Data_Sheet_11_Pan-Genomic Study of Mycobacterium tuberculosis Reflecting the Primary/Secondary Genes, Generality/Individuality, and the Interconversion Through Copy Number Variations.PDF

Tuberculosis (TB) has surpassed HIV as the leading infectious disease killer worldwide since 2014. The main pathogen, Mycobacterium tuberculosis (Mtb), contains ~4,000 genes that account for ~90% of the genome. However, it is still unclear which of these genes are primary/secondary, which are responsible for generality/individuality, and which interconvert during evolution. Here we utilized a pan-genomic analysis of 36 Mtb genomes to address these questions. We identified 3,679 Mtb core (i.e., primary) genes, determining their phenotypic generality (e.g., virulence, slow growth, dormancy). We also observed 1,122 dispensable and 964 strain-specific secondary genes, reflecting partially shared and lineage-/strain-specific individualities. Among which, five L2 lineage-specific genes might be related to the increased virulence of the L2 lineage. Notably, we discovered 28 Mtb “Super Core Genes” (SCGs: more than a copy in at least 90% strains), which might be of increased importance, and reflected the “super phenotype generality.” Most SCGs encode PE/PPE, virulence factors, antigens, and transposases, and have been verified as playing crucial roles in Mtb pathogenicity. Further investigation of the 28 SCGs demonstrated the interconversion among SCGs, single-copy core, dispensable, and strain-specific genes through copy number variations (CNVs) during evolution; different mutations on different copies highlight the delicate adaptive-evolution regulation amongst Mtb lineages. This reflects that the importance of genes varied through CNVs, which might be driven by selective pressure from environment/host-adaptation. In addition, compared with Mycobacterium bovis (Mbo), Mtb possesses 48 specific single core genes that partially reflect the differences between Mtb and Mbo individuality.

自2014年以来，结核病（Tuberculosis, TB）已超越人类免疫缺陷病毒（HIV），成为全球范围内致死率最高的传染病。其主要致病原结核分枝杆菌（Mycobacterium tuberculosis, Mtb）的基因组中约包含4000个基因，占其基因组总序列的90%左右。但目前仍未明确这些基因中哪些属于一级/二级功能基因，哪些决定了表型共性/株特异性，以及哪些在进化过程中会发生功能转换。本研究针对36株Mtb基因组开展泛基因组分析，以解答上述科学问题。我们共鉴定出3679个Mtb核心（即一级）基因，并明确了它们的表型共性，例如毒力、缓慢生长、休眠特性。同时还发现了1122个附属基因与964个菌株特异性二级基因，分别对应部分共享的表型特征以及谱系/菌株特异性的个体差异。其中，5个L2谱系特异性基因可能与L2谱系的毒力增强密切相关。值得关注的是，本研究发现了28个Mtb“超级核心基因”（Super Core Genes, SCGs：在至少90%的菌株中存在至少一个拷贝），这类基因的重要性可能更高，反映了“超级表型共性”。绝大多数SCGs编码PE/PPE家族蛋白、毒力因子、抗原以及转座酶，且已被证实对Mtb的致病性发挥关键作用。对这28个SCGs的进一步研究表明，在进化过程中，SCGs、单拷贝核心基因、附属基因以及菌株特异性基因之间可通过拷贝数变异（Copy Number Variations, CNVs）实现功能转换；不同拷贝上携带的不同突变，体现了Mtb各谱系间精细的适应性进化调控机制。这反映出基因的重要性可通过拷贝数变异发生改变，而这一过程可能由环境或宿主适应性带来的选择压力所驱动。此外，与牛分枝杆菌（Mycobacterium bovis, Mbo）相比，Mtb拥有48个特异性单拷贝核心基因，这在一定程度上反映了Mtb与Mbo之间的个体差异。