Bader Daniel M, Wilkening Stefan, Lin Gen, Tekkedil Manu M, Dietrich Kim, Steinmetz Lars M, Gagneur Julien
Computational Genomics, Gene Center, Ludwig Maximilians University, Munich, Germany.
European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
Mol Syst Biol. 2015 Jan 29;11(1):785. doi: 10.15252/msb.20145844.
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.
赋予对调控变异具有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错误表达在蛋白质水平上存在广泛的缓冲作用。但我们并未发现翻译缓冲普遍存在的证据。相反，我们发现RNA表达水平存在广泛的缓冲作用，这是通过反式作用的负反馈调节实现的，该调节降低了调控变异对基因表达的影响。我们的方法基于一种新颖的实验设计，即将酵母杂交菌株中的等位基因差异表达与其孢子库中的等位基因差异表达进行比较。杂交体中的等位基因差异表达仅归因于顺式调控差异。相反，在孢子库中，等位基因差异表达不仅归因于顺式调控差异，还归因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节的缓冲作用广泛存在，通常可补偿个体基因上约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，而且对低至中等表达水平的基因也更强，对这些基因而言，严格调控最为重要。我们认为，负反馈是沃丁顿（Waddington）定向化作用的一种机制，有助于积累可能在不同环境中具有选择优势的遗传变异。
