Spontaneous mutations can alter tissue dynamics and lead to cancer initiation. Although large-scale sequencing projects have illuminated processes that influence somatic mutation and subsequent tumor evolution, the mutational dynamics operating in the very early stages of cancer development are currently not well understood. To explore mutational processes in the early stages of cancer evolution, we exploited neoplasia arising spontaneously in the Drosophila intestine. Analysing whole-genome sequencing data with a dedicated bioinformatic pipeline, we found neoplasia formation to be driven largely through the inactivation of Notch by structural variants, many of which involve highly complex genomic rearrangements. The genome-wide mutational burden in neoplasia was found to be similar to that of several human cancers. Finally, we identified genomic features associated with spontaneous mutation, and defined the evolutionary dynamics and mutational landscape operating within intestinal neoplasia over the short lifespan of the adult fly. Our findings provide unique insight into mutational dynamics operating over a short timescale in the genetic model system, Drosophila melanogaster.

中文翻译：

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果蝇肠道干细胞自发体细胞突变的进化和基因组特征

自发突变可以改变组织动力学并导致癌症发生。尽管大规模测序项目已经阐明了影响体细胞突变和随后的肿瘤进化的过程，但目前尚不清楚在癌症发展的早期阶段发生的突变动力学。为了探索癌症进化早期的突变过程，我们利用了果蝇肠道中自发产生的瘤形成。使用专用的生物信息学管道分析全基因组测序数据，我们发现瘤形成主要是通过Notch的失活驱动的通过结构变异，其中许多涉及高度复杂的基因组重排。发现瘤形成中的全基因组突变负担与几种人类癌症相似。最后，我们确定了与自发突变相关的基因组特征，并定义了成虫短暂寿命内肠道肿瘤内的进化动力学和突变景观。我们的研究结果提供了对遗传模型系统黑腹果蝇在短时间内运行的突变动力学的独特见解。