Aberrant gene expression in humans.
Aberrant gene expression in humans.
复制标题
DOI：
10.1371/journal.pgen.1004942
复制
发表时间：
2015-01
期刊：
影响因子：
4.5
通讯作者：
Cai JJ
中科院分区：
文献类型：
--
作者：
Zeng Y;Wang G;Yang E;Ji G;Brinkmeyer-Langford CL;Cai JJ
基因表达作为一种中间分子表型一直是研究的热点。特别是，表达数量性状位点（eQTL）的研究通过发现解释基因表达水平变化的遗传变异，为理解基因调控提供了希望。现有的eQTL方法是为评估常见变异的影响而设计的，而不是罕见变异。在这里，我们通过建立一个新的分析框架来评估罕见或私有变异对基因表达的影响，从而解决了这个问题。我们的方法从识别与大多数群体表现出明显不同的基因表达的异常个体开始，然后揭示这些异常个体中私人snp对异常基因表达的贡献。使用群体规模的mRNA测序数据，我们使用多变量方法识别异常个体。我们发现，涉及细胞调控和信号转导的基因组更容易检测到异常个体，而涉及代谢途径和其他基本分子功能的基因组则不太可能检测到异常个体。多态性数据分析表明，异常个体的私有snp富集在相应异常表达基因的增强子和启动子区域，表明私有snp具有特定的调控作用，而常见的调控遗传变异（即eQTL SNPs）几乎没有证据表明其参与。其他数据表明，非遗传因素也可能是基因表达异常的基础。综上所述，我们的研究结果提出了一个新的观点，即当存在遗传的、罕见的个体间变异时，常见的eqtl无法预测基因表达。我们描述的分析框架，考虑到现实的差异表型稳健性，可能是有价值的研究复杂的性状和条件。个体的独特性是由于遗传、表观遗传和环境决定因素组合的差异。了解表型变异的遗传基础是遗传学的一个关键目标。基因表达一直被认为是一种中间表型，基因表达与普通人群中常见的遗传变异之间的关联已经得到了令人信服的证实。然而，很少有方法来评估罕见的遗传变异，如私有snp，对基因表达的影响。在这里，我们描述了一种基于多变量异常值检测理论的系统方法，以识别相对于研究队列的其余部分显示异常或异常基因表达的个体。通过表征检测到的异常值和相应的基因集，我们能够确定哪些基因集倾向于异常表达，哪些个体在群体中表现出异常基因表达。我们的主要发现之一是，私人snp可能导致异常个体的异常表达。这些私人snp更频繁地位于异常表达基因的增强子和启动子区域，这表明这些snp可能具有调节功能。总的来说，我们的研究结果为个体间变异的决定因素提供了新的见解，这些因素尚未通过大规模人群水平的队列研究进行评估。
Gene expression as an intermediate molecular phenotype has been a focus of research interest. In particular, studies of expression quantitative trait loci (eQTL) have offered promise for understanding gene regulation through the discovery of genetic variants that explain variation in gene expression levels. Existing eQTL methods are designed for assessing the effects of common variants, but not rare variants. Here, we address the problem by establishing a novel analytical framework for evaluating the effects of rare or private variants on gene expression. Our method starts from the identification of outlier individuals that show markedly different gene expression from the majority of a population, and then reveals the contributions of private SNPs to the aberrant gene expression in these outliers. Using population-scale mRNA sequencing data, we identify outlier individuals using a multivariate approach. We find that outlier individuals are more readily detected with respect to gene sets that include genes involved in cellular regulation and signal transduction, and less likely to be detected with respect to the gene sets with genes involved in metabolic pathways and other fundamental molecular functions. Analysis of polymorphic data suggests that private SNPs of outlier individuals are enriched in the enhancer and promoter regions of corresponding aberrantly-expressed genes, suggesting a specific regulatory role of private SNPs, while the commonly-occurring regulatory genetic variants (i.e., eQTL SNPs) show little evidence of involvement. Additional data suggest that non-genetic factors may also underlie aberrant gene expression. Taken together, our findings advance a novel viewpoint relevant to situations wherein common eQTLs fail to predict gene expression when heritable, rare inter-individual variation exists. The analytical framework we describe, taking into consideration the reality of differential phenotypic robustness, may be valuable for investigating complex traits and conditions. The uniqueness of individuals is due to differences in the combination of genetic, epigenetic and environmental determinants. Understanding the genetic basis of phenotypic variation is a key objective in genetics. Gene expression has been considered as an intermediate phenotype, and the association between gene expression and commonly-occurring genetic variants in the general population has been convincingly established. However, there are few methods to assess the impact of rare genetic variants, such as private SNPs, on gene expression. Here we describe a systematic approach, based on the theory of multivariate outlier detection, to identify individuals that show unusual or aberrant gene expression, relative the rest of the study cohort. Through characterizing detected outliers and corresponding gene sets, we are able to identify which gene sets tend to be aberrantly expressed and which individuals show deviant gene expression within a population. One of our major findings is that private SNPs may contribute to aberrant expression in outlier individuals. These private SNPs are more frequently located in the enhancer and promoter regions of genes that are aberrantly expressed, suggesting a possible regulatory function of these SNPs. Overall, our results provide new insight into the determinants of inter-individual variation, which have not been evaluated by large population-level cohort studies.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Fairfax, Benjamin P.;Makino, Seiko;Radhakrishnan, Jayachandran;Plant, Katharine;Leslie, Stephen;Dilthey, Alexander;Ellis, Peter;Langford, Cordelia;Vannberg, Fredrik O.;Knight, Julian C.
通讯作者：
Knight, Julian C.
通过替代变量分析捕获基因表达研究中的异质性。
影响因子：
4.5
作者：
Leek, Jeffrey T.;Storey, John D.
通讯作者：
Storey, John D.
DOI：
10.1126/science.1217283
发表时间：
2012-05-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Keinan A;Clark AG
通讯作者：
Clark AG
影响因子：
3.7
作者：
ROUSSEEUW, PJ
通讯作者：
ROUSSEEUW, PJ