Deciphering the genetic control of gene expression following Mycobacterium leprae antigen stimulation.
Deciphering the genetic control of gene expression following Mycobacterium leprae antigen stimulation.
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在麻风病刺激分枝杆菌抗原刺激后，解读基因表达的遗传控制。
DOI：
10.1371/journal.pgen.1006952
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发表时间：
2017-08
期刊：
影响因子：
4.5
通讯作者：
Schurr E
中科院分区：
文献类型：
--
作者：
Manry J;Nédélec Y;Fava VM;Cobat A;Orlova M;Thuc NV;Thai VH;Laval G;Barreiro LB;Schurr E
麻风病是由麻风分枝杆菌引起的人类传染病。一个强大的宿主遗传贡献麻风易感性是公认的。然而，对感染的转录应答的调节和疾病控制的机制知之甚少。为了解决麻风病致病性知识的这一差距，我们进行了全基因组搜索与M刺激前后转录变异相关的表达数量性状位点（eQTL）。麻风病人全血细胞超声波处理我们表明，M。麻风抗原刺激主要触发免疫相关基因的上调，并且相当大比例的差异基因表达是遗传控制的。实际上，使用严格的标准，我们鉴定了318个在FDR为0.01处显示cis-eQTL的基因，包括66个显示响应eQTL（reQTL）的基因，即显示与M.麻风病刺激这种reQTL对应于影响人全血细胞与M.麻风菌的超声波处理，因此，可能在人类宿主和M之间。麻风杆菌我们发现，reQTL显着丰富的转录因子的结合位点，在感染时被激活，他们是丰富的单核苷酸多态性（SNP）与麻风病本身的易感性和I型反应，其中7个已被最近的正选择。我们的研究表明，自然选择塑造了我们的基因组多样性，以面对包括M。麻风病感染全世界每年报告20万新的麻风病例。虽然有明确的证据表明宿主遗传学在麻风病发病机制中的作用，但人类宿主对抗感染的机制却知之甚少。在这里，我们强调寻找自然发生的遗传变异，调节基因表达水平暴露后，超声处理的麻风分枝杆菌，细菌引起的疾病。因为M.麻风是不可培养的，并且在感染期间参与宿主反应的真正免疫细胞仍然是未知的，我们在用M.麻风病超声治疗该设计为宿主对M.麻风病，并概述了宿主遗传学对麻风病发病机制的贡献。在M.麻风病依赖的基因表达水平的遗传调节因子存在（i）与麻风病相关的、（ii）位于转录因子结合位点的和（iii）被最近的正选择靶向的变异体的富集。
Leprosy is a human infectious disease caused by Mycobacterium leprae. A strong host genetic contribution to leprosy susceptibility is well established. However, the modulation of the transcriptional response to infection and the mechanism(s) of disease control are poorly understood. To address this gap in knowledge of leprosy pathogenicity, we conducted a genome-wide search for expression quantitative trait loci (eQTL) that are associated with transcript variation before and after stimulation with M. leprae sonicate in whole blood cells. We show that M. leprae antigen stimulation mainly triggered the upregulation of immune related genes and that a substantial proportion of the differential gene expression is genetically controlled. Indeed, using stringent criteria, we identified 318 genes displaying cis-eQTL at an FDR of 0.01, including 66 genes displaying response-eQTL (reQTL), i.e. cis-eQTL that showed significant evidence for interaction with the M. leprae stimulus. Such reQTL correspond to regulatory variations that affect the interaction between human whole blood cells and M. leprae sonicate and, thus, likely between the human host and M. leprae bacilli. We found that reQTL were significantly enriched among binding sites of transcription factors that are activated in response to infection, and that they were enriched among single nucleotide polymorphisms (SNPs) associated with susceptibility to leprosy per se and Type-I Reaction, and seven of them have been targeted by recent positive selection. Our study suggested that natural selection shaped our genomic diversity to face pathogen exposure including M. leprae infection. Each year, 200,000 new leprosy cases are reported worldwide. While there is unambiguous evidence for a role of host genetics in leprosy pathogenesis, the mechanisms by which the human host fights the infection are poorly understood. Here, we highlight the search for naturally occurring genetic variations that modulate gene expression levels following exposure to sonicate of Mycobacterium leprae, the bacterium causing the disease. Because M. leprae is not cultivable and the genuine immune cells involved in the host response during infection are still unknown, we performed a genome-wide search for such genetic variations after stimulation of whole-blood from leprosy patients with M. leprae sonicate. This design allowed to provide a general framework for the genetic control of host responses to M. leprae and outlined the contribution of host genetics to leprosy pathogenesis. Among the M. leprae-dependent genetic regulators of gene expression levels there was an enrichment of variants (i) associated with leprosy, (ii) located in transcription factor binding sites and (iii) targeted by recent positive selection.
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影响因子：
5.3
作者：
Alter A;de Léséleuc L;Van Thuc N;Thai VH;Huong NT;Ba NN;Cardoso CC;Grant AV;Abel L;Moraes MO;Alcaïs A;Schurr E
通讯作者：
Schurr E
影响因子：
6.4
作者：
Fava, Vinicius M.;Cobat, Aurelie;Schurr, Erwin
通讯作者：
Schurr, Erwin
影响因子：
5.3
作者：
Alter, Andrea;Fava, Vinicius Medeiros;Schurr, Erwin
通讯作者：
Schurr, Erwin
DOI：
10.1126/science.1224026
发表时间：
2012-09-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bogunovic D;Byun M;Durfee LA;Abhyankar A;Sanal O;Mansouri D;Salem S;Radovanovic I;Grant AV;Adimi P;Mansouri N;Okada S;Bryant VL;Kong XF;Kreins A;Velez MM;Boisson B;Khalilzadeh S;Ozcelik U;Darazam IA;Schoggins JW;Rice CM;Al-Muhsen S;Behr M;Vogt G;Puel A;Bustamante J;Gros P;Huibregtse JM;Abel L;Boisson-Dupuis S;Casanova JL
通讯作者：
Casanova JL
影响因子：
6.4
作者：
Grant, Audrey V.;Alter, Andrea;Alcais, Alexandre
通讯作者：
Alcais, Alexandre