In silico evolution of the Drosophila gap gene regulatory sequence under elevated mutational pressure.
In silico evolution of the Drosophila gap gene regulatory sequence under elevated mutational pressure.
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DOI：
10.1186/s12862-016-0866-y
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发表时间：
2017-02-07
影响因子：
3.4
通讯作者：
Gursky VV
中科院分区：
文献类型：
--
作者：
Chertkova AA;Schiffman JS;Nuzhdin SV;Kozlov KN;Samsonova MG;Gursky VV
顺式调控序列通常由许多低亲和力转录因子结合位点（TFBS）组成。如果没有基因型-表型图谱的详细知识，确定调节序列组成的进化和功能重要性就会受到阻碍。我们模拟的调控序列参与果蝇胚胎分割在早期发育过程中的演变。自然选择评估由发育网络的计算模型产生的基因表达动态。我们观察到的转录因子结合位点的总数在进化过程中急剧减少。尽管随着时间的推移平均序列结合能降低，但调控序列倾向于含有增加的高亲和力转录因子结合位点的组织。此外，不同序列片段的结合能显示出随时间的普遍存在的相互关联。在整个模拟过程中，只有不到10%的初始TFBS得到维护，被视为“核心”站点。这些位点具有增加的功能重要性，如在野生型条件下评估的，并且它们的结合能分布高度保守。此外，TFBS内的核心站点的紧密接近表现出增加的寿命，反映了与核心站点的功能调节相互作用。为了应对突变压力的升高，进化倾向于对具有较少（尽管平均而言）较强功能性转录因子结合位点的调控序列组织进行采样。这些组织也是由核心结合位点与其局部附近的位点之间的调节相互作用形成的。本文的在线版本（doi：10.1186/s12862-016-0866-y）包含补充材料，可供授权用户使用。
Cis-regulatory sequences are often composed of many low-affinity transcription factor binding sites (TFBSs). Determining the evolutionary and functional importance of regulatory sequence composition is impeded without a detailed knowledge of the genotype-phenotype map. We simulate the evolution of regulatory sequences involved in Drosophila melanogaster embryo segmentation during early development. Natural selection evaluates gene expression dynamics produced by a computational model of the developmental network. We observe a dramatic decrease in the total number of transcription factor binding sites through the course of evolution. Despite a decrease in average sequence binding energies through time, the regulatory sequences tend towards organisations containing increased high affinity transcription factor binding sites. Additionally, the binding energies of separate sequence segments demonstrate ubiquitous mutual correlations through time. Fewer than 10% of initial TFBSs are maintained throughout the entire simulation, deemed ‘core’ sites. These sites have increased functional importance as assessed under wild-type conditions and their binding energy distributions are highly conserved. Furthermore, TFBSs within close proximity of core sites exhibit increased longevity, reflecting functional regulatory interactions with core sites. In response to elevated mutational pressure, evolution tends to sample regulatory sequence organisations with fewer, albeit on average, stronger functional transcription factor binding sites. These organisations are also shaped by the regulatory interactions among core binding sites with sites in their local vicinity. The online version of this article (doi:10.1186/s12862-016-0866-y) contains supplementary material, which is available to authorized users.