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.

JE was supported through a Postdoc scholarship from the Volkswagenstiftung (Az: I/85 198). This work was partially funded by grants BFU2008-01046, SAF2011-29239, SAF2012-38140, CGL2012-36682 and SAF2010-16725 from the Spanish Ministry of Economy and Competitiveness, Fondo de Investigación Sanitaria (Red HERACLES RD12/0042/0014), and FEDER Funds as well as by grants 2009SGR-1101 and 2009SGR-1369 from Direcció General de Recerca, Generalitat de Catalunya. El Sidrón research was also supported by Consejería de Cultura del Principado de Asturias. MAV is the recipient of an ICREA Academia Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript