Department of Physics, Florida Atlantic University, Boca Raton, FL, 33431, USA.
Department of Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL, 33431, USA.
J Mol Evol. 2022 Dec;90(6):429-437. doi: 10.1007/s00239-022-10073-1. Epub 2022 Sep 30.
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.
上位性是一种进化现象，其中突变的适合度效应取决于它出现的遗传背景。RNA 分子中上位性的一个主要来源是其二级结构，它包含由沃森-克里克（WC）碱基对之间的氢键保持在一起的具有重要功能的拓扑基序。在这里，我们通过检查在 15 个保守拓扑基序中在祖先 WC 碱基配对和非配对（UP）位点处发生取代突变所产生的衍生等位基因的特性，研究了 SARS-CoV-2 二级结构中的上位性。我们发现，在 WC 位点的衍生等位基因数量和频率都低于 UP 位点，这支持了这样一种假设，即对二级结构的修饰通常是有害的。在 WC 位点，我们还发现，与产生 G·U“摆动”的突变相比，那些导致碱基配对消除的突变的衍生等位基因频率更低，这表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，受最强上位性约束的 WC 位点位于一个三茎假结基序中，该基序在程序性核糖体移码中起着至关重要的作用，而受最弱上位性约束的 WC 位点位于调节病毒复制和致病性的 3'UTR 基序中。我们的发现表明，上位性在 SARS-CoV-2 二级结构的进化中非常重要，同时也突出了不同形式自然选择的潜在结构和功能靶点。
