Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.
Proc Biol Sci. 2013 Aug 14;280(1768):20131313. doi: 10.1098/rspb.2013.1313. Print 2013 Oct 7.
Requirements for gene regulation vary widely both within and among species. Some genes are constitutively expressed, whereas other genes require complex regulatory control. Transcriptional regulation is often controlled by a module of multiple transcription factor binding sites that, in combination, mediate the expression of a target gene. Here, we study how such regulatory modules evolve in response to natural selection. Using a population-genetic model, we show that complex regulatory modules which contain a larger number of binding sites must employ binding motifs that are less specific, on average, compared with smaller regulatory modules. This effect is extremely general, and it holds regardless of the selected binding logic that a module experiences. We attribute this phenomenon to the inability of stabilizing selection to maintain highly specific sites in large regulatory modules. Our analysis helps to explain broad empirical trends in the Saccharomyces cerevisiae regulatory network: those genes with a greater number of distinct transcriptional regulators feature less-specific binding motifs, compared with genes with fewer regulators. Our results also help to explain empirical trends in module size and motif specificity across species, ranging from prokaryotes to single-cellular and multi-cellular eukaryotes.
基因调控的要求在物种内和物种间差异很大。有些基因是组成型表达的，而有些基因则需要复杂的调控控制。转录调控通常由多个转录因子结合位点模块控制，这些结合位点模块组合起来介导靶基因的表达。在这里，我们研究了这种调节模块如何响应自然选择而进化。使用群体遗传学模型，我们表明，与较小的调节模块相比，包含更多结合位点的复杂调节模块平均必须采用特异性较低的结合基序。这种效应非常普遍，并且无论模块经历的选择结合逻辑如何，这种效应都成立。我们将这种现象归因于稳定选择无法维持大型调节模块中高度特异性的位点。我们的分析有助于解释酿酒酵母调控网络中的广泛经验趋势：与具有较少调控因子的基因相比，具有更多转录调控因子的基因具有特异性较低的结合基序。我们的结果还有助于解释从原核生物到单细胞和多细胞真核生物的跨物种的模块大小和基序特异性的经验趋势。
