Paralog dispensability shapes homozygous deletion patterns in tumor genomes.

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Molecular Systems Biology Pub Date : 2023-12-06 Epub Date: 2023-11-14 DOI:10.15252/msb.202311987
Barbara De Kegel, Colm J Ryan
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引用次数: 5

Abstract

Genomic instability is a hallmark of cancer, resulting in tumor genomes having large numbers of genetic aberrations, including homozygous deletions of protein coding genes. That tumor cells remain viable in the presence of such gene loss suggests high robustness to genetic perturbation. In model organisms and cancer cell lines, paralogs have been shown to contribute substantially to genetic robustness-they are generally more dispensable for growth than singletons. Here, by analyzing copy number profiles of > 10,000 tumors, we test the hypothesis that the increased dispensability of paralogs shapes tumor genome evolution. We find that genes with paralogs are more likely to be homozygously deleted and that this cannot be explained by other factors known to influence copy number variation. Furthermore, features that influence paralog dispensability in cancer cell lines correlate with paralog deletion frequency in tumors. Finally, paralogs that are broadly essential in cancer cell lines are less frequently deleted in tumors than non-essential paralogs. Overall, our results suggest that homozygous deletions of paralogs are more frequently observed in tumor genomes because paralogs are more dispensable.

平行可有可无的形状纯合缺失模式在肿瘤基因组。
基因组不稳定是癌症的一个标志,导致肿瘤基因组具有大量的遗传畸变,包括蛋白质编码基因的纯合缺失。肿瘤细胞在这种基因丢失的情况下仍能存活,这表明肿瘤细胞对遗传扰动具有很高的稳健性。在模式生物和癌细胞系中,相似子已被证明对遗传稳健性有重大贡献——它们通常比单个子在生长过程中更不可或缺。在这里,通过分析1,000,000个肿瘤的拷贝数谱,我们验证了类似物的可有可无性增加影响肿瘤基因组进化的假设。我们发现,具有类似物的基因更有可能被纯合删除,这不能用已知的影响拷贝数变化的其他因素来解释。此外,影响癌细胞系中平行缺失的特征与肿瘤中平行缺失的频率相关。最后,在癌细胞系中广泛必需的旁系在肿瘤中被删除的频率低于非必需的旁系。总的来说,我们的研究结果表明,在肿瘤基因组中更经常观察到同源物的纯合缺失,因为同源物更可有可无。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems. Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.
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