Epistasis-Driven Evolution of the SARS-CoV-2 Secondary Structure.
Epistasis-Driven Evolution of the SARS-CoV-2 Secondary Structure.
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DOI：
10.1007/s00239-022-10073-1
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发表时间：
2022-12
影响因子：
3.9
通讯作者：
中科院分区：
文献类型：
--
作者：
上位性是一种进化现象，即突变的适应性效应取决于它产生的遗传背景。RNA分子中上位性的一个关键来源是其二级结构，其包含通过沃森-克里克（WC）碱基对之间的氢键保持在一起的功能上重要的拓扑基序。在这里，我们研究上位性严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的二级结构，通过检查在整个基因组的15个保守的拓扑基序的祖先WC碱基配对和不配对（UP）位点的取代突变所产生的衍生等位基因的属性。我们发现更少的衍生等位基因和较低的衍生等位基因频率在WC比在UP网站，支持的假设，修改的二级结构往往是有害的。在WC位点，我们还发现，与产生G·U“摆动”的突变相比，废除碱基配对的突变的衍生等位基因频率较低，说明弱碱基配对可以部分保持二级结构的完整性。最后，我们表明，WC网站下最强的上位性约束驻留在一个三茎假结基序，在程序性核糖体移码中起着至关重要的作用，而那些下最弱的上位性约束位于3'非翻译区基序，调节病毒的复制和致病性。我们的研究结果证明了上位性在SARS-CoV-2二级结构进化中的重要性，并强调了不同形式的自然选择的推定结构和功能目标。在线版本包含补充材料，可通过10.1007/s 00239 -022-10073-1获取。
Epistasis is an evolutionary phenomenon whereby the fitness effect of a mutation depends on the genetic background in which it arises. A key source of epistasis in an RNA molecule is its secondary structure, which contains functionally important topological motifs held together by hydrogen bonds between Watson–Crick (WC) base pairs. Here we study epistasis in the secondary structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by examining properties of derived alleles arising from substitution mutations at ancestral WC base-paired and unpaired (UP) sites in 15 conserved topological motifs across the genome. We uncover fewer derived alleles and lower derived allele frequencies at WC than at UP sites, supporting the hypothesis that modifications to the secondary structure are often deleterious. At WC sites, we also find lower derived allele frequencies for mutations that abolish base pairing than for those that yield G·U “wobbles,” illustrating that weak base pairing can partially preserve the integrity of the secondary structure. Last, we show that WC sites under the strongest epistatic constraint reside in a three-stemmed pseudoknot motif that plays an essential role in programmed ribosomal frameshifting, whereas those under the weakest epistatic constraint are located in 3’ UTR motifs that regulate viral replication and pathogenicity. Our findings demonstrate the importance of epistasis in the evolution of the SARS-CoV-2 secondary structure, as well as highlight putative structural and functional targets of different forms of natural selection. The online version contains supplementary material available at 10.1007/s00239-022-10073-1.
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影响因子：
11.4
作者：
Lynch, Michael
通讯作者：
Lynch, Michael
影响因子：
16
作者：
Huston NC;Wan H;Strine MS;de Cesaris Araujo Tavares R;Wilen CB;Pyle AM
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DOI：
10.1073/pnas.92.20.9047
发表时间：
1995-09-26
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Kondrashov, Fyodor A.
DOI：
10.1073/pnas.1932834100
发表时间：
2003-09-30
影响因子：
11.1
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通讯作者：
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