中国西南地区人乳头瘤病毒 51 型 E6、E7、L1 和 L2 基因的遗传变异。
Genetic variability of human papillomavirus type 51 E6, E7, L1 and L2 genes in Southwest China.
机构信息
Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, China; Bio-resource Research and Utilization Joint Key Laboratory of Sichuan and Chongqing, Sichuan and Chongqing, China.
Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, China; Bio-resource Research and Utilization Joint Key Laboratory of Sichuan and Chongqing, Sichuan and Chongqing, China.
出版信息
Gene. 2019 Mar 30;690:99-112. doi: 10.1016/j.gene.2018.12.032. Epub 2018 Dec 21.
Genetic variations among HR-HPV types lead to altered biological functions with possible clinical significance in different geographical locations. To explore intratype genetic variations of HPV51 E6, E7, L1 and L2 genes originating from Southwest China, a total of 5204 cervical scraped cell samples were collected for DNA extraction and HPV typing. And then the E6, E7, L1 and L2 genes of HPV51 (n = 79) were sequenced and compared to the reference sequence (M62877). The ConSurf server was used for identification of conserved structural and functional amino acids of the E6 and E7 oncogenes, and the changes of the secondary structure were analyzed by PSIPred software. Phylogenetic trees were constructed by the maximum likelihood method implemented in IQ-TREE. The selection pressure acting on the E6, E7, L1 and L2 genes was estimated by Datamonkey web server. 13 nucleotide polymorphism sites were observed in E6-E7 gene and the most common mutation sites were C395T (S100L), C756T (S66L), C796T, A832G. 36 nucleotide polymorphism sites were identified in full length L1 gene and the non-synonymous mutations T6311G, A6312T (V264G), G6313A (G265S) A5674C (I52L), A6335C (N272T), A6586C (T354P) and synonymous mutations A5649T, C6147T, A6435G, G6570A, A6651G, T6774C, A6784C, A6882G, C6918A, and G6984A were the most common mutations. 53 nucleotide variation sites were identified in full-length L2 gene including four insertion sites (4418A, 4670G, 4693A, 4694C) and one deletion site (A4430). Besides, the non-synonymous mutations G4227A (V32I), A4407G (I92V), G4945A (D271N), C4985A (T284K), T5260G (L376V), A5335C (T401P) and the synonymous mutations A4166G, G4229A, G4283A, T4453C, C4566A, T4596C, C4695T, C4830T, G4839A, A5160C, and T5286G were the most common mutations. Specially, a triallelic mutation site (G4461C/A) in L2 was identified, with 26% G4461C (E109D) being non-synonymous mutation. Selective pressure analysis showed that only codon site 66 in E7 and 52 in L1 were the positively selected sites and codon sites 72, 107, 342, 412, 427 were negatively selected sites in L2 gene. Our investigation also suggests that A2 and A4 were the most frequent HPV51 lineage in Southwest China.
HPV51 E6、E7、L1 和 L2 基因的遗传变异导致不同地理位置的生物学功能发生改变，可能具有临床意义。为了探索中国西南地区 HPV51 病毒株内的遗传变异，我们收集了 5204 例宫颈刮片细胞样本进行 DNA 提取和 HPV 分型。然后对 79 例 HPV51 （n=79）的 E6、E7、L1 和 L2 基因进行测序，并与参考序列（M62877）进行比较。使用 ConSurf 服务器鉴定 E6 和 E7 癌基因的保守结构和功能氨基酸，并用 PSIPred 软件分析二级结构的变化。通过 IQ-TREE 中的最大似然法构建系统进化树。Datamonkey 网络服务器用于估计 E6、E7、L1 和 L2 基因的选择压力。在 E6-E7 基因中观察到 13 个核苷酸多态性位点，最常见的突变位点是 C395T（S100L）、C756T（S66L）、C796T、A832G。全长 L1 基因中鉴定出 36 个核苷酸多态性位点，非同义突变 T6311G、A6312T（V264G）、G6313A（G265S）A5674C（I52L）、A6335C（N272T）、A6586C（T354P）和同义突变 A5649T、C6147T、A6435G、G6570A、A6651G、T6774C、A6784C、A6882G、C6918A 和 G6984A 是最常见的突变。全长 L2 基因中鉴定出 53 个核苷酸变异位点，包括 4 个插入位点（4418A、4670G、4693A、4694C）和 1 个缺失位点（A4430）。此外，非同义突变 G4227A（V32I）、A4407G（I92V）、G4945A（D271N）、C4985A（T284K）、T5260G（L376V）、A5335C（T401P）和同义突变 A4166G、G4229A、G4283A、T4453C、C4566A、T4596C、C4695T、C4830T、G4839A、A5160C 和 T5286G 是最常见的突变。特别的是，在 L2 中鉴定出一个三等位突变位点（G4461C/A），其中 26%的 G4461C（E109D）为非同义突变。选择压力分析表明，只有 E7 中的 66 位和 L1 中的 52 位是正选择位点，而 L2 基因中的 72、107、342、412 和 427 位是负选择位点。我们的研究还表明，A2 和 A4 是中国西南地区最常见的 HPV51 株系。
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