Graudenzi Alex, Maspero Davide, Angaroni Fabrizio, Piazza Rocco, Ramazzotti Daniele
Inst. of Molecular Bioimaging and Physiology, Consiglio Nazionale delle Ricerche (IBFM-CNR), Segrate, Milan, Italy.
Bicocca Bioinformatics, Biostatistics and Bioimaging Centre - B4, Milan, Italy.
iScience. 2021 Feb 19;24(2):102116. doi: 10.1016/j.isci.2021.102116. Epub 2021 Jan 28.
To dissect the mechanisms underlying the inflation of variants in the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) genome, we present a large-scale analysis of intra-host genomic diversity, which reveals that most samples exhibit heterogeneous genomic architectures, due to the interplay between host-related mutational processes and transmission dynamics. The decomposition of minor variants profiles unveils three non-overlapping mutational signatures related to nucleotide substitutions and likely ruled by APOlipoprotein B Editing Complex (APOBEC), Reactive Oxygen Species (ROS), and Adenosine Deaminase Acting on RNA (ADAR), highlighting heterogeneous host responses to SARS-CoV-2 infections. A corrected-for-signatures analysis demonstrates that such mutational processes are affected by purifying selection, with important exceptions. In fact, several mutations appear to transit toward clonality, defining new clonal genotypes that increase the overall genomic diversity. Furthermore, the phylogenomic analysis shows the presence of homoplasies and supports the hypothesis of transmission of minor variants. This study paves the way for the integrated analysis of intra-host genomic diversity and clinical outcomes of SARS-CoV-2 infections.
为剖析严重急性呼吸综合征冠状病毒2（SARS-CoV-2）基因组中变异膨胀的潜在机制，我们对宿主内基因组多样性进行了大规模分析，结果表明，由于宿主相关突变过程与传播动态之间的相互作用，大多数样本呈现出异质的基因组结构。次要变异谱的分解揭示了与核苷酸替换相关的三个不重叠的突变特征，可能由载脂蛋白B编辑复合体（APOBEC）、活性氧（ROS）和作用于RNA的腺苷脱氨酶（ADAR）所主导，突出了宿主对SARS-CoV-2感染的异质反应。经特征校正的分析表明，此类突变过程受纯化选择影响，但存在重要例外。事实上，一些突变似乎朝着克隆性转变，定义了增加整体基因组多样性的新克隆基因型。此外，系统基因组分析显示了平行进化的存在，并支持次要变异传播的假设。本研究为SARS-CoV-2感染的宿主内基因组多样性与临床结果的综合分析铺平了道路。
