Inferring polymorphism-induced regulatory gene networks active in human lymphocyte cell lines by weighted linear mixed model analysis of multiple RNA-Seq datasets.
Inferring polymorphism-induced regulatory gene networks active in human lymphocyte cell lines by weighted linear mixed model analysis of multiple RNA-Seq datasets.
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DOI：
10.1371/journal.pone.0078868
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhang K
中科院分区：
文献类型：
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作者：
Zhang W;Edwards A;Flemington EK;Zhang K
单核苷酸多态性（SNPs）导致了许多基因在个体间的表达差异。调控（性状相关）SNP通常位于（宿主）基因附近或内部，可能影响基因的转录或/和转录后修饰。但它的目标也可能包括物理上离它较远的基因。对这种多靶点干扰的一种启发式解释是，宿主基因通过转录或信号级联将SNP基因型效应转移到远端基因。宿主基因（调控基因）和远端基因（靶基因）之间的这些联系使得基因表达特征的遗传分析成为鉴定未知调控关系的一种很有前途的方法。在本研究中，通过对140个人类淋巴细胞系（LCLs）和国际HapMap项目分布的基因型的多源数字表达谱进行混合模型分析，我们确定了4.5万个潜在的SNP诱导基因之间的调控关系（表达性状与SNP基因型之间潜在关联的显著性水平为FDR < 0.01）。根据调控snp影响顺式和反式调控基因、改变mRNA水平或改变转录物剪接模式的两种不同机制，我们将鉴定出的关系分为四类（范式）。我们进一步将每一类中的关系组织成一组以顺式调控基因为中心的网络模块。我们发现网络模块中的目标基因通常具有显著的功能相似性，并且四个网络中的三个目标基因的分布大致类似于幂律，这是从突变实验中获得的基因网络的典型模式。通过两个案例研究，我们还证明了从已识别的网络模块中可以推断出重要的生物学见解。
Single-nucleotide polymorphisms (SNPs) contribute to the between-individual expression variation of many genes. A regulatory (trait-associated) SNP is usually located near or within a (host) gene, possibly influencing the gene’s transcription or/and post-transcriptional modification. But its targets may also include genes that are physically farther away from it. A heuristic explanation of such multiple-target interferences is that the host gene transfers the SNP genotypic effects to the distant gene(s) by a transcriptional or signaling cascade. These connections between the host genes (regulators) and the distant genes (targets) make the genetic analysis of gene expression traits a promising approach for identifying unknown regulatory relationships. In this study, through a mixed model analysis of multi-source digital expression profiling for 140 human lymphocyte cell lines (LCLs) and the genotypes distributed by the international HapMap project, we identified 45 thousands of potential SNP-induced regulatory relationships among genes (the significance level for the underlying associations between expression traits and SNP genotypes was set at FDR < 0.01). We grouped the identified relationships into four classes (paradigms) according to the two different mechanisms by which the regulatory SNPs affect their cis- and trans- regulated genes, modifying mRNA level or altering transcript splicing patterns. We further organized the relationships in each class into a set of network modules with the cis- regulated genes as hubs. We found that the target genes in a network module were often characterized by significant functional similarity, and the distributions of the target genes in three out of the four networks roughly resemble a power-law, a typical pattern of gene networks obtained from mutation experiments. By two case studies, we also demonstrated that significant biological insights can be inferred from the identified network modules.
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来自1,092个人基因组的遗传变异的综合图。
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通讯作者：
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作者：
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通讯作者：
Franke L
影响因子：
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作者：
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通讯作者：
Lempicki, Richard A.
影响因子：
64.8
作者：
通讯作者：
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