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Extreme population differentiation in a Human Zinc Transporter Explained by Positive Selection in Sub-Saharan African Populations

AuthorsEngelken, Johannes ; Carnero-Montoro, Elena ; Pybus, Marc ; Andrews, Glen K.; Lalueza-Fox, Carles ; Comas, David ; Sekler, Israel; Rasilla, Marco de la; Rosas, Antonio ; Stoneking, Mark; Valverde, Miguel A.; Vicente, Rubén; Bosch, Elena
Issue DateJul-2013
CitationXIII Jornada de Biologia Evolutiva (2013)
AbstractExtreme differences in allele frequency between West Africans and Eurasians are observed for a non-synonymous polymorphism in a human zinc uptake transporter. However, there is no further evidence for a selective sweep around this gene. By interrogating allele frequencies in more than 100 diverse human populations and resequencing Neanderthal DNA, we have confirmed the ancestral state of this locus and found a strong geographical gradient for the derived allele with near fixation in West Africa. In extensive coalescent simulations, we show that the extreme allele frequency differences yet absence of a classical sweep signature can be explained by the effect of a local recombination hotspot, together with strong directional selection favoring this allele in Sub-Saharan Africans. Next, we examined the possible functional effect this substitution. Transient overexpression of the zinc transporter in HeLa cells revealed that the predominantly Sub-Saharan variant displayed significantly reduced surface protein expression, reduced basal levels of intracellular zinc and reduced zinc uptake, when compared with the ancestral variant. We speculate that reduced zinc uptake may act to starve certain pathogens from zinc, and hence may have been advantageous in Sub-Saharan Africa. Moreover, these functional results may indicate the existence of zinc homeostasis differences among modern human populations, which could be relevant for disease risk.
DescriptionTrabajo presentado en la XIII Jornada de Biologia Evolutiva, celebrada en Barcelona el 2 de julio de 2013.
Appears in Collections:(IBE) Comunicaciones congresos
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