Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing
Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing
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DOI：
10.1016/j.cell.2019.10.026
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发表时间：
2019-11-14
期刊：
影响因子：
64.5
通讯作者：
Aparicio, Samuel
中科院分区：
文献类型：
--
作者：
Laks, Emma;McPherson, Andrew;Aparicio, Samuel
准确测量克隆基因型，突变过程，和复制状态从个别肿瘤细胞基因组将有助于提高对肿瘤演变的理解。我们开发了DLP+，这是一个可扩展的单细胞全基因组测序平台，使用商品仪器，基于图像的对象识别和开源计算方法实现。使用DLP+，我们已经生成了51，926个单细胞基因组的资源，并匹配了来自不同细胞类型的细胞图像，包括细胞系，异种移植物和材料有限的诊断样本。从这个资源，我们已经定义了有丝分裂的错误分离率在组织类型和基因型的变化。匹配的基因组和图像测量的分析揭示了细胞形态和基因组倍性状态之间的相关性。共享拷贝数谱的细胞的聚集允许计算单核苷酸分辨率克隆基因型和推断克隆同源性，并避免了批量去卷积的限制。最后，对上述特征的联合分析定义了多克隆群体中的克隆特异性染色体非整倍性。
Accurate measurement of clonal genotypes, mutational processes, and replication states from individual tumor-cell genomes will facilitate improved understanding of tumor evolution. We have developed DLP+, a scalable single-cell whole-genome sequencing platform implemented using commodity instruments, image-based object recognition, and open source computational methods. Using DLP+, we have generated a resource of 51,926 single-cell genomes and matched cell images from diverse cell types including cell lines, xenografts, and diagnostic samples with limited material. From this resource we have defined variation in mitotic mis-segregation rates across tissue types and genotypes. Analysis of matched genomic and image measurements revealed correlations between cellular morphology and genome ploidy states. Aggregation of cells sharing copy number profiles allowed for calculation of single-nucleotide resolution clonal genotypes and inference of clonal phylogenies and avoided the limitations of bulk deconvolution. Finally, joint analysis over the above features defined clone-specific chromosomal aneuploidy in polyclonal populations.