甲型流感病毒H3抗原进化及变异规律研究

发布时间：2018-01-01 02:35

本文关键词：甲型流感病毒H3抗原进化及变异规律研究　出处：《复旦大学》2005年博士论文　论文类型：学位论文

【摘要】：甲型流感病毒长期以来一直是威胁人类健康的重要病原体之一,对其变异规律进行深入的分析研究在流感的防治工作中具有重要的现实意义。本研究借助近年来发展起来的数据挖掘技术和进化树分析方法,从生物信息学的角度对流感病毒H3抗原的变异规律进行了系统研究,主要包括以下内容: 1.针对生物信息数据动态更新,不断增加的特点,确定采用数据拆分技术进行样本采集,并使用聚类分析对序列的变异规律进行初步分析。两步聚类和自组织图这两种新的聚类方法被加以应用,结果显示全部H3A1序列可以被清楚的分为6类,各类在宿主间的分布特征清楚的反映了不同宿主序列间亲缘关系的远近,而时间分布上则反映了H3亚型病毒在人间不断传播和变异的过程。 2.在聚类分析基础上,使用随机森林模型进行了人H3序列变异关键位点的分析。借助于随机重排技术,最终筛选出了27个高度变异位点,除2号位点外,其余26个均属于五个抗原决定区域之一。这一结果充分说明H3A1序列在人间的变异主要应当是宿主的免疫屏障所驱动的。在变异的预测上,这些位点也显示出了一定的作用。 3.为了进一步刻画H3序列的变异规律,本研究绘制出了全部序列的进化树。分析结果显示进化树结构和聚类结果高度一致,相应结果不仅详细刻画了数十年来流感病毒变异的基本规律,还明确回答了以下两个关键问题:猪宿主在人流感病毒变异中所起的作用是非常小的,主要起抗原存储器的作用;而与全球其余地区相比,中国南部地区在人H3亚型的抗原漂移中并未显出更高的重要性,不应当被认为是人群中已有亚型新变异株的发源地。 4.基于已经得到的进化树结构,本研究又进一步分析了进化树主干上正向选择位点的出现规律,Yang的正向选择模型被用于分析。结果表明人流感病毒H3抗原所承受的选择压力是逐渐增大的,并且在1995年后达到高峰。在被筛选出的28个正向位点中,绝大多数都只是在流感病毒的某一段进化时期内承受着正向选择压力。综合上述分析结果,我们认为H3亚型流感病毒在人间的变异呈现出逐渐加速的趋势,而这主要是受到了越来越强大的免疫屏障的筛选作用所致。目前免疫策略的核心任务是保护高危人群,但是这种策略并不能够阻止,反而可能加速了新变异株的出现。通过更进一步的生物信息学分析,并且在全球采取统一的主动
[Abstract]:Influenza A virus has long been one of the important pathogens that threaten human health, in-depth analysis and Research on the prevention of influenza has important practical significance for its variation. This study uses recently developed data mining technique and phylogenetic analysis method, variation from the perspective of bioinformatics on influenza virus H3 antigen was studied, mainly include the following contents:
1. according to the dynamic biological data update features increasing, determine the sampling data by splitting technique, and use clustering analysis of sequence variation were analyzed. The two step clustering and self organizing map of the two new clustering methods are applied, results showed that all H3A1 sequences can be clearly divided 6 types, distribution characteristics of different kinds in the host between clearly reflected the genetic relationship between different host sequence distance and time distribution is the reflection of the H3 virus subtype in human spread and variation.
2. in the clustering analysis based on the analysis of H3 sequence variation in key sites using random forest model. With the help of random permutation, finally we selected 27 highly variable sites, except for site 2, the remaining 26 belong to the area of one of the five antigenic determinants. This result shows that the sequence of H3A1 in the variation of human should be mainly driven by host immune barrier. In the prediction of variation, these sites also show a certain role.
3. in order to further characterize the variation of H3 sequences, this study draw the phylogenetic tree. The analysis results showed that the phylogenetic tree structure and clustering results were highly consistent with the corresponding results not only describe the basic rules of the influenza virus mutates in decades, but also a clear answer to the following two key problems: the host plays in pigs the effect of variation of human influenza virus is very small, the main antigen memory effect; compared with the rest of the world, South China antigenic drift in H3 subtype did not show the importance of higher, should not be considered the birthplace of the new subtype variants of the crowd.
4. based on the phylogenetic tree structure has been obtained, this study further analyzes the evolutionary tree trunk of positively selected sites regularly, positive selection of Yang model was used for analysis. The results show that the selective pressure of human influenza virus H3 antigen bearing is gradually increasing, and reached the peak in 1995. In 28 positive sites to be selected, most of them are only a section of the evolution period of influenza virus in under positive selection pressure.
Based on the above analysis results, we believe that the influenza virus subtype H3 showed a gradually accelerating trend in the variation of human, which is mainly due to the screening effect caused by the increasingly powerful immune barrier. At present, the core task is to protect the immune strategy of high-risk groups, but this strategy can not stop, but may be accelerated by the emergence of new the mutants. By farther bioinformatics analysis, and in the world to adopt a unified initiative

【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R373

【引证文献】