欧洲分子生物学实验室Jan O. Korbel团队宣布他们的论文发现了通过耦合成像和基因组学揭示染色体不稳定性的起源。这一研究成果发表在2025年10月29日出版的国际学术期刊《自然》上。

在这里，研究人员介绍了机器学习辅助基因组学和成像收敛（MAGIC），这是一个自主操作的平台，集成了微核细胞的活细胞成像、机器学习和单细胞基因组学，以系统地研究CA的形成。将MAGIC应用于近二倍体，非转化细胞系，课题组研究人员在连续的细胞周期中跟踪从头CAs，突出了双中心染色体作为起始事件的共同作用。课题组人员确定了基线CA突变率，在TP53缺陷细胞中大约翻倍，并观察到染色体丢失比获得更频繁。沿染色体臂的DNA双链断裂的靶向诱导触发了不同的CA过程，揭示了稳定的同工染色体、协调的分离和多倍的等离心片段扩增，以及受染色体断裂位置影响的复杂CA结果。他们的数据对比了选择发生后体细胞突变景观的从头CA谱。通过MAGIC进行的实验推进了DNA重排过程的解剖，揭示了染色体不稳定性的基本决定因素。

据悉，在癌症进化过程中，体细胞染色体不稳定导致了广泛的结构和数量染色体异常（CAs）。尽管CA与核非典型性产生的有丝分裂错误有关，但人类细胞中自发CA形成的潜在过程和速率尚未得到充分研究。

附：英文原文

Title: Origins of chromosome instability unveiled by coupled imaging and genomics

Author: Cosenza, Marco Raffaele, Gaiatto, Alice, Erarslan Uysal, Bra, Andrades, lvaro, Sautter, Nina Luisa, Simunovic, Marina, Jendrusch, Michael Adrian, Zumalave, Sonia, Rausch, Tobias, Halavatyi, Aliaksandr, Geissen, Eva-Maria, Eigenmann, Joshua Lucas, Weber, Thomas, Hasenfeld, Patrick, Benito, Eva, Stober, Catherine, Cortes-Ciriano, Isidro, Kulozik, Andreas E., Pepperkok, Rainer, Korbel, Jan O.

Issue&Volume: 2025-10-29

Abstract: Somatic chromosome instability results in widespread structural and numerical chromosomal abnormalities (CAs) during cancer evolution1,2,3. Although CAs have been linked to mitotic errors resulting in the emergence of nuclear atypia4,5,6,7, the underlying processes and rates of spontaneous CA formation in human cells are underexplored. Here we introduce machine-learning-assisted genomics and imaging convergence (MAGIC)—an autonomously operated platform that integrates live-cell imaging of micronucleated cells, machine learning on-the-fly and single-cell genomics to systematically investigate CA formation. Applying MAGIC to near-diploid, non-transformed cell lines, we track de novo CAs over successive cell cycles, highlighting the common role of dicentric chromosomes as initiating events. We determine the baseline CA mutation rate, which approximately doubles in TP53-deficient cells, and observe that chromosome losses arise more frequently than gains. The targeted induction of DNA double-strand breaks along chromosome arms triggers distinct CA processes, revealing stable isochromosomes, coordinated segregation and amplification of isoacentric segments in multiples of two, as well as complex CA outcomes, influenced by the chromosomal break location. Our data contrast de novo CA spectra from somatic mutational landscapes after selection occurred. The experimentation enabled by MAGIC advances the dissection of DNA rearrangement processes, shedding light on fundamental determinants of chromosomal instability.

DOI: 10.1038/s41586-025-09632-5

Source: https://www.nature.com/articles/s41586-025-09632-5