Extreme population differences in the human zinc transporter ZIP4 (SLC39A4) are explained by positive selection in Sub-Saharan Africa.
Extreme population differences in the human zinc transporter ZIP4 (SLC39A4) are explained by positive selection in Sub-Saharan Africa.
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DOI：
10.1371/journal.pgen.1004128
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发表时间：
2014-02
期刊：
影响因子：
4.5
通讯作者：
Bosch E
中科院分区：
文献类型：
--
作者：
Engelken J;Carnero-Montoro E;Pybus M;Andrews GK;Lalueza-Fox C;Comas D;Sekler I;de la Rasilla M;Rosas A;Stoneking M;Valverde MA;Vicente R;Bosch E
在人类肠道锌摄取转运蛋白 ZIP4 中，观察到亮氨酸至缬氨酸取代 (Leu372Val) 的等位基因频率在西非人和欧亚人之间存在极大差异，但没有发现 ZIP4 基因 (SLC39A4) 周围选择性扫描的进一步证据。通过询问 100 多个不同人群中的等位基因频率并对尼安德特人 DNA 进行重新测序，我们确认了该基因座的祖先状态，并发现衍生等位基因 (Val372) 具有很强的地理梯度，几乎固定在西非。在广泛的聚结模拟中，我们表明，等位基因频率的极端差异，但缺乏经典的扫描特征，可以通过局部重组热点的影响以及有利于撒哈拉以南非洲人的 Val372 等位基因的方向选择来解释。通过人 ZIP4 蛋白在 HeLa 细胞中的瞬时过表达，研究了 Leu372Val 取代以及同一密码子（Leu372Pro 和 Leu372Arg）上的两个病理突变可能引起的功能影响，这些突变导致肠病性肢端皮炎（一种以极度缺锌为特征的疾病表型）。两种肢端皮炎突变均导致 ZIP4 转运蛋白细胞表面表达缺失和锌摄取几乎缺失，而与 Leu372 变体相比，Val372 变体表现出表面蛋白表达显着降低、细胞内锌基础水平降低和锌摄取减少。我们推测，ZIP4 衍生的 Val372 同种型减少锌的吸收可能是通过使某些病原体缺乏锌来发挥作用，因此可能对撒哈拉以南非洲地区有利。此外，这些功能结果可能表明现代人群中锌稳态的差异，可能与疾病风险相关。锌是体内必需的微量元素，具有多种生物功能，其浓度受到不同膜转运蛋白的严格调节。在这里，我们报告了人类肠道锌摄取转运蛋白 ZIP4 中氨基酸替代的正自然选择的不寻常案例。这种取代被认为是人类群体中差异最强烈的全基因组多态性之一。然而，由于这个非同义位点的极端种群分化并未伴随自然选择的额外特征，因此尚不清楚这是否是遗传适应的结果。通过计算机模拟，我们证明这种不寻常的模式可以通过局部重组的效应以及撒哈拉以南非洲的正选择来解释。此外，我们提供的证据表明两种 ZIP4 亚型在转运细胞表面表达和锌摄取方面存在功能差异。这一结果首次表明现代人群中锌的调节可能存在差异，这一发现可能对健康研究产生影响。此外，我们推测衍生变体介导的锌吸收减少可能对撒哈拉以南非洲地区有利，可能是通过减少地理上限制的病原体对这种微量营养素的获取而实现的。
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. Zinc is an essential trace element with many biological functions in the body, whose concentrations are tightly regulated by different membrane transporters. Here we report an unusual case of positive natural selection for an amino acid replacement in the human intestinal zinc uptake transporter ZIP4. This substitution is recognized as one of the most strongly differentiated genome-wide polymorphisms among human populations. However, since the extreme population differentiation of this non-synonymous site was not accompanied by additional signatures of natural selection, it was unclear whether it was the result of genetic adaptation. Using computer simulations we demonstrate that such an unusual pattern can be explained by the effect of local recombination, together with positive selection in Sub-Saharan Africa. Moreover, we provide evidence to suggest functional differences between the two ZIP4 isoforms in terms of the transporter cell surface expression and zinc uptake. This result is the first genetic indication that zinc regulation may differ among modern human populations, a finding that may have implications for health research. Further, we speculate that reduced zinc uptake mediated by the derived variant may have been advantageous in Sub-Saharan Africa, possibly by reducing access of a geographically restricted pathogen to this micronutrient.
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影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
2.8
作者：
Fenner, JN
通讯作者：
Fenner, JN
影响因子：
9.8
作者：
Hamblin, MT;Di Rienzo, A
通讯作者：
Di Rienzo, A
影响因子：
56.9
作者：
Grossman, Sharon R.;Shylakhter, Ilya;Sabeti, Pardis C.
通讯作者：
Sabeti, Pardis C.
影响因子：
10.7
作者：
Beleza, Sandra;Santos, Antonio M.;Rocha, Jorge
通讯作者：
Rocha, Jorge