Genome-wide strand asymmetry in massively parallel reporter activity favors genic strands.
Genome-wide strand asymmetry in massively parallel reporter activity favors genic strands.
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DOI：
10.1101/gr.270751.120
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发表时间：
2021-05
期刊：
影响因子：
7
通讯作者：
Cooper GM
中科院分区：
文献类型：
--
作者：
Roberts BS;Partridge EC;Moyers BA;Agarwal V;Newberry KM;Martin BK;Shendure J;Myers RM;Cooper GM
大规模平行报告基因分析（MPRA）是表征人类基因组中调控元件的有用工具。通常不是分析焦点的MPRA的一个方面是其固有的区分给定序列元件的活性水平的能力，当相对于报告构建体以其两种可能的方向放置时。在这里，我们描述了普遍的链不对称性的MPRA信号的数据集，从多个报告配置在已发表的和新报道的数据。这些效应在不同的细胞类型中以及在细胞类型内的不同处理中是可再现的，并且在注释的调控元件之内和之外都被观察到。从基因体中的元件来看，MPRA链的不对称性有利于有义链，这表明与内源性转录相关的功能正在驱动这一现象。同样，我们发现在Alu移动的元件插入中，链的不对称性有利于祖先反转录转座子的转录链。这种效应在人类基因组中Alu元件的多样性中是一致的，并且在分歧较小的Alu元件中更为明显。我们发现驱动MPRA链不对称性的序列特征，并显示其预测单独从序列。我们看到了一些RNA稳定和转录激活机制的证据，并假设这种效应是由有利于有效转录的自然选择驱动的。我们的研究结果表明，链的不对称性是一个普遍的和可重复的MPRA数据的功能。更重要的是，MPRA不对称性有利于自然转录的链，这表明它源于对基因和基因组进化具有重大全球影响的保留生物功能。
Massively parallel reporter assays (MPRAs) are useful tools to characterize regulatory elements in human genomes. An aspect of MPRAs that is not typically the focus of analysis is their intrinsic ability to differentiate activity levels for a given sequence element when placed in both of its possible orientations relative to the reporter construct. Here, we describe pervasive strand asymmetry of MPRA signals in data sets from multiple reporter configurations in both published and newly reported data. These effects are reproducible across different cell types and in different treatments within a cell type and are observed both within and outside of annotated regulatory elements. From elements in gene bodies, MPRA strand asymmetry favors the sense strand, suggesting that function related to endogenous transcription is driving the phenomenon. Similarly, we find that within Alu mobile element insertions, strand asymmetry favors the transcribed strand of the ancestral retrotransposon. The effect is consistent across the multiplicity of Alu elements in human genomes and is more pronounced in less diverged Alu elements. We find sequence features driving MPRA strand asymmetry and show its prediction from sequence alone. We see some evidence for RNA stabilization and transcriptional activation mechanisms and hypothesize that the effect is driven by natural selection favoring efficient transcription. Our results indicate that strand asymmetry is a pervasive and reproducible feature in MPRA data. More importantly, the fact that MPRA asymmetry favors naturally transcribed strands suggests that it stems from preserved biological functions that have a substantial, global impact on gene and genome evolution.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
1.5
作者：
Jurka, J;Kapitonov, VV;Smit, AFA
通讯作者：
Smit, AFA
影响因子：
8.8
作者：
Agarwal, Vikram;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
3
作者：
Haiminen, Niina;Mannila, Heikki;Terzi, Evimaria
通讯作者：
Terzi, Evimaria