Makarova Kira S, Wolf Yuri I, Koonin Eugene V
National Center for Biotechnology Information, NLM, National Institutes of Health, Bethesda, Maryland 20894, USA.
Biol Direct. 2009 Jun 3;4:19. doi: 10.1186/1745-6150-4-19.
The prokaryotic toxin-antitoxin systems (TAS, also referred to as TA loci) are widespread, mobile two-gene modules that can be viewed as selfish genetic elements because they evolved mechanisms to become addictive for replicons and cells in which they reside, but also possess "normal" cellular functions in various forms of stress response and management of prokaryotic population. Several distinct TAS of type 1, where the toxin is a protein and the antitoxin is an antisense RNA, and numerous, unrelated TAS of type 2, in which both the toxin and the antitoxin are proteins, have been experimentally characterized, and it is suspected that many more remain to be identified.
We report a comprehensive comparative-genomic analysis of Type 2 toxin-antitoxin systems in prokaryotes. Using sensitive methods for distant sequence similarity search, genome context analysis and a new approach for the identification of mobile two-component systems, we identified numerous, previously unnoticed protein families that are homologous to toxins and antitoxins of known type 2 TAS. In addition, we predict 12 new families of toxins and 13 families of antitoxins, and also, predict a TAS or TAS-like activity for several gene modules that were not previously suspected to function in that capacity. In particular, we present indications that the two-gene module that encodes a minimal nucleotidyl transferase and the accompanying HEPN protein, and is extremely abundant in many archaea and bacteria, especially, thermophiles might comprise a novel TAS. We present a survey of previously known and newly predicted TAS in 750 complete genomes of archaea and bacteria, quantitatively demonstrate the exceptional mobility of the TAS, and explore the network of toxin-antitoxin pairings that combines plasticity with selectivity.
The defining properties of the TAS, namely, the typically small size of the toxin and antitoxin genes, fast evolution, and extensive horizontal mobility, make the task of comprehensive identification of these systems particularly challenging. However, these same properties can be exploited to develop context-based computational approaches which, combined with exhaustive analysis of subtle sequence similarities were employed in this work to substantially expand the current collection of TAS by predicting both previously unnoticed, derived versions of known toxins and antitoxins, and putative novel TAS-like systems. In a broader context, the TAS belong to the resistome domain of the prokaryotic mobilome which includes partially selfish, addictive gene cassettes involved in various aspects of stress response and organized under the same general principles as the TAS. The "selfish altruism", or "responsible selfishness", of TAS-like systems appears to be a defining feature of the resistome and an important characteristic of the entire prokaryotic pan-genome given that in the prokaryotic world the mobilome and the "stable" chromosomes form a dynamic continuum.
This paper was reviewed by Kenn Gerdes (nominated by Arcady Mushegian), Daniel Haft, Arcady Mushegian, and Andrei Osterman. For full reviews, go to the Reviewers' Reports section.
原核生物毒素-抗毒素系统（TAS，也称为TA位点）是广泛存在的、可移动的双基因模块，可被视为自私的遗传元件，因为它们进化出了使自身对其所驻留的复制子和细胞具有成瘾性的机制，但同时在各种形式的应激反应和原核生物群体管理中也具有“正常”的细胞功能。1型的几种不同TAS（其中毒素是一种蛋白质，抗毒素是一种反义RNA）以及2型的许多不相关TAS（其中毒素和抗毒素都是蛋白质）已通过实验进行了表征，并且怀疑还有更多有待鉴定。
我们报告了原核生物中2型毒素-抗毒素系统的全面比较基因组分析。使用敏感的远源序列相似性搜索方法、基因组背景分析以及一种识别可移动双组分系统的新方法，我们鉴定出了许多以前未被注意到的与已知2型TAS的毒素和抗毒素同源的蛋白质家族。此外，我们预测了12个新的毒素家族和13个抗毒素家族，并且还预测了几个以前不被怀疑具有该功能的基因模块具有TAS或TAS样活性。特别是，我们提供了证据表明，编码最小核苷酸转移酶和伴随的HEPN蛋白的双基因模块在许多古细菌和细菌中极为丰富，尤其是嗜热菌中可能构成一种新型TAS。我们对古细菌和细菌的750个完整基因组中先前已知和新预测的TAS进行了调查，定量证明了TAS的异常可移动性，并探索了将可塑性与选择性相结合的毒素-抗毒素配对网络。
TAS的定义特性，即毒素和抗毒素基因通常较小、进化迅速以及广泛的水平移动性，使得全面鉴定这些系统的任务极具挑战性。然而，这些相同的特性可被用于开发基于背景的计算方法，结合对细微序列相似性的详尽分析，本研究采用这些方法通过预测已知毒素和抗毒素以前未被注意到的衍生版本以及假定的新型TAS样系统，大幅扩展了当前的TAS集合。在更广泛的背景下，TAS属于原核生物可移动基因组的抗性组域，其中包括部分自私的、成瘾性的基因盒，这些基因盒参与应激反应的各个方面，并按照与TAS相同的一般原则组织起来。鉴于在原核生物世界中，可移动基因组和“稳定”染色体形成一个动态连续体，TAS样系统的“自私利他主义”或“负责任的自私性”似乎是抗性组的一个定义特征，也是整个原核生物泛基因组的一个重要特征。
本文由Kenn Gerdes（由Arcady Mushegian提名）、Daniel Haft、Arcady Mushegian和Andrei Osterman审阅。完整的审阅内容，请转至“审阅者报告”部分。
