精确调控编码的动态进化产生了发育增强子的聚类特征
Dynamic evolution of precise regulatory encodings creates the clustered signature of developmental enhancers
摘要：
一种被称为Dorsal的形态发生蛋白，通过与基因组中的转录增强子结合，形成果蝇胚胎背腹体轴的模式。每个这样的增强子在Dorsal的独特阈值浓度下激活邻近基因。这些增强子中的背结合位点簇和其他增强子中的类似簇的存在激发了位点密度中的阈值编码模型。然而，我们发现分隔一对专门的Dorsal和Twist结合位点的间隔区的精确长度决定了阈值响应。尽管有这个结果，由这个间隔元件决定的功能范围以及其周围背侧位点簇的作用和起源仍然完全未知。在这里，我们的实验与增强子从不同的果蝇基因组，包括大型未压缩的基因组从ananassae和willistoni，并报告三个主要的相互依赖的结果。首先，我们映射阈值编码间隔变量的功能范围。其次，我们发现，大多数网站在集群是非功能性的发散元件，已被分离超出编码的功能范围。第三，我们验证了一个进化模型，涉及频繁更换的阈值编码，其精度很容易过时的移位精度。编码被更新的编码所取代的过程是由Dorsal和Twist结合基序的回文性质以及专门的Twist结合位点中固有的重复不稳定性促进的，这严重影响了将其连接到Dorsal的间隔区的长度。随着时间的推移，编码的选择性弃用和替换的动态过程增加了越来越多的deadened元素或necro-elements，并强烈地影响了局部序列组成。... [摘要截断]
英文摘要：
A morphogenic protein known as Dorsal patterns the embryonic dorsoventral body axis of Drosophila by binding to transcriptional enhancers across the genome. Each such enhancer activates a neighboring gene at a unique threshold concentration of Dorsal. The presence of Dorsal binding site clusters in these enhancers and of similar clusters in other enhancers has motivated models of threshold-encoding in site density. However, we found that the precise length of a spacer separating a pair of specialized Dorsal and Twist binding sites determines the threshold-response. Despite this result, the functional range determined by this spacer element as well as the role and origin of its surrounding Dorsal site cluster remained completely unknown. Here, we experiment with enhancers from diverse Drosophila genomes, including the large uncompacted genomes from ananassae and willistoni, and report three major interdependent results. First, we map the functional range of the threshold-encoding spacer variable. Second, we show that the majority of sites at the cluster are non-functional divergent elements that have been separated beyond the encoding's functional range. Third, we verify an evolutionary model involving the frequent replacement of a threshold encoding, whose precision is easily outdated by shifting accuracy. The process by which encodings are replaced by newer ones is facilitated by the palindromic nature of the Dorsal and Twist binding motifs and by intrinsic repeat-instability in the specialized Twist binding site, which critically impacts the length of the spacer linking it to Dorsal. Over time, the dynamic process of selective deprecation and replacement of encodings adds to a growing cluster of deadened elements, or necro-elements, and strongly biases local sequence composition. ... [ABSTRACT TRUNCATED]
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