病毒基因组学与 病毒进化 刘翟博士研究员 中国科学院微生物研究所

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1 病毒基因组学与 病毒进化 刘翟博士研究员 中国科学院微生物研究所

2 新一代测序技术带来了测序成本的大大降低!!! $100,000,000 $10,000,000 Moore s Law $1,000,000 $100,000 $10,000 $1,000 $1,000 $100

3 Pathogens Genomics Pathogen infections are among the leading causes of infirmity and mortality among humans and other animals in the world. Until recently, it has been difficult to compile information to understand the generation of pathogen virulence factors as well as pathogen behaviour in a host environment. The study of Pathogenomics attempts to utilize genomic and metagenomics data gathered from high through-put technologies to understand microbe diversity and interaction as well as host-microbe interactions involved in disease states.

4 Bacteria/Fungi/Protozoan Causes of Genomic Diversity Gene Loss / Genome Decay Gene Gain/ Gene Duplication Genome Rearrangement Single Nucleotide Polymorphism Analysis of Genomic Diversity Pan-genomes and core genomes Mobile Genetic Elements that Encode Virulence factors

5 Virus Causes of Genomic Diversity Gene Loss / Genome Decay Gene Gain/ Gene Duplication Genome Rearrangement / Reassortment Single Nucleotide Polymorphism Analysis of Genomic Diversity Pan-genomes and core genomes Mobile Genetic Elements that Encode Virulence factors

6 (Virus) Evolution 进化生物学是研究生命的起源及进化的过程 原因 机制 速率和方向的科学 起源 (Origin): 从哪里来? 进程 (Process/Route): 怎么来的? 原因 (Causes): 为什么会来? 机制 (Selection): 谁驱动它? 速率 (Dynamics): 快? 慢? 方向 (Direction): 要去哪?

7 H7N9 Avian Influenza Virus

8 February 26, the first human infection March 31, identification of H7N9 April 11, the first publication on the New England Journal of Medicine China CDC, et al.

9 H7N3 virus from ducks of Zhejiang H7N9 virus from wild birds flying across Korea Internal genes from H9N2 virus

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11 April 26, the preliminary epidemiology report was published on the New England Journal of Medicine China CDC, et al.

12 H7N9 病毒起源

13 Long-branch Lancet, 2013

14 Different neighbors Lancet, 2013

15 Origin and Route 1:The HA and NA genes were most probably transmitted from wild birds to domestic birds and then to humans 2:The six internal genes were from at least two distinct H9N2 virus populations of poultry 3:The intermediate hosts were still unknown, but ducks and chickens were the most suspects 4: The H7N9 viruses have possibly been evolved for at least one year in poultry Lancet, 2013

16 Homology Modeling & Sequence Alignment Conclusions: 1:Shanghai/1 virus could have more affinity to mammalian-host adaptors 2:Shanghai/1 virus has a set of aminoacids that differed from the other H7N9 viruses, including an oseltamivirresistant site in NA 3:The H7N9 viruses of this outbreak could have formed two separate groups Lancet, 2013

17 May 1, our results were published on the Lancet

18 H7N9 病毒重配过程

19 The time of most recent common ancestors (tmrca) of HA, NA and NS were estimated to be middle of 2011 ; The emergence of the other five gene segments could be dated to early 2012 MP, NP, PA, PB1 and PB2 was much more divergent The diverse genotypes existed of the novel H7N9 viruses Wu et al., Cell Host & Microbe, 2013

20 Wu et al., Cell Host & Microbe, 2013

21 9 月 19 日, Cell Host & Microbe 上线蒋太交研究员研究团队关于 H7N9 病毒连续重配模式的研究成果 The Scientist 和 ScienceDaily 分别发表评论文章

22 Diversity and Dynamics

23 Internal genes shows more heterogeneity than the surface genes Nature Commu., 2014

24 Phylogenetics: 1:No new clade of HA and NA 2:Diversified clades of the internal genes 3:Human isolations clustered together Nature Commu., 2014

25 H7N9 genotyping: 1:27 genotypes during the outbreak 2:genotypes have no relation to region or time peroid 3:human isolations are major in G0 4:G0 and G2.6 cocirculated in poultry 5:genotypes increased during poultry transportation Nature Commu., 2014

26 H7N9 gene flow and genealogy: 1:from Shanghai and then spread out 2:transmission between provinces 3:new genotype generated during transmission 4:G0 is the major genotype for transmission 5:H7N9 is not fitting poultry hosts or human Nature Commu., 2014

27 H7N9 dynamic reassortments model: 1:Gene recruitment from poultry H9N2 2:Adaptation through reassorments 3:Poultry transportation will increase the genotypes 4:New genotypes would do harm to human 5:It is important to control H7N9 by reduced the chance of genetic reassortments Nature Commu., 2014

28 在随后的 2013 冬 春流感季 H7N9 变异规律符合我们提出的动态重配模型

29 人感染 H10N8 禽流感病毒的起源与传播模型类似于 H7N9

30 禽流感病毒的形成过程

31 Protein & Cell, 年以来, 我国家禽中出现的不同亚型禽流感分布

32 Protein & Cell, 2014

33 1: 携带有 H9N2 病毒的家禽作为 孵化器 有助于新型禽流感病毒进入家禽, 并最终感染人 Lancet,2014 2: 携带有禽流感病毒的家禽将会作为一类新的病毒 混合器 Sci China Life Sci, 2014

34 重要结论 通过 H7N9 H10N8 等禽流感病毒的起源以及遗传变异研究, 揭示了新型禽流感病毒由野生候鸟 家养水禽 家养陆禽 哺乳动物 / 人的传播路径 ( 关注野鸟!!! 关注家鸭!!!) 禽流感病毒借助家禽运输和活禽交易, 快速扩散 ; 并和当地病毒快速重配获得适应性变异 ( 管控活禽市场, 活禽交易!!!) 携带有 H9N2 病毒的家禽对新型流感病毒起源起关键作用, 最终造成人感染的隐患 ( 控制 H9N2 病毒在我国的传播!!!)

35 H5N1 Avian Influenza Virus

36 J Gen Virol, 2008

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38 Virologica Sinica, 2016

39 H5N2 H5N8

40 H5N6

41 病毒进化研究的发展趋势

42 病毒进化研究方法的更新 简单分子数据 简单个体样本 Phylogenetics Intra-host Dynamics 复杂分子数据 复杂群体样本 Coalescence???

43 研究病毒在个体或群体中持续变化趋势将是病毒进化研究的发展方向 通过研究病毒进化的历史 现状, 可以推测病毒进化的方向 二代 + 三代混合测序模式将成为主流的研究手段 二代 : 病毒群体特征 三代 : 群体中个体特征 Illumina MiSeq PacBio Sequel

44 QUANTIFY INFLUENZA VIRUS DIVERSITY AND TRANSMISSION IN HUMANS 关键词 : 单分子 + 高通量测序 Nature Genetics, Jan 4, 2016

45 Transmission of influenza in humans

46 华点云生物科技有限公司 高通量测序整体解决方案 分子标志物检测 panel 研发数据产出数据分析 挖掘 核酸提取靶向扩增文库构建 NGS 测序 生物信息分析 分子诊断检测试剂盒 临床检测 检测分析报告 科研成果 检测产品 临床应用

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48 谢谢大家!