北京系结核分枝杆菌遗传多样性与核心基因组进化机制研究

China has the second largest tuberculosis (TB) patients in the world. Considering our national situation of disease control and prevention, TB is still a major public health problem. As the primary pathogen causing TB, Mycobacterium tuberculosis complex (MTBC) mainly consists of eight lineages: Beijing lineage, India and East Africa lineage, Europe and Americas lineage, etc. Comparing with the other lineages, Mycobacterium tuberculosis (MTB) Beijing lineage is more pathogenic and infective. The research of MTB Beijing lineage genetic diversity and genome evolution will uncover the essence of high virulence and infectivity. The project will sequence the whole genomes of 15 MTB Beijing lineage strains using PacBio single-molecule real-time (SMRT) technology, and integrate these genome data with published ones of MTB Beijing lineage strains. With pan-genome analysis methods, the core-genome of MTB Beijing lineage will be identified. Moreover, the proposal will investigate the core-genome evolution rules in MTB Beijing lineage, including gene duplication, gain, mutation and loss of the PE/PPE family, ESX family, virulence factors and antigen genes, closely related with MTB pathogenicity through large-scale genome-wide comparison with other seven MTBC lineages. Finally, the function of special genetic variations in MTB Beijing lineage will be verified using molecular biology techniques.The deep research on evolution mechanism of the core-genome of MTB Beijing lineage will provide new strategies and theoretical basis for TB prevention and treatment.

我国结核病患者位居世界第二，结核病仍然是我国重大公共卫生问题。结核分枝杆菌复合群（MTBC）是引起结核病主要致病菌，主要分为北京系、东非印度系和欧美系等8个谱系。北京系结核分枝杆菌（MTB）相比其它谱系具有更强致病性和传染力，研究北京系MTB遗传多样性和基因组进化可揭示北京系高毒力和传染力机制。本项目将对15株北京系MTB进行三代单分子全基因组测序，并整合已公开的北京系MTB全基因组数据，借助泛基因组分析手段，挖掘出北京系MTB核心基因组。然后，通过与MTBC其它7个谱系全基因组大数据比较，鉴定北京系特异核心基因组进化规律，包括分析与结核致病性紧密相关的PE/PPE、ESX家族、毒力因子和抗原基因等相关核心基因的复制、获得、突变和丢失。最后，借助分子生物学手段对北京系MTB特有差异基因进行功能验证。北京系MTB核心基因组进化机制深入研究，将为结核病防控和治疗提供新的研究思路及理论基础。

我国结核病患者位居世界第二，结核病仍然是我国重大公共卫生问题。结核分枝杆菌复合群（Mycobacterium tuberculosis complex, MTBC）是引起结核病主要致病菌，主要分为北京系、东非印度系和欧美系等8个谱系。本项目对15株结核分枝杆菌(Mycobacterium tuberculosis, Mtb)进行三代单分子全基因组测序，并整合已公开的Mtb全基因组数据，借助泛基因组分析手段，挖掘出Mtb核心基因组，进一步解析了主要基因和次要基因、探明各谱系的共性与个性及其相互转化。此外还发现了Mtb基因的重要性在进化过程中并不是一成不变，常见多拷贝核心基因（Common Multicopy Core Genes, CMCGs）、核心基因、非必需基因及菌株特异基因可以相互转化，与宿主共进化等是基因重要性转化的驱动力。为结核病防控和治疗提供了新的研究思路及理论基础。