title: Extreme population differences in the human zinc transporter ZIP4 (SLC39A4) are explained by positive selection in Sub-Saharan Africa.
abstract: Extreme differences in allele frequency between West Africans and Eurasians were observed for a leucine-to-valine substitution (Leu372Val) in the human intestinal zinc uptake transporter, ZIP4, yet no further evidence was found for a selective sweep around the ZIP4 gene (SLC39A4). By interrogating allele frequencies in more than 100 diverse human populations and resequencing Neanderthal DNA, we confirmed the ancestral state of this locus and found a strong geographical gradient for the derived allele (Val372), with near fixation in West Africa. In extensive coalescent simulations, we show that the extreme differences in allele frequency, yet absence of a classical sweep signature, can be explained by the effect of a local recombination hotspot, together with directional selection favoring the Val372 allele in Sub-Saharan Africans. The possible functional effect of the Leu372Val substitution, together with two pathological mutations at the same codon (Leu372Pro and Leu372Arg) that cause acrodermatitis enteropathica (a disease phenotype characterized by extreme zinc deficiency), was investigated by transient overexpression of human ZIP4 protein in HeLa cells. Both acrodermatitis mutations cause absence of the ZIP4 transporter cell surface expression and nearly absent zinc uptake, while the Val372 variant displayed significantly reduced surface protein expression, reduced basal levels of intracellular zinc, and reduced zinc uptake in comparison with the Leu372 variant. We speculate that reduced zinc uptake by the ZIP4-derived Val372 isoform may act by starving certain pathogens of zinc, and hence may have been advantageous in Sub-Saharan Africa. Moreover, these functional results may indicate differences in zinc homeostasis among modern human populations with possible relevance for disease risk.
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain ; Department of Evolutionary Genetics, Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Engelken
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Carnero-Montoro
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Pybus
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Glen K
authors.initials: GK
authors.lastname: Andrews
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Lalueza-Fox
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Comas
authors.affiliation: Department of Physiology, Ben-Gurion University, Beer-Sheva, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Sekler
authors.affiliation: Área de Prehistoria, Departamento de Historia, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Marco
authors.initials: M
authors.lastname: de la Rasilla
authors.affiliation: Group of Paleoanthropology MNCN-CSIC, Department of Paleobiology, National Museum of Natural Sciences, CSIC, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosas
authors.affiliation: Department of Evolutionary Genetics, Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Stoneking
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Valverde
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Vicente
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Bosch
mesh_terms: D000169:Acrodermatitis / Q000235:genetics* / Q000473:pathology; D017954:Africa South of the Sahara; D027682:Cation Transport Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D005787:Gene Frequency; D005828:Genetics, Population; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D012641:Selection, Genetic / Q000235:genetics*; D015032:Zinc / Q000172:deficiency*
chemical_list: D027682:Cation Transport Proteins; C486791:SLC39A4 protein, human; D015032:Zinc