Under-dominance constrains the evolution of negative autoregulation in diploids.
Under-dominance constrains the evolution of negative autoregulation in diploids.
复制标题
DOI：
10.1371/journal.pcbi.1002992
复制
发表时间：
2013
影响因子：
4.3
通讯作者：
Reuter M
中科院分区：
文献类型：
--
作者：
Stewart AJ;Seymour RM;Pomiankowski A;Reuter M
调控网络已经进化，使基因表达能够快速跟踪环境的变化，并在没有变化的情况下缓冲扰动和维持细胞动态平衡。理论工作和对大肠杆菌的实证研究表明，负自动调节既能提供快速反应时间，又能减少固有噪声，这反映在几乎一半的大肠杆菌转录因子是负自动调节的事实上。然而，在酿酒酵母的转录因子中很少有负的自我调节。这种差异是令人惊讶的，因为在其他方面，大肠杆菌和酿酒酵母具有相似的网络基序。在这项研究中，我们研究了果蝇和人类转录因子之间的调节相互作用，并表明它们具有与酿酒酵母相似的负自动调节的缺乏。然后，我们提出了一个模型，证明了物种之间使用的降噪策略的这种显著差异可以通过对二倍体中负自动调节进化的限制来解释。我们发现，同一细胞内同源基因对之间的调控相互作用可以导致欠显性突变，从而导致更强的自动调节，并减少纯合子中的噪声，矛盾的是，可能会导致杂合子中噪声的增加。这严重限制了二倍体进化负自动调节作为降噪机制的能力。我们的工作为大肠杆菌和酵母、果蝇和人类之间的调控结构之间的差异提供了一个简单而一般的解释。它还表明，基因网络中的二倍体效应可能会产生与直觉相反的后果，可能会深刻影响进化过程。所有的基因都必须处理固有的噪音，并且已经进化出各种机制来减少它。转录因子降噪的一个重要机制是负自动调节，即基因产物抑制其自身的转录速率。负自我调节在大肠杆菌中经常发生，但我们发现，在酿酒酵母、黑腹葡萄球菌和人类中发生的更少。虽然这些生物体的遗传结构有许多重要的差异，但它们往往共享相似的网络基序轮廓，除了负自动调节之外。这使得负面自动监管程度的差异变得更加引人注目，因为它缺乏任何明显的解释。我们的研究提供了一个潜在的解释，通过比较单倍体和二倍体中负自动调节作为降噪机制的进化性。我们发现，在二倍体中，在一个基因拷贝上增加负自动调节强度的突变通常会增加基因表达的总体噪音。这导致了欠显性，即杂合子比纯合子更不适合。结果是，二倍体中负自我调节的进化受到了显著的限制。我们使用详细的分子模拟和进化模拟的组合来验证我们的结果
Regulatory networks have evolved to allow gene expression to rapidly track changes in the environment as well as to buffer perturbations and maintain cellular homeostasis in the absence of change. Theoretical work and empirical investigation in Escherichia coli have shown that negative autoregulation confers both rapid response times and reduced intrinsic noise, which is reflected in the fact that almost half of Escherichia coli transcription factors are negatively autoregulated. However, negative autoregulation is rare amongst the transcription factors of Saccharomyces cerevisiae. This difference is surprising because E. coli and S. cerevisiae otherwise have similar profiles of network motifs. In this study we investigate regulatory interactions amongst the transcription factors of Drosophila melanogaster and humans, and show that they have a similar dearth of negative autoregulation to that seen in S. cerevisiae. We then present a model demonstrating that this stiking difference in the noise reduction strategies used amongst species can be explained by constraints on the evolution of negative autoregulation in diploids. We show that regulatory interactions between pairs of homologous genes within the same cell can lead to under-dominance — mutations which result in stronger autoregulation, and decrease noise in homozygotes, paradoxically can cause increased noise in heterozygotes. This severely limits a diploid's ability to evolve negative autoregulation as a noise reduction mechanism. Our work offers a simple and general explanation for a previously unexplained difference between the regulatory architectures of E. coli and yeast, Drosophila and humans. It also demonstrates that the effects of diploidy in gene networks can have counter-intuitive consequences that may profoundly influence the course of evolution. All genes have to deal with intrinsic noise, and a variety of mechanisms have evolved to reduce it. One important mechanism of noise reduction for transcription factors is negative autoregulation, in which a gene product represses its own rate of transcription. Negative auotregulation occurs frequently in E. coli but, we find, occurs much more rarely in S. cerevisiae, D. melanogaster and humans. Whilst there are a great many important differences in the genetic architectures of these organisms, they tend to share, with the exception of negative autoregulation, similar profiles of network motifs. This makes the discrepancy in the degree of negative autoregulation all the more striking, as it lacks any obvious explanation. Our study presents a potential explanation, by comparing the evolvability of negative autoregulation as a noise reduction mechanism in haploids and diploids. We show that, in diploids, mutations that increase the strength of negative autoregulation at one gene copy often increase overall noise in gene expression. This results in under-dominance, in which heterozygotes are less fit than homozygotes. The result is that the evolution of negative autoregulation in diploids is significantly constrained. We verify our results using a combination of detailed molecular simulations and evolutionary simulations
登录
查看更多内容
影响因子：
64.8
作者：
Becskei, A;Serrano, L
通讯作者：
Serrano, L
DOI：
10.1073/pnas.0808500106
发表时间：
2009-06-02
影响因子：
11.1
作者：
Gerland, Ulrich;Hwa, Terence
通讯作者：
Hwa, Terence
TransFac及其模块移植：真核生物中的转录基因调节。
影响因子：
14.9
作者：
Matys V;Kel-Margoulis OV;Fricke E;Liebich I;Land S;Barre-Dirrie A;Reuter I;Chekmenev D;Krull M;Hornischer K;Voss N;Stegmaier P;Lewicki-Potapov B;Saxel H;Kel AE;Wingender E
通讯作者：
Wingender E
影响因子：
3
作者：
Lässig M
通讯作者：
Lässig M
影响因子：
5.8
作者：
Bergman, CM;Carlson, JW;Celniker, SE
通讯作者：
Celniker, SE