The massive worldwide spread of the SARS-CoV-2 virus is fueling the COVID-19 pandemic. Since the first whole-genome sequence was published in January 2020, a growing database of tens of thousands of viral genomes has been constructed. This offers opportunities to study pathways of molecular change in the expanding viral population that can help identify molecular culprits of virulence and virus spread. Here we investigate the genomic accumulation of mutations at various time points of the early pandemic to identify changes in mutationally highly active genomic regions that are occurring worldwide. We used the Wuhan NC_045512.2 sequence as a reference and sampled 15 342 indexed sequences from GISAID, translating them into proteins and grouping them by month of deposition. The per-position amino acid frequencies and Shannon entropies of the coding sequences were calculated for each month, and a map of intrinsic disorder regions and binding sites was generated. The analysis revealed dominant variants, most of which were located in loop regions and on the surface of the proteins. Mutation entropy decreased between March and April of 2020 after steady increases at several sites, including the D614G mutation site of the spike (S) protein that was previously found associated with higher case fatality rates and at sites of the NSP12 polymerase and the NSP13 helicase proteins. Notable expanding mutations include R203K and G204R of the nucleocapsid (N) protein inter-domain linker region and G251V of the viroporin encoded by ORF3a between March and April. The regions spanning these mutations exhibited significant intrinsic disorder, which was enhanced and decreased by the N-protein and viroporin 3a protein mutations, respectively. These results predict an ongoing mutational shift from the spike and replication complex to other regions, especially to encoded molecules known to represent major β-interferon antagonists. The study provides valuable information for therapeutics and vaccine design, as well as insight into mutation tendencies that could facilitate preventive control.

SARS-CoV-2病毒在全球的广泛传播正在助长COVID-19大流行。自2020年1月发布第一个全基因组序列以来，已经建立了一个不断发展的包含数万个病毒基因组的数据库。这为研究不断扩大的病毒种群中分子变化的途径提供了机会，可以帮助确定毒力和病毒传播的分子元凶。在这里，我们调查了大流行早期各个时间点的突变的基因组积累，以识别全球范围内发生的突变型高活性基因组区域的变化。我们以武汉NC_045512.2序列为参考，并从GISAID采样了15342个索引序列，将其翻译为蛋白质并按沉积月份进行分组。每月计算编码序列的每位氨基酸频率和香农熵，并生成内在的无序区域和结合位点的图。分析显示显性变体，其中大多数位于环区域和蛋白质表面。在几个位点稳定增加后，突变熵在2020年3月至4月之间下降，包括先前发现与病死率较高相关的穗（S）蛋白的D614G突变位点，以及NSP12聚合酶和NSP13解旋酶蛋白的位点。值得注意的扩展突变包括3月至4月之间核衣壳（N）蛋白域间接头区域的R203K和G204R和ORF3a编码的viroporin的G251V。跨越这些突变的区域表现出显着的内在障碍，其分别由N蛋白和virororin 3a蛋白突变增强和降低。这些结果预测了从刺突和复制复合体到其他区域，特别是已知代表主要β-干扰素拮抗剂的编码分子的持续突变转移。该研究为治疗和疫苗设计提供了有价值的信息，并深入了解了有助于预防性控制的突变趋势。