异常染色体数量（非整倍体）和染色体错位增加频率（染色体不稳定性）是癌症的显著特征。对肿瘤基因组数据的分析已经确定了某些肿瘤中的非整倍体模式，然而选择它们的基础仍然不为人所知。通过建立长期适应性的时间解析协议，我们发现人类细胞通过获取特定的染色体臂增益和损失适应于有持续的纺锤体装配检查点（SAC）抑制。独立适应的群体将汇聚成复杂的核型，在一段时间后，将变得越来越精细，包括越来越小的染色体变化。值得注意的是，适应细胞中的染色体臂增益频率与癌症中检测到的频率相关，这表明我们的细胞适应方法重现了许多癌症类型中频繁观察到的非整倍体选择性特征。我们进一步通过设计特定的非整倍体来确定观察到的核型模式的遗传基础。这些实验表明，适应的和设计的非整倍体细胞系通过延长有丝分裂期来限制染色体错位。关键SAC和APC / C基因的杂合性缺失重复了单倍体染色体的拯救表型。我们得出结论，非整倍体诱导的单倍体染色体调节基因的基因剂量失衡足以改变有丝分裂时间，从而减少染色体不稳定性。 ©2023 Adell等人；由Cold Spring Harbor实验室出版。

Both the presence of an abnormal complement of chromosomes (aneuploidy) and an increased frequency of chromosome missegregation (chromosomal instability) are hallmarks of cancer. Analyses of cancer genome data have identified certain aneuploidy patterns in tumors; however, the bases behind their selection are largely unexplored. By establishing time-resolved long-term adaptation protocols, we found that human cells adapt to persistent spindle assembly checkpoint (SAC) inhibition by acquiring specific chromosome arm gains and losses. Independently adapted populations converge on complex karyotypes, which over time are refined to contain ever smaller chromosomal changes. Of note, the frequencies of chromosome arm gains in adapted cells correlate with those detected in cancers, suggesting that our cellular adaptation approach recapitulates selective traits that dictate the selection of aneuploidies frequently observed across many cancer types. We further engineered specific aneuploidies to determine the genetic basis behind the observed karyotype patterns. These experiments demonstrated that the adapted and engineered aneuploid cell lines limit CIN by extending mitotic duration. Heterozygous deletions of key SAC and APC/C genes recapitulated the rescue phenotypes of the monosomic chromosomes. We conclude that aneuploidy-induced gene dosage imbalances of individual mitotic regulators are sufficient for altering mitotic timing to reduce CIN.© 2023 Adell et al.; Published by Cold Spring Harbor Laboratory Press.