single Nucleotide; D057079:Pongo; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism
chemical_list: C473745:ACKR1 protein, human; D004375:Duffy Blood-Group System; D011956:Receptors, Cell Surface