Data_Sheet_1_Genetic characterization and molecular epidemiology of Coxsackievirus A12 from mainland China during 2010–2019.docx

Coxsackievirus A12 (CVA12) is an enterovirus that has been isolated in many countries in recent years. However, studies on CVA12 are limited, and its effective population size, evolutionary dynamics and recombination patterns have not been clarified now. In this study, we described the phylogenetic characteristics of 16 CVA12 strains isolated from pediatric HFMD patients in mainland China from 2010 to 2019. Comparison of the nucleotide sequences and amino acid sequences with the CVA12 prototype strain revealed that the 16 CVA12 strains are identical in 78.8–79% and 94–94.2%, respectively. A phylodynamic analysis based on the 16 full-length VP1 sequences from this study and 21 sequences obtained from GenBank revealed a mean substitution rate of 6.61 × 10−3 substitutions/site/year (95% HPD: 5.16–8.20 × 10−3), dating the time to most recent common ancestor (tMRCA) of CVA12 back to 1946 (95% HPD: 1942–1947). The Bayesian skyline plot showed that the effective population size has experienced twice dynamic fluctuations since 2007. Phylogeographic analysis identified two significant migration pathways, indicating the existence of cross-provincial transmission of CVA12 in mainland China. Recombination analysis revealed two recombination patterns between 16 CVA12 strains and other EV-A, suggesting that there may be extensive genetic exchange between CVA12 and other enteroviruses. In summary, a total of 16 full-length CVA12 strains were reported in this study, providing valuable references for further studies of CVA12 worldwide.

柯萨奇病毒A12（Coxsackievirus A12, CVA12）是一种近年来在多个国家分离得到的肠道病毒（enterovirus）。然而目前针对CVA12的研究仍较为有限，其有效种群规模（effective population size）、进化动力学特征以及重组模式尚未阐明。本研究对2010年至2019年间从中国大陆儿童手足口病（Hand, Foot and Mouth Disease, HFMD）患者体内分离的16株CVA12毒株的系统发育特征进行了描述。将这16株CVA12毒株的核苷酸序列与氨基酸序列分别与CVA12原型毒株进行比对后发现，二者的核苷酸序列同源性为78.8%~79%，氨基酸序列同源性为94%~94.2%。基于本研究获得的16条全长VP1序列（full-length VP1 sequences）以及从基因银行（GenBank）获取的21条序列开展的系统动力学分析显示，CVA12的平均替换速率为6.61×10⁻³ 替换位点/年（95%最高后验密度区间，95% highest posterior density, HPD：5.16~8.20×10⁻³），并推算出其最近共同祖先时间（time to most recent common ancestor, tMRCA）可追溯至1946年（95%最高后验密度区间：1942~1947）。贝叶斯天际线图（Bayesian skyline plot）分析结果表明，自2007年以来，CVA12的有效种群规模曾经历两次动态波动。系统地理分析（phylogeographic analysis）鉴定出两条显著的迁移路径，提示CVA12在中国大陆境内存在跨省份传播现象。重组分析显示，本研究中的16株CVA12毒株与其他A组肠道病毒（Enterovirus A, EV-A）之间存在两种重组模式，这表明CVA12可能与其他肠道病毒发生了广泛的遗传交换。综上，本研究共报道了16株全长CVA12毒株，可为全球范围内CVA12的后续研究提供有价值的参考依据。