Large-Scale trans-eQTLs Affect Hundreds of Transcripts and Mediate Patterns of Transcriptional Co-regulation
Large-Scale trans-eQTLs Affect Hundreds of Transcripts and Mediate Patterns of Transcriptional Co-regulation
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DOI：
10.1016/j.ajhg.2017.02.004
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发表时间：
2017-04-06
影响因子：
9.8
通讯作者：
Cotsapas, Chris
中科院分区：
文献类型：
--
作者：
Brynedal, Boel;Choi, JinMyung;Cotsapas, Chris
努力破译基因调控的差异和相应的表型差异之间的因果关系，已经阻碍了几个基本的技术挑战。虽然检测本地的顺式eQTL现在是常规的，但距离起源基因较远的反式eQTL要困难得多，因为目前必须将数百万个SNP与数千个转录本进行比较。在这里，我们展示了一种替代方法：我们同时寻找与许多基因表达相关的SNP，发现数百个trans-eQTL各自影响三个非洲人群淋巴母细胞系中的数百个转录本。这些反式eQTL在三个群体中靶向相同的基因，并显示出相同的效应方向。我们发现，一组高置信度的trans-eQTL的靶转录本编码的蛋白质相互作用比预期的更频繁的机会，由相同的转录因子结合，并丰富的路径注释指示的作用，在基本的细胞内稳态。因此，我们证明，我们的方法可以揭示影响共调节基因组的反式作用转录控制电路：理解细胞通路和过程是如何编排的关键。
Efforts to decipher the causal relationships between differences in gene regulation and corresponding differences in phenotype have been stymied by several basic technical challenges. Although detecting local, cis-eQTLs is now routine, trans-eQTLs, which are distant from the genes of origin, are far more difficult to find because millions of SNPs must currently be compared to thousands of transcripts. Here, we demonstrate an alternative approach: we looked for SNPs associated with the expression of many genes simultaneously and found that hundreds of trans-eQTLs each affect hundreds of transcripts in lymphoblastoid cell lines across three African populations. These trans-eQTLs target the same genes across the three populations and show the same direction of effect. We discovered that target transcripts of a high-confidence set of trans-eQTLs encode proteins that interact more frequently than expected by chance, are bound by the same transcription factors, and are enriched for pathway annotations indicative of roles in basic cell homeostasis. We thus demonstrate that our approach can uncover trans-acting transcriptional control circuits that affect co-regulated groups of genes: a key to understanding how cellular pathways and processes are orchestrated.