Mapping of genotype-phenotype diversity among clinical isolates of mycobacterium tuberculosis by sequence-based transcriptional profiling.
Mapping of genotype-phenotype diversity among clinical isolates of mycobacterium tuberculosis by sequence-based transcriptional profiling.
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DOI：
10.1093/gbe/evt138
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发表时间：
2013
影响因子：
3.3
通讯作者：
Young DB
中科院分区：
文献类型：
--
作者：
Rose G;Cortes T;Comas I;Coscolla M;Gagneux S;Young DB
基因组测序已鉴定出结核分枝杆菌临床分离株中广泛的单核苷酸多态性，但这些差异对细菌表型特性的影响程度仍有待阐明。为了确定这些多态性是否会引起表型多样性，我们将基因组数据集与 RNA 测序相结合，以评估它们对属于结核分枝杆菌谱系 1 和 2 的菌株的比较转录组谱的影响。我们观察到基因型和转录表型之间存在明显的相关性。这些是由三种机制产生的。首先，转录调节因子氨基酸序列的谱系特异性变化与其控制基因表达的能力的改变相关。其次，核苷酸序列的变化与启动子活性的改变以及基因间区域和编码序列内新转录起始位点的产生有关。我们表明，在某些情况下，这种机制有望产生参与先天免疫识别的功能活性截短蛋白。最后，显示谱系特异性差异表达模式与初级突变不直接相关的基因的特征是毒素-抗毒素对的显着过度表达。总而言之，这些发现增进了我们对分枝杆菌进化的理解，有助于对这种重要的人类病原体的系统水平理解，并更广泛地证明了最先进技术的应用，为基因间突变和沉默突变促进多样性的机制提供了新的见解。
Genome sequencing has identified an extensive repertoire of single nucleotide polymorphisms among clinical isolates of Mycobacterium tuberculosis, but the extent to which these differences influence phenotypic properties of the bacteria remains to be elucidated. To determine whether these polymorphisms give rise to phenotypic diversity, we have integrated genome data sets with RNA sequencing to assess their impact on the comparative transcriptome profiles of strains belonging to M. tuberculosis Lineages 1 and 2. We observed clear correlations between genotype and transcriptional phenotype. These arose by three mechanisms. First, lineage-specific changes in amino acid sequence of transcriptional regulators were associated with alterations in their ability to control gene expression. Second, changes in nucleotide sequence were associated with alteration of promoter activity and generation of novel transcriptional start sites in intergenic regions and within coding sequences. We show that in some cases this mechanism is expected to generate functionally active truncated proteins involved in innate immune recognition. Finally, genes showing lineage-specific patterns of differential expression not linked directly to primary mutations were characterized by a striking overrepresentation of toxin–antitoxin pairs. Taken together, these findings advance our understanding of mycobacterial evolution, contribute to a systems level understanding of this important human pathogen, and more broadly demonstrate the application of state-of-the-art techniques to provide novel insight into mechanisms by which intergenic and silent mutations contribute to diversity.
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影响因子：
2.8
作者：
Bagchi, G;Chauhan, S;Tyagi, JS
通讯作者：
Tyagi, JS
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
3.2
作者：
Fisher, MA;Plikaytis, BB;Shinnick, TM
通讯作者：
Shinnick, TM
影响因子：
4.1
作者：
Gurcha, SS;Baulard, AR;Besra, GS
通讯作者：
Besra, GS
DOI：
10.1126/science.1217283
发表时间：
2012-05-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Keinan A;Clark AG
通讯作者：
Clark AG