Positive selection signals of hepatitis B virus and their association with disease stages and viral genotypes.
Positive selection signals of hepatitis B virus and their association with disease stages and viral genotypes.
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DOI：
10.1016/j.meegid.2013.07.011
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发表时间：
2013-10
期刊：
影响因子：
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通讯作者：
Zhe Xu;Guanghua Wu;Feifei Li;J. Bai;W. Xing;Dake Zhang;Changqing Zeng
中科院分区：
文献类型：
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作者：
Zhe Xu;Guanghua Wu;Feifei Li;J. Bai;W. Xing;Dake Zhang;Changqing Zeng
乙型肝炎病毒（HBV）是一种全球性健康问题，可导致不同类型的肝脏疾病。B型肝炎病毒（HBV）是一种全球性健康问题，可导致不同类型的肝脏疾病。HBV的高突变率，这是由于缺乏病毒聚合酶的校对活性，导致突变株在各种选择压力下的主动适应性进化。本研究的重点是在整个HBV基因组中的阳性选择信号，以及这些选择信号与疾病阶段和/或病毒基因型的关联。来自不同疾病类别的HBV感染个体的总共486个完整的HBV基因组（即，急性、慢性和重型肝炎）进行分析。为了获得选择信号的全景图，对来自不同阶段肝炎受试者的基因型B和C HBV进行基于密码子的最大似然分析、三维（3D）作图和等位基因频率比较。共解析了95个选定的密码子，并且与急性组相比，在慢性和重型肝炎组中发现了显著更高数量的阳性选择签名。许多选定的密码子与独特的疾病阶段或特定的基因型相关。对病毒核心蛋白（HBcAg）中选择信号的保守性分析表明，在高度多样化的区域中存在所选密码子。基于等位基因频率的分析确定了8个额外的核苷酸取代，并且发现这些突变的频率随着疾病进展而增加。此外，我们发现三个替换，包括A1762 T，G1764 A和A2739 C，几乎是固定的。所有选定的密码子和核苷酸取代的病毒蛋白质的功能域的映射表明，超过60%的突变受到来自宿主免疫监视，抗病毒治疗和复制健身的选择力。
The hepatitis B virus (HBV) is a global health problem that causes different types of liver diseases. The high mutation rate of HBV, which results from a lack of proofreading activity of the viral polymerase, leads to the actively adaptive evolution of mutant strains under various selection pressures. This study focuses on the positive selection signals in the whole HBV genome and the association of these selection signals with the disease stages and/or viral genotypes. A total of 486 complete HBV genomes from HBV-infected individuals of different illness categories (i.e., acute, chronic, and severe hepatitis) were analyzed. To obtain a panoramic view of the selection signals, codon-based maximum likelihood analysis, three-dimensional (3D) mapping, and allele frequency comparison were conducted on genotypes B and C HBV from subjects with different stages of hepatitis. A total of 95 selected codons were resolved, and a significantly higher number of positive selection signatures were found in the chronic and severe hepatitis groups compared with the acute groups. Many of the selected codons were associated with either a unique disease stage or a specific genotype. The conservation analysis of the selection signals in the viral core protein (HBcAg) illustrated the occurrence of selected codons in the highly diversified regions. The allele-frequency-based analysis identified eight additional nucleotide substitutions, and the frequencies of these mutations were found to increase with disease progression. Moreover, we found that three substitutions, including A1762T, G1764A, and A2739C, were nearly fixed. The mapping of all of the selected codons and nucleotide substitutions to the functional domains of the viral proteins suggested that more than 60% of the mutations were subject to selection forces from host immune surveillance, antiviral therapy, and replication fitness.