Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Genome Res. 2011 Apr;21(4):545-54. doi: 10.1101/gr.111211.110. Epub 2010 Dec 20.
Expression levels of many human genes are under the genetic control of expression quantitative trait loci (eQTLs). Despite technological advances, the precise molecular mechanisms underlying most eQTLs remain elusive. Here, we use deep mRNA sequencing of two CEU individuals to investigate those mechanisms, with particular focus on the role of splicing control loci (sQTLs). We identify a large number of genes that are differentially spliced between the two samples and associate many of those differences with nearby single nucleotide polymorphisms (SNPs). Subsequently, we investigate the potential effect of splicing SNPs on eQTL control in general. We find a significant enrichment of alternative splicing (AS) events within a set of highly confident eQTL targets discovered in previous studies, suggesting a role of AS in regulating overall gene expression levels. Next, we demonstrate high correlation between the levels of mature (exonic) and unprocessed (intronic) RNA, implying that ∼75% of eQTL target variance can be explained by control at the level of transcription, but that the remaining 25% may be regulated co- or post-transcriptionally. We focus on eQTL targets with discordant mRNA and pre-mRNA expression patterns and use four examples: USMG5, MMAB, MRPL43, and OAS1, to dissect the exact downstream effects of the associated genetic variants.
许多人类基因的表达水平受到表达数量性状基因座 (eQTL) 的遗传控制。尽管技术不断进步,但大多数 eQTL 的精确分子机制仍然难以捉摸。在这里,我们使用两个 CEU 个体的深度 mRNA 测序来研究这些机制,特别关注剪接调控位点 (sQTL) 的作用。我们鉴定出大量在两个样本之间存在差异剪接的基因,并将这些差异中的许多与附近的单核苷酸多态性 (SNP) 相关联。随后,我们研究了剪接 SNP 对一般 eQTL 控制的潜在影响。我们发现,在先前研究中发现的一组高度可信的 eQTL 靶标中,存在大量替代剪接 (AS) 事件的显著富集,这表明 AS 在调节整体基因表达水平中发挥作用。接下来,我们证明了成熟 (外显子) 和未加工 (内含子) RNA 水平之间存在高度相关性,这意味着约 75%的 eQTL 靶标方差可以通过转录水平的控制来解释,但剩余的 25%可能在转录后或共转录水平上受到调节。我们关注具有不一致 mRNA 和前体 mRNA 表达模式的 eQTL 靶标,并使用四个例子:USMG5、MMAB、MRPL43 和 OAS1,来剖析相关遗传变异的精确下游效应。