Genome chaos Survival strategy during crisis
Genome chaos Survival strategy during crisis
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DOI：
10.4161/cc.27378
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发表时间：
2014-02-15
期刊：
影响因子：
4.3
通讯作者：
Heng, Henry H.
中科院分区：
文献类型：
--
作者：
Liu, Guo;Stevens, Joshua B.;Heng, Henry H.
基因组混沌是一个复杂的、快速的基因组重组过程，它导致了混沌基因组的形成，随之而来的是建立稳定基因组的潜力。它最初是通过细胞遗传学分析检测到的，最近通过全基因组测序工作确认了多个亚型，包括“染色体thripsis”、“染色体丛”、“染色体合成”和“染色体发育”。尽管基因组混乱在肿瘤中很常见，但由于无法在临床样本中观察其随时间的演变，因此该过程的机制和细节方面都是未知的。在此，我们建立了一个实验系统来监测基因组混乱的进化过程，以阐明其机制。基因组混乱发生在暴露于具有不同机制的化疗药物后，这些机制共同作为应激源。染色体断裂（C-Frag）发生在混沌基因组形成之前、期间和之后，染色体的核型特征及其动态变化表明染色体断裂（C-Frag）恰好发生在混沌基因组形成之前。混沌基因组似乎是由染色体片段的随机重新连接形成的，部分是通过非同源末端连接（NHEJ）形成的。应激诱导的基因组混乱导致核型异质性增加。这种增加的进化潜力通过鉴定与高水平核型变异相关的增加的转录组动力学来证明。与影响有限数量的癌症基因相比，重组的基因组导致了癌症进化所必需的新系统动力学。基因组混乱作为一种快速、适应性的、基于基因组的进化机制，在促进危机期间新的基因组定义系统的快速宏观进化中起着至关重要的作用，这可能解释了癌症治疗的一些意想不到的后果。
Genome chaos, a process of complex, rapid genome re-organization, results in the formation of chaotic genomes, which is followed by the potential to establish stable genomes. It was initially detected through cytogenetic analyses, and recently confirmed by whole-genome sequencing efforts which identified multiple subtypes including "chromothripsis", "chromoplexy", "chromoanasynthesis", and "chromoanagenesis". Although genome chaos occurs commonly in tumors, both the mechanism and detailed aspects of the process are unknown due to the inability of observing its evolution over time in clinical samples. Here, an experimental system to monitor the evolutionary process of genome chaos was developed to elucidate its mechanisms. Genome chaos occurs following exposure to chemotherapeutics with different mechanisms, which act collectively as stressors. Characterization of the karyotype and its dynamic changes prior to, during, and after induction of genome chaos demonstrates that chromosome fragmentation (C-Frag) occurs just prior to chaotic genome formation. Chaotic genomes seem to form by random rejoining of chromosomal fragments, in part through non-homologous end joining (NHEJ). Stress induced genome chaos results in increased karyotypic heterogeneity. Such increased evolutionary potential is demonstrated by the identification of increased transcriptome dynamics associated with high levels of karyotypic variance. In contrast to impacting on a limited number of cancer genes, re-organized genomes lead to new system dynamics essential for cancer evolution. Genome chaos acts as a mechanism of rapid, adaptive, genome-based evolution that plays an essential role in promoting rapid macroevolution of new genome-defined systems during crisis, which may explain some unwanted consequences of cancer treatment.