Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross.
Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross.
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使用协作十字架对SARS-COV敏感性基因座的基因组广泛识别。
DOI：
10.1371/journal.pgen.1005504
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发表时间：
2015-10
期刊：
影响因子：
4.5
通讯作者：
Baric RS
中科院分区：
文献类型：
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作者：
Gralinski LE;Ferris MT;Aylor DL;Whitmore AC;Green R;Frieman MB;Deming D;Menachery VD;Miller DR;Buus RJ;Bell TA;Churchill GA;Threadgill DW;Katze MG;McMillan L;Valdar W;Heise MT;Pardo-Manuel de Villena F;Baric RS
需要新的系统遗传学方法来快速识别调节复杂疾病结果的宿主基因和遗传网络。使用来自协作交叉小鼠小组早期系的遗传多样性动物，我们证明了与SARS-CoV感染的经典小鼠模型相比，表型范围大大扩大，包括肺部病理、体重减轻和病毒滴度。遗传图谱揭示了几个与不同疾病反应有关的位点，包括3号染色体上一个与血管弯曲相关的8.5Mb位点，包含23个基因和13个非编码rna。综合表型和遗传数据将该区域缩小到一个单一基因Trim55，这是一种E3泛素连接酶，在肌肉纤维维持中起作用。研究人员利用Trim55基因缺陷小鼠的肺病理和转录组学数据来验证其在sars - cov诱导的血管弯曲和炎症中的作用。这些数据建立了协作跨平台作为一个强大的遗传资源，用于揭示在远交种群体模型中微生物疾病严重程度、炎症和病毒复制的复杂性状的遗传贡献。新出现的病原体对人类健康构成重大威胁，在过去15年中，至少有六种高致病性病毒（包括四种呼吸道病毒）已从动物宿主传播到人群中。随着新病原体的出现，需要新的和更好的动物模型，以便更好地了解这些病原体引起的疾病；促进治疗方法的快速发展；重要的是评估自然宿主遗传变异在调节疾病结果中的作用。我们使用协作杂交（Collaborative Cross）的初始系（一种新获得的重组近交系小鼠组）来鉴定与SARS-CoV发病有关的多态宿主基因。我们发现了新的动物模型，可以更好地捕捉人类SARS患者的疾病范围，还发现了四个新的易感位点，控制着SARS诱导发病机制的各个方面。通过整合统计、遗传和生物信息学方法，我们能够缩小候选基因组区域，以高度可能的候选基因。我们将一个基因座缩小到一个候选基因Trim55，并通过敲除小鼠证实了它在SARS-CoV感染的炎症反应中的作用。这项工作确定了Trim55的新功能，也证明了CC作为鉴定复杂性状遗传贡献的平台的实用性。
New systems genetics approaches are needed to rapidly identify host genes and genetic networks that regulate complex disease outcomes. Using genetically diverse animals from incipient lines of the Collaborative Cross mouse panel, we demonstrate a greatly expanded range of phenotypes relative to classical mouse models of SARS-CoV infection including lung pathology, weight loss and viral titer. Genetic mapping revealed several loci contributing to differential disease responses, including an 8.5Mb locus associated with vascular cuffing on chromosome 3 that contained 23 genes and 13 noncoding RNAs. Integrating phenotypic and genetic data narrowed this region to a single gene, Trim55, an E3 ubiquitin ligase with a role in muscle fiber maintenance. Lung pathology and transcriptomic data from mice genetically deficient in Trim55 were used to validate its role in SARS-CoV-induced vascular cuffing and inflammation. These data establish the Collaborative Cross platform as a powerful genetic resource for uncovering genetic contributions of complex traits in microbial disease severity, inflammation and virus replication in models of outbred populations. New emerging pathogens are a significant threat to human health with at least six highly pathogenic viruses, including four respiratory viruses, having spread from animal hosts into the human population within the past 15 years. With the emergence of new pathogens, new and better animal models are needed in order to better understand the disease these pathogens cause; to assist in the rapid development of therapeutics; and importantly to evaluate the role of natural host genetic variation in regulating disease outcome. We used incipient lines of the Collaborative Cross, a newly available recombinant inbred mouse panel, to identify polymorphic host genes that contribute to SARS-CoV pathogenesis. We discovered new animal models that better capture the range of disease found in human SARS patients and also found four novel susceptibility loci governing various aspects of SARS-induced pathogenesis. By integrating statistical, genetic and bioinformatic approaches we were able to narrow candidate genome regions to highly likely candidate genes. We narrowed one locus to a single candidate gene, Trim55, and confirmed its role in the inflammatory response to SARS-CoV infection through the use of knockout mice. This work identifies a novel function for Trim55 and also demonstrates the utility of the CC as a platform for identifying the genetic contributions of complex traits.