Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations.
Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations.
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DOI：
10.1016/j.cell.2016.09.024
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发表时间：
2016-10-20
期刊：
影响因子：
64.5
通讯作者：
Quintana-Murci, Lluis
中科院分区：
文献类型：
--
作者：
Quach, Helene;Rotival, Maxime;Pothlichet, Julien;Loh, Yong-Hwee Eddie;Dannemann, Michael;Zidane, Nora;Laval, Guillaume;Patin, Etienne;Harmant, Christine;Lopez, Marie;Deschamps, Matthieu;Naffakh, Nadia;Duffy, Darragh;Coen, Anja;Leroux-Roels, Geert;Clement, Frederic;Boland, Anne;Deleuze, Jean-Francois;Kelso, Janet;Albert, Matthew L.;Quintana-Murci, Lluis
人类在接触危及生命的病原体后的结果不同，但在免疫反应及其遗传和进化决定因素方面的人群差异程度仍不清楚。本研究中，我们利用RNA测序技术表征了非洲人和欧洲人的原代单核细胞对激活toll样受体通路（TLR1/2、TLR4和TLR7/8）和流感病毒的细菌和病毒刺激配体的转录反应，并绘制了表达数量性状位点（eQTLs）。我们发现了许多顺式- eqtl，这些顺式- eqtl有助于在人群内和人群之间检测到的免疫反应的显着差异，以及TLR1上的强反式- eqtl热点，仅在欧洲人中减少促炎基因的表达。我们发现免疫应答性调节变异在自然选择的群体特异性信号中丰富，并表明与尼安德特人的混合将调节变异引入欧洲基因组，优先影响对病毒挑战的反应。总之，我们的研究揭示了人类群体之间宿主免疫反应差异的进化重要决定因素。人类群体对免疫挑战的转录反应不同，顺式和反式qtl导致免疫反应的群体差异免疫反应调节变异参与了人类适应尼安德特人将影响免疫反应的变异引入欧洲基因组，这些变异富含自然选择的群体特异性信号，在欧洲人中，尼安德特人祖先的基因在不同人群对炎症和感染挑战的转录反应差异中发挥了重要作用。
Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli—ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus—and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations. Human populations differ in their transcriptional responses to immune challenges Cis- and trans-eQTLs contribute to population differences in immune responses Immune-responsive regulatory variants have participated in human adaptation Neandertals introduced variants affecting immune responses into European genomes Genetic variants enriched in population-specific signals of natural selection and, among Europeans, of Neandertal ancestry play a major role in the differences in transcriptional responses to inflammatory and infectious challenges observed between human populations.
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影响因子：
46.9
作者：
Ernst J;Kellis M
通讯作者：
Kellis M
影响因子：
64.8
作者：
Fu Q;Posth C;Hajdinjak M;Petr M;Mallick S;Fernandes D;Furtwängler A;Haak W;Meyer M;Mittnik A;Nickel B;Peltzer A;Rohland N;Slon V;Talamo S;Lazaridis I;Lipson M;Mathieson I;Schiffels S;Skoglund P;Derevianko AP;Drozdov N;Slavinsky V;Tsybankov A;Cremonesi RG;Mallegni F;Gély B;Vacca E;Morales MR;Straus LG;Neugebauer-Maresch C;Teschler-Nicola M;Constantin S;Moldovan OT;Benazzi S;Peresani M;Coppola D;Lari M;Ricci S;Ronchitelli A;Valentin F;Thevenet C;Wehrberger K;Grigorescu D;Rougier H;Crevecoeur I;Flas D;Semal P;Mannino MA;Cupillard C;Bocherens H;Conard NJ;Harvati K;Moiseyev V;Drucker DG;Svoboda J;Richards MP;Caramelli D;Pinhasi R;Kelso J;Patterson N;Krause J;Pääbo S;Reich D
通讯作者：
Reich D
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
7
作者：
Battle A;Mostafavi S;Zhu X;Potash JB;Weissman MM;McCormick C;Haudenschild CD;Beckman KB;Shi J;Mei R;Urban AE;Montgomery SB;Levinson DF;Koller D
通讯作者：
Koller D
影响因子：
7
作者：
Chen, Hua;Patterson, Nick;Reich, David
通讯作者：
Reich, David