A hepatitis B virus (HBV) sequence variation graph improves sequence alignment and sample-specific consensus sequence construction for genetic analysis of HBV.
A hepatitis B virus (HBV) sequence variation graph improves sequence alignment and sample-specific consensus sequence construction for genetic analysis of HBV.
复制标题
乙型肝炎病毒 (HBV) 序列变异图可改善 HBV 遗传分析的序列比对和样本特异性共有序列构建。
DOI：
10.1101/2023.01.11.523611
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Wojcik,GenevieveL
中科院分区：
文献类型：
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作者：
Duchen,Dylan;Clipman,Steven;Vergara,Candelaria;Thio,ChloeL;Thomas,DavidL;Duggal,Priya;Wojcik,GenevieveL
乙肝病毒(HBV)仍然是一个全球公共卫生问题，有超过2.5亿人患有慢性乙肝(CHB)，目前还没有治愈的方法。病毒的多样性与CHB的发病机制和感染的免疫控制有关。在种群和宿主内部水平上描述病毒基因组的改进方法可以帮助药物开发工作。传统上，将乙肝病毒测序数据与线性参考基因组进行比对，并且仅捕获能够与参考比对的序列用于分析。参考文献的选择有额外的结果，包括特定样本的“共识”序列的构建。目前尚不清楚如何从可用序列中选择参考文献，以及单一参考文献是否足以用于遗传分析。使用从可公开获得的全长乙肝病毒基因组序列产生的模拟短读测序数据和来自CHB患者的纵向样本的乙肝病毒测序数据，我们研究了替代的基于图形的比对方法。我们证明，使用具有系统发育代表性的‘基因组图’进行比对，而不是使用线性参考序列，避免了参考歧义的问题，改进了比对，并促进了构建遗传上类似于个体感染的样本特异性共识序列。因此，基于图形的方法可以提高对包括乙肝病毒在内的病毒病原体的遗传学特征的研究，并可能在宿主病原体研究中具有广泛的意义。
Hepatitis B virus (HBV) remains a global public health concern, with over 250 million individuals living with chronic HBV infection (CHB) and no curative therapy currently available. Viral diversity is associated with CHB pathogenesis and immunological control of infection. Improved methods to characterize the viral genome at both the population and intra-host level could aid drug development efforts. Conventionally, HBV sequencing data are aligned to a linear reference genome and only sequences capable of aligning to the reference are captured for analysis. Reference selection has additional consequences, including sample-specific ‘consensus’ sequence construction. It remains unclear how to select a reference from available sequences and whether a single reference is sufficient for genetic analyses. Using simulated short-read sequencing data generated from full-length publicly available HBV genome sequences and HBV sequencing data from a longitudinally sampled individual with CHB, we investigate alternative graph-based alignment approaches. We demonstrate that using a phylogenetically representative ‘genome graph’ for alignment, rather than linear reference sequences, avoids issues of reference ambiguity, improves alignment, and facilitates the construction of sample-specific consensus sequences genetically similar to an individual’s infection. Graph-based methods can therefore improve efforts to characterize the genetics of viral pathogens, including HBV, and may have broad implications in host pathogen research.