Selection on a variant associated with improved viral clearance drives local, adaptive pseudogenization of interferon lambda 4 (IFNL4).
Selection on a variant associated with improved viral clearance drives local, adaptive pseudogenization of interferon lambda 4 (IFNL4).
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DOI：
10.1371/journal.pgen.1004681
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发表时间：
2014-10
期刊：
影响因子：
4.5
通讯作者：
Andrés AM
中科院分区：
文献类型：
--
作者：
Key FM;Peter B;Dennis MY;Huerta-Sánchez E;Tang W;Prokunina-Olsson L;Nielsen R;Andrés AM
干扰素λ 4（IFN-λ 4）基因编码IFN-λ4，是IFN-λ家族中具有抗病毒活性的新成员。在人类中，IFNL 4开放阅读框被多态性移码插入截短，从而消除IFN-λ4并将IFNL 4转化为多态性假基因。功能性IFN-λ4具有抗病毒活性，但通过假基因化消除IFN-λ4与改善丙型肝炎病毒（HCV）感染的清除密切相关。我们发现，功能性IFN-λ4在哺乳动物中是保守的，并且在进化上受到限制，因此在功能上相关。然而，假基因在非洲、美洲和欧洲已达到中等高频率，在东亚接近固定。事实上，假基因化变体是非洲和东亚全基因组之间0.8%最分化的SNP之一。其频率的增加与正选择的额外证据相关，这在东亚是最强的，其中该变体福尔斯落在具有最近全基因组正选择的最强特征的SNP的0.5%尾部。使用一种新的近似贝叶斯计算（ABC）的方法，我们推断，pseudogenizing等位基因出现在非洲移民之前，并立即有针对性的适度的积极选择，选择随后加强在欧洲和亚洲人群中，导致今天观察到的高频率。这为适应性过程的改变提供了证据，该适应性过程通过促进IFN-λ4的失活，塑造了当今的表型多样性和对疾病的易感性。与丙型肝炎病毒（HCV）清除的遗传关联是已知与疾病最强和最难以捉摸的关联之一。与改善HCV清除率更密切相关的遗传变异使最近发现的编码抗病毒IFN-λ4蛋白的IFNL 4基因失活，并将其转化为多态性假基因。我们表明，功能性IFN-λ4是保守的，在哺乳动物中的功能重要。然而，在人类中，失活突变出现在非洲，就在非洲移民之前，并迅速变得有利，选择的强度（优势程度）在人类群体中各不相同。特别是，选择在非洲以外变得更强，在东亚最强，提高了假基因的频率，导致几个亚洲人群中功能性IFN-λ4蛋白的实际丧失。虽然环境力量驱动的选择是未知的，这一过程导致在现代人群中的HCV的可变清除。因此，IFNL 4失活等位基因的复杂选择历史不仅在遗传变异方面，而且在相关表型和疾病易感性方面形成了当今人群间的异质性。
Interferon lambda 4 gene (IFNL4) encodes IFN-λ4, a new member of the IFN-λ family with antiviral activity. In humans IFNL4 open reading frame is truncated by a polymorphic frame-shift insertion that eliminates IFN-λ4 and turns IFNL4 into a polymorphic pseudogene. Functional IFN-λ4 has antiviral activity but the elimination of IFN-λ4 through pseudogenization is strongly associated with improved clearance of hepatitis C virus (HCV) infection. We show that functional IFN-λ4 is conserved and evolutionarily constrained in mammals and thus functionally relevant. However, the pseudogene has reached moderately high frequency in Africa, America, and Europe, and near fixation in East Asia. In fact, the pseudogenizing variant is among the 0.8% most differentiated SNPs between Africa and East Asia genome-wide. Its raise in frequency is associated with additional evidence of positive selection, which is strongest in East Asia, where this variant falls in the 0.5% tail of SNPs with strongest signatures of recent positive selection genome-wide. Using a new Approximate Bayesian Computation (ABC) approach we infer that the pseudogenizing allele appeared just before the out-of-Africa migration and was immediately targeted by moderate positive selection; selection subsequently strengthened in European and Asian populations resulting in the high frequency observed today. This provides evidence for a changing adaptive process that, by favoring IFN-λ4 inactivation, has shaped present-day phenotypic diversity and susceptibility to disease. The genetic association with clearance of Hepatitis C virus (HCV) is one of the strongest and most elusive known associations with disease. The genetic variant more strongly associated with improved HCV clearance inactivates the recently discovered IFNL4 gene, which encodes for antiviral IFN-λ4 protein, and turns it into a polymorphic pseudogene. We show that functional IFN-λ4 is conserved and functionally important in mammals. In humans though the inactivating mutation appeared in Africa just before the out-of-Africa migration and quickly became advantageous, with the strength of selection (the degree of advantage) varying across human groups. In particular, selection became stronger out of Africa and was strongest in East Asia, raising the frequency of the pseudogene and resulting in the virtual loss of functional IFN-λ4 protein in several Asian populations. Although the environmental force driving selection is unknown, this process resulted in variable clearance of HCV in modern human populations. The complex selective history of IFNL4-inactivating allele has thus shaped present-day heterogeneity across populations not only in genetic variation, but also in relevant phenotypes and susceptibility to disease.
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影响因子：
4.5
作者：
Gutenkunst RN;Hernandez RD;Williamson SH;Bustamante CD
通讯作者：
Bustamante CD
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
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：
11.4
作者：
Hamming, Ole J.;Terczynska-Dyla, Ewa;Vieyres, Gabrielle;Dijkman, Ronald;Jorgensen, Sanne E.;Akhtar, Hashaam;Siupka, Piotr;Pietschmann, Thomas;Thiel, Volker;Hartmann, Rune
通讯作者：
Hartmann, Rune
影响因子：
9.5
作者：
Boulesteix, Anne-Laure;Strimmer, Korbinian
通讯作者：
Strimmer, Korbinian