Selection and thermostability suggest G-quadruplexes are novel functional elements of the human genome.
Selection and thermostability suggest G-quadruplexes are novel functional elements of the human genome.
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DOI：
10.1101/gr.269589.120
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发表时间：
2021-07
期刊：
影响因子：
7
通讯作者：
Makova KD
中科院分区：
文献类型：
--
作者：
Guiblet WM;DeGiorgio M;Cheng X;Chiaromonte F;Eckert KA;Huang YF;Makova KD
大约1%的人类基因组有能力折叠成G-四链(G4S)--在富含G的基序上形成的非规范链特异性DNA结构。G4S调节几个关键的细胞过程(例如，转录)，并被假设参与其他过程(例如，启动复制起点)。此外，G4S的热稳定性不同，这可能会影响它们的功能。然而，G4S也可能阻碍复制、转录和翻译，并可能增加基因组的不稳定性和突变率。因此，根据它们的基因组位置、热稳定性和功能，G4基因座可能在不同的选择压力下进化，这一点从未被研究过。在这里，我们对G4的分布、热稳定性和选择进行了第一次全基因组分析。我们发现G4S在基因组分中存在过度表达、高热稳定性和纯化选择，其中G4S可能是功能启动子、CpG岛以及5‘和3’UTRs。G4S在复制起始区、增强子、eQTL和TAD边界区域也观察到了类似的模式，强烈表明它们的功能。相比之下，外显子非转录链上的G4S表达不足，不稳定，并且进化中性。一般来说，基因组分非转录链上的G4S密度低于转录链上的G4S，且稳定性较差，表明前者在RNA水平上是避免的。在整个基因组中，纯化选择在稳定的G4S时更强。我们的结果表明，纯化选择保留了功能性G4S的序列，而非功能性G4S的成本太高，无法在基因组中容忍。因此，G4S正在成为基本的、有功能的基因组元件。
Approximately 1% of the human genome has the ability to fold into G-quadruplexes (G4s)—noncanonical strand-specific DNA structures forming at G-rich motifs. G4s regulate several key cellular processes (e.g., transcription) and have been hypothesized to participate in others (e.g., firing of replication origins). Moreover, G4s differ in their thermostability, and this may affect their function. Yet, G4s may also hinder replication, transcription, and translation and may increase genome instability and mutation rates. Therefore, depending on their genomic location, thermostability, and functionality, G4 loci might evolve under different selective pressures, which has never been investigated. Here we conducted the first genome-wide analysis of G4 distribution, thermostability, and selection. We found an overrepresentation, high thermostability, and purifying selection for G4s within genic components in which they are expected to be functional—promoters, CpG islands, and 5′ and 3′ UTRs. A similar pattern was observed for G4s within replication origins, enhancers, eQTLs, and TAD boundary regions, strongly suggesting their functionality. In contrast, G4s on the nontranscribed strand of exons were underrepresented, were unstable, and evolved neutrally. In general, G4s on the nontranscribed strand of genic components had lower density and were less stable than those on the transcribed strand, suggesting that the former are avoided at the RNA level. Across the genome, purifying selection was stronger at stable G4s. Our results suggest that purifying selection preserves the sequences of functional G4s, whereas nonfunctional G4s are too costly to be tolerated in the genome. Thus, G4s are emerging as fundamental, functional genomic elements.
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影响因子：
64.8
作者：
Cheng, MY;Bullock, CM;Zhou, QY
通讯作者：
Zhou, QY
影响因子：
14.9
作者：
Gomez, D;Lemarteleur, T;Riou, JF
通讯作者：
Riou, JF
DOI：
10.1038/nrg3296
发表时间：
2012-11
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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影响因子：
46.9
作者：
Chambers, Vicki S.;Marsico, Giovanni;Balasubramanian, Shankar
通讯作者：
Balasubramanian, Shankar
影响因子：
14.9
作者：
Bugaut A;Balasubramanian S
通讯作者：
Balasubramanian S