TY - JOUR
T1 - Extreme Population Differences in the Human Zinc Transporter ZIP4 (SLC39A4) Are Explained by Positive Selection in Sub-Saharan Africa
AU - Engelken, Johannes
AU - Carnero-Montoro, Elena
AU - Pybus, Marc
AU - Andrews, Glen K.
AU - Lalueza-Fox, Carles
AU - Comas, David
AU - Sekler, Israel
AU - de la Rasilla, Marco
AU - Rosas, Antonio
AU - Stoneking, Mark
AU - Valverde, Miguel A.
AU - Vicente, Rubén
AU - Bosch, Elena
N1 - Funding Information:
We thank Jean-Marie Hombert and Lolke van der Veen (Dynamique du Langage, Institut des Sciences De l'Homme, Lyon France) as well as Patrick Mouguiama Daouda (University Omar Bongo, Libreville, Gabon) and the Centre International des Recherches Médicales de Franceville (CIRMF, Gabon) for sharing the Gabon samples. We also acknowledge Karima Fadhlaoui-Zid from the University Tunis El Manar (Tunisia) for providing the Libyan samples and Francesc Calafell and Pierre Luisi for discussion as well as Nino Spataro and the National Institute of Bioinformatics ( http://www.inab.org ) for computational support.
PY - 2014/2/1
Y1 - 2014/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84901743813&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1004128
DO - 10.1371/journal.pgen.1004128
M3 - Article
AN - SCOPUS:84901743813
SN - 1553-7390
VL - 10
JO - PLoS Genetics
JF - PLoS Genetics
IS - 2
M1 - e1004128
ER -