Integrative Analysis of mRNA Expression and Half-Life Data Reveals Trans-Acting Genetic Variants Associated with Increased Expression of Stable Transcripts
Integrative Analysis of mRNA Expression and Half-Life Data Reveals Trans-Acting Genetic Variants Associated with Increased Expression of Stable Transcripts
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DOI：
10.1371/journal.pone.0079627
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发表时间：
2013-11-18
期刊：
影响因子：
3.7
通讯作者：
Seoighe, Cathal
中科院分区：
文献类型：
--
作者：
Nguyen, Thong T.;Seoighe, Cathal
基因表达的遗传变异对表型变异和疾病易感性有重要贡献。最近，一组顺式作用表达定量位点（eqtl）被发现是由影响RNA稳定性的多态性引起的。在这里，我们对影响RNA稳定性的反式作用变异进行了研究。我们首先证明，在高通量基因表达实验中，通过比较长寿命（稳定）和短寿命（不稳定）转录本的表达水平，可以检测稳定RNA的反式作用因子活性的差异。利用来自8个HapMap3群体的基因表达微阵列数据，我们计算了每个样本中长寿命转录本与短寿命转录本的相对表达等级。将其作为一种数量性状，采用全基因组关联方法，在北京CHB -汉族两个亚洲人群中鉴定出了与该性状密切相关的染色体20p13单核苷酸多态性（SNP） rs6137010；p=1x10(-4) in JPT - Japanese from Tokyo)。该SNP在CHB和JPT中是SNRPB的顺式eqtl，但在其他6个HapMap3群体中不是。SNRPB是剪接体的核心组成部分，先前已被证明影响许多RNA加工因子的表达。我们认为SNRPB的顺式eqtl可能直接导致亚洲人群中长寿命转录本相对表达的个体间差异。为了支持这一假设，敲除SNRPB导致长寿命转录本相对于短寿命转录本的相对表达显著减少。与非编码RNA相比，长寿命转录本相对表达较高的样本编码RNA的相对表达也较高，而来自内务管理基因的RNA的相对表达也高于非内务管理基因，这是由于编码RNA的衰变率较低，特别是那些执行内务管理功能的RNA，与非编码RNA相比。
Genetic variation in gene expression makes an important contribution to phenotypic variation and susceptibility to disease. Recently, a subset of cis-acting expression quantitative loci (eQTLs) has been found to result from polymorphisms that affect RNA stability. Here we carried out a search for trans-acting variants that influence RNA stability. We first demonstrate that differences in the activity of trans-acting factors that stabilize RNA can be detected by comparing the expression levels of long-lived (stable) and short-lived (unstable) transcripts in high-throughput gene expression experiments. Using gene expression microarray data generated from eight HapMap3 populations, we calculated the relative expression ranks of long-lived transcripts versus short-lived transcripts in each sample. Treating this as a quantitative trait, we applied genome-wide association and identified a single nucleotide polymorphism (SNP), rs6137010, on chromosome 20p13 with which it is strongly associated in two Asian populations (p=4x10(-10) in CHB - Han Chinese from Beijing; p=1x10(-4) in JPT - Japanese from Tokyo). This SNP is a cis-eQTL for SNRPB in CHB and JPT but not in the other six HapMap3 populations. SNRPB is a core component of the spliceosome, and has previously been shown to affect the expression of many RNA processing factors. We propose that a cis-eQTL of SNRPB may be directly responsible for inter-individual variation in relative expression of long-lived versus short-lived transcript in Asian populations. In support of this hypothesis, knockdown of SNRPB results in a significant reduction in the relative expression of long-lived versus short-lived transcripts. Samples with higher relative expression of long-lived transcripts also had higher relative expression of coding compared to non-coding RNA and of RNA from housekeeping compared to non-housekeeping genes, due to the lower decay rates of coding RNAs, particularly those that perform housekeeping functions, compared to non-coding RNAs.