Single-cell DNA replication dynamics in genomically unstable cancers.
Single-cell DNA replication dynamics in genomically unstable cancers.
复制标题
基因组不稳定癌症中的单细胞 DNA 复制动态。
DOI：
10.1101/2023.04.10.536250
复制
发表时间：
2023
期刊：
影响因子：
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通讯作者：
McPherson,Andrew
中科院分区：
文献类型：
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作者：
Weiner,AdamC;Williams,MarcJ;Shi,Hongyu;Vázquez-García,Ignacio;Salehi,Sohrab;Rusk,Nicole;Aparicio,Samuel;Shah,SohrabP;McPherson,Andrew
DNA复制失调既是非整倍体的原因，也是非整倍体的结果，但非整倍体细胞群体中DNA复制的动力学仍未得到充分研究。我们开发了一种新的方法，PERT，从单细胞全基因组测序中推断细胞特异性DNA复制状态，并研究了从非整倍体和克隆异质细胞系，异种移植物和原发性癌症组织中获得的bb500000个细胞的克隆特异性DNA复制动力学。克隆复制时间（RT）谱与连续传代细胞系未来拷贝数变化相关。细胞类型是RT异质性的最强决定因素，而全基因组加倍和突变过程与晚期s期细胞的积累和较弱的RT相关性相关。影响X染色体的拷贝数变化对RT有显著影响，失活X等位基因的丢失使复制提前，失活Xq的丢失导致Xp的重新激活。最后，对时间序列异种移植物的分析说明了细胞周期分布如何近似于克隆增殖，概括了在治疗初期和化疗背景下增殖和适应性之间的预期关系。
Dysregulated DNA replication is both a cause and a consequence of aneuploidy, yet the dynamics of DNA replication in aneuploid cell populations remains understudied. We developed a new method, PERT, for inferring cell-specific DNA replication states from single-cell whole genome sequencing, and investigated clone-specific DNA replication dynamics in >50,000 cells obtained from a collection of aneuploid and clonally heterogeneous cell lines, xenografts and primary cancer tissues. Clone replication timing (RT) profiles correlated with future copy number changes in serially passaged cell lines. Cell type was the strongest determinant of RT heterogeneity, while whole genome doubling and mutational process were associated with accumulation of late S-phase cells and weaker RT associations. Copy number changes affecting chromosome X had striking impact on RT, with loss of the inactive X allele shifting replication earlier, and loss of inactive Xq resulting in reactivation of Xp. Finally, analysis of time series xenografts illustrate how cell cycle distributions approximate clone proliferation, recapitulating expected relationships between proliferation and fitness in treatment-naive and chemotherapeutic contexts.