Negative feedback buffers effects of regulatory variants.
Negative feedback buffers effects of regulatory variants.
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DOI：
10.15252/msb.20145844
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发表时间：
2015-01-29
影响因子：
9.9
通讯作者：
Gagneur, Julien
中科院分区：
文献类型：
--
作者：
Bader, Daniel M;Wilkening, Stefan;Gagneur, Julien
赋予抗调控变异的稳健性的机制一直存在争议。先前的研究表明，在翻译过程中，RNA错表达在蛋白质水平上广泛缓冲。我们没有发现证据表明翻译缓冲是常见的。相反，我们发现在RNA表达水平上，通过反式作用的负反馈调控发挥了广泛的缓冲作用，从而降低了调控变异体对基因表达的影响。我们的方法是基于一种新颖的实验设计，其中等位基因差异表达在酵母杂交菌株比较其孢子池等位基因差异表达。杂种中等位基因的差异表达仅仅是由于顺式调控差异。相反，在孢子池中，等位基因的差异表达不仅是由于顺式调控的差异，还由于包括负反馈在内的局部反式效应。我们发现，通过这种局部反式调控的缓冲作用是普遍存在的，通常补偿了单个基因上约15%的顺式调控效应。负反馈不仅对必需基因更强，表明其功能相关性，而且对中低表达水平的基因也更强，对这些基因最重要的是严格调控。我们认为负反馈是Waddington's渠化的一种机制，它促进了遗传变异的积累，从而可能在不同的环境中获得选择优势。
Mechanisms conferring robustness against regulatory variants have been controversial. Previous studies suggested widespread buffering of RNA misexpression on protein levels during translation. We do not find evidence that translational buffering is common. Instead, we find extensive buffering at the level of RNA expression, exerted through negative feedback regulation acting in trans, which reduces the effect of regulatory variants on gene expression. Our approach is based on a novel experimental design in which allelic differential expression in a yeast hybrid strain is compared to allelic differential expression in a pool of its spores. Allelic differential expression in the hybrid is due to cis-regulatory differences only. Instead, in the pool of spores allelic differential expression is not only due to cis-regulatory differences but also due to local trans effects that include negative feedback. We found that buffering through such local trans regulation is widespread, typically compensating for about 15% of cis-regulatory effects on individual genes. Negative feedback is stronger not only for essential genes, indicating its functional relevance, but also for genes with low to middle levels of expression, for which tight regulation matters most. We suggest that negative feedback is one mechanism of Waddington's canalization, facilitating the accumulation of genetic variants that might give selective advantage in different environments.