Identification of human-to-human transmissibility factors in PB2 proteins of influenza A by large-scale mutual information analysis.
Identification of human-to-human transmissibility factors in PB2 proteins of influenza A by large-scale mutual information analysis.
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DOI：
10.1186/1471-2105-9-s1-s18
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发表时间：
2008
影响因子：
3
通讯作者：
Brusic V
中科院分区：
文献类型：
--
作者：
Miotto O;Heiny A;Tan TW;August JT;Brusic V
识别赋予病原体独特特性（例如宿主范围）的突变对于对抗疾病至关重要。本文描述了一种通过匹配比对的比较分析来识别区分特定蛋白质序列组的氨基酸位点的新方法。使用互信息来识别负责功能变异的独特残基使得该方法非常适合分析大量序列。为了支持互信息分析，我们开发了 AVANA 软件，该软件根据用户指定的标准，利用序列注释来选择用于比较的集。该方法应用于甲型流感PB2蛋白序列分析，目的是鉴定适应人际传播的成分，并重建这些成分的突变历史。我们比较了 3,000 多个人类传播和禽类分离株的 PB2 蛋白序列，以生成涉及适应人际传播的位点目录。这项分析确定了 17 个特征位点，其中 5 个位点自 1918 年西班牙流感大流行以来一直存在于人类传播毒株中。其中十六个位点位于功能域中，表明它们可能在宿主范围特异性中发挥功能作用。特征位点目录用于从历史分离株中获取序列特征。这些按时间顺序排列的特征揭示了 PB2 蛋白适应人类宿主的进化时间表。通过对参与 PB2 蛋白适应人类的功能成分提供迄今为止最完整的阐明，本研究证明互信息是序列集比较表征的强大工具。除了证实之前报道的发现外，还报道了 PB2 内的几个新特征位点。使用特征位点目录生成的序列签名简明地表征了各个分离株的适应特征。从早期人类流感分离株的特征得出的进化时间表表明，特征性变异迅速出现，并在随后的大流行中保持非常稳定。此外，感染人类的 H5N1 分离株的特征表明，这种禽类亚型目前具有较低的大流行潜力，尽管它比大多数禽类亚型表现出更多的人类适应成分。
The identification of mutations that confer unique properties to a pathogen, such as host range, is of fundamental importance in the fight against disease. This paper describes a novel method for identifying amino acid sites that distinguish specific sets of protein sequences, by comparative analysis of matched alignments. The use of mutual information to identify distinctive residues responsible for functional variants makes this approach highly suitable for analyzing large sets of sequences. To support mutual information analysis, we developed the AVANA software, which utilizes sequence annotations to select sets for comparison, according to user-specified criteria. The method presented was applied to an analysis of influenza A PB2 protein sequences, with the objective of identifying the components of adaptation to human-to-human transmission, and reconstructing the mutation history of these components. We compared over 3,000 PB2 protein sequences of human-transmissible and avian isolates, to produce a catalogue of sites involved in adaptation to human-to-human transmission. This analysis identified 17 characteristic sites, five of which have been present in human-transmissible strains since the 1918 Spanish flu pandemic. Sixteen of these sites are located in functional domains, suggesting they may play functional roles in host-range specificity. The catalogue of characteristic sites was used to derive sequence signatures from historical isolates. These signatures, arranged in chronological order, reveal an evolutionary timeline for the adaptation of the PB2 protein to human hosts. By providing the most complete elucidation to date of the functional components participating in PB2 protein adaptation to humans, this study demonstrates that mutual information is a powerful tool for comparative characterization of sequence sets. In addition to confirming previously reported findings, several novel characteristic sites within PB2 are reported. Sequence signatures generated using the characteristic sites catalogue characterize concisely the adaptation characteristics of individual isolates. Evolutionary timelines derived from signatures of early human influenza isolates suggest that characteristic variants emerged rapidly, and remained remarkably stable through subsequent pandemics. In addition, the signatures of human-infecting H5N1 isolates suggest that this avian subtype has low pandemic potential at present, although it presents more human adaptation components than most avian subtypes.