Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, 35 Keyen Road, Zhunan, Miaoli County, 350 Taiwan.
Gene. 2013 Apr 10;518(1):187-93. doi: 10.1016/j.gene.2012.11.033. Epub 2012 Dec 7.
Mycobacterium tuberculosis is one of the most deadly human pathogens. The major mechanism for the adaptations of M. tuberculosis is nucleotide substitution. Previous studies have relied on the nonsynonymous-to-synonymous substitution rate (dN/dS) ratio as a measurement of selective constraint based on the assumed selective neutrality of synonymous substitutions. However, this assumption has been shown to be untrue in many cases. In this study, we used the substitution rate in intergenic regions (di) of the M. tuberculosis genome as the neutral reference, and conducted a genome-wide profiling for di, dS, and the rate of insertions/deletions (indel rate) as compared with the genome of M. canettii using a 50kb sliding window. We demonstrate significant variations in all of the three evolutionary measurements across the M. tuberculosis genome, even for regions in close vicinity. Furthermore, we identified a total of 233 genes with their dS deviating significantly from di within the same window. Interestingly, dS also varies significantly in some of the windows, indicating drastic changes in mutation rate and/or selection pressure within relatively short distances in the M. tuberculosis genome. Importantly, our results indicate that selection on synonymous substitutions is common in the M. tuberculosis genome. Therefore, the dN/dS ratio test must be applied carefully for measuring selection pressure on M. tuberculosis genes.
结核分枝杆菌是最致命的人类病原体之一。结核分枝杆菌适应的主要机制是核苷酸取代。以前的研究依赖于非同义替换与同义替换率（dN/dS）比值作为基于同义替换的选择性中性的选择约束的衡量标准。然而，在许多情况下，这一假设已被证明是不正确的。在这项研究中，我们使用结核分枝杆菌基因组基因间区（di）的替换率作为中性参考，并用 50kb 滑动窗口，与 M. canettii 的基因组相比，对 di、dS 和插入/缺失率（indel rate）进行了全基因组分析。我们证明了在结核分枝杆菌基因组中，所有这三种进化测量值都存在显著差异，即使是在邻近的区域也是如此。此外，我们总共鉴定了 233 个基因，它们在同一窗口内的 dS 明显偏离 di。有趣的是，在一些窗口中 dS 也有很大的变化，这表明在结核分枝杆菌基因组中，在相对较短的距离内，突变率和/或选择压力发生了剧烈变化。重要的是，我们的结果表明，同义替换的选择在结核分枝杆菌基因组中很常见。因此，dN/dS 比值检验必须谨慎应用于测量结核分枝杆菌基因的选择压力。
