Quantitative epistasis analysis and pathway inference from genetic interaction data.
Quantitative epistasis analysis and pathway inference from genetic interaction data.
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DOI：
10.1371/journal.pcbi.1002048
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发表时间：
2011-05
影响因子：
4.3
通讯作者：
Kærn M
中科院分区：
文献类型：
--
作者：
Phenix H;Morin K;Batenchuk C;Parker J;Abedi V;Yang L;Tepliakova L;Perkins TJ;Kærn M
从定量遗传相互作用数据中推断调控和代谢网络模型仍然是系统生物学中的一个主要挑战。在这里，我们提出了一个新的定量模型来解释上位性的途径响应外部信号。该模型提供了一个实验方法的基础，以确定这种途径的架构，并建立了一套新的规则来推断其中的基因顺序。该方法还允许提取定量参数，使新的信息水平被添加到遗传网络模型。它适用于任何系统，其中组合功能丧失突变的影响可以足够准确地量化。我们测试的方法进行了系统的分析，一个彻底的特点真核基因网络，半乳糖利用途径在酿酒酵母。为了这个目的，我们量化了单基因和双基因缺失对两个表型性状，健身和报告基因表达的影响。我们表明，应用我们的方法健身性状揭示了代谢酶的顺序和积累代谢中间产物的影响。相反，对表达性状的分析揭示了转录调控基因的顺序、次级调控信号及其相对强度。令人惊讶的是，当两个性状的分析相结合时，该方法正确地推断出80%的已知关系，而没有任何误报。细胞已经进化出复杂的途径，使它们能够最佳地利用可用的营养物质，例如，改变基因表达以应对外部挑战。这些途径的映射提供了对细胞功能的理解，这些功能对于从生物燃料生产到药物发现的许多领域的进步至关重要。在这项研究中，我们开发了一种新的方法来映射在细胞对给定信号或压力的反应中起作用的基因的通路。该方法代表了一个重大的进步，因为它充分利用现代基因组学技术，提供有关基因功能的新的，详细的信息，包括不同基因单独的贡献，以及与其他基因或途径的组合。我们在酵母中的一条途径上测试了这种方法，该途径在人类中的等同物与一种严重的、可能致命的遗传性疾病半乳糖血症有关。我们证明，该方法可以高度准确地重建这一途径，正确地分离基因的主要和次要功能，并概括已知的机制与疾病。
Inferring regulatory and metabolic network models from quantitative genetic interaction data remains a major challenge in systems biology. Here, we present a novel quantitative model for interpreting epistasis within pathways responding to an external signal. The model provides the basis of an experimental method to determine the architecture of such pathways, and establishes a new set of rules to infer the order of genes within them. The method also allows the extraction of quantitative parameters enabling a new level of information to be added to genetic network models. It is applicable to any system where the impact of combinatorial loss-of-function mutations can be quantified with sufficient accuracy. We test the method by conducting a systematic analysis of a thoroughly characterized eukaryotic gene network, the galactose utilization pathway in Saccharomyces cerevisiae. For this purpose, we quantify the effects of single and double gene deletions on two phenotypic traits, fitness and reporter gene expression. We show that applying our method to fitness traits reveals the order of metabolic enzymes and the effects of accumulating metabolic intermediates. Conversely, the analysis of expression traits reveals the order of transcriptional regulatory genes, secondary regulatory signals and their relative strength. Strikingly, when the analyses of the two traits are combined, the method correctly infers ∼80% of the known relationships without any false positives. Cells have evolved elaborate pathways that allow them to optimally use available nutrients, for example, and alter gene expression in response to external challenges. The mapping of these pathways provides an understanding of cell function critical for advancements in a number of fields, from biofuel production to drug discovery. In this study, we developed a novel method to map pathways of genes that function in the cellular response to a given signal or stress. The method represents a significant advancement since it takes full advantage of modern genomics techniques to provide novel, detailed information about gene function, including the contribution from different genes individually, and in combination with other genes or pathways. We tested the method on a pathway in yeast whose human equivalent is associated with a serious and potentially fatal hereditary disease called galactosemia. We demonstrate that the method allows a highly accurate reconstruction of this pathway, correctly segregating genes with major and minor functions, and recapitulating the known mechanisms associated with the disease.
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影响因子：
3.8
作者：
HALEY, CS;KNOTT, SA
通讯作者：
KNOTT, SA
DOI：
10.1073/pnas.0712255105
发表时间：
2008-03-04
影响因子：
11.1
作者：
Mani, Ramamurthy;Onge, Robert P. St.;Roth, Frederick P.
通讯作者：
Roth, Frederick P.
影响因子：
3.8
作者：
de Jongh, Willem A.;Bro, Christoffer;Nielsen, Jens
通讯作者：
Nielsen, Jens
影响因子：
4.4
作者：
Batenchuk, Cory;Tepliakova, Lioudmila;Kaern, Mads
通讯作者：
Kaern, Mads
DOI：
10.1073/pnas.220392197
发表时间：
2000-10-24
影响因子：
11.1
作者：
Butte, AJ;Tamayo, P;Kohane, IS
通讯作者：
Kohane, IS