加拿大癌症研究中心Samuel Aparicio和Sohrab P. Shah研究组合作利用单细胞基因组测序法确定了克隆分解和DNA复制状态。该项研究成果发表在2019年11月14日出版的《细胞》上。
研究人员开发的DLP+系统，是一个利用商品化仪器进行可扩展的单细胞全基因组测序平台，利用图像识别目标和开源计算方法来工作。使用DLP+，研究人员已经生成了51,926个单细胞基因组数据集，并从多种细胞类型（包括细胞系、异种骨质移植和来源有限的诊断样品）中匹配了细胞影像。通过对这些数据集分析，研究人员确定了跨组织类型和基因型的有丝分裂错误隔离率的变化。对匹配基因组和图像测量结果分析揭示了细胞形态与基因组倍性状态之间的相关性。共享拷贝数分布的细胞聚集实现了在单核苷酸分辨率基础上计算克隆基因型和推断克隆系统的发育，并且避免了大量反卷积的局限性。最后，对以上特征的联合分析确定了多克隆群体中克隆特异性的染色体非整倍性。
据悉，准确测量单个肿瘤细胞基因组中克隆基因型、突变过程和复制状态将有助于增进对肿瘤进化的了解。
附：英文原文
Title: Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing
Author: Emma Laks, Andrew McPherson, Hans Zahn, Daniel Lai, Adi Steif, Jazmine Brimhall, Justina Biele, Beixi Wang, Tehmina Masud, Jerome Ting, Diljot Grewal, Cydney Nielsen, Samantha Leung, Viktoria Bojilova, Maia Smith, Oleg Golovko, Steven Poon, Peter Eirew, Farhia Kabeer, Teresa Ruiz de Algara, So Ra Lee, M. Jafar Taghiyar, Curtis Huebner, Jessica Ngo, Tim Chan, Spencer Vatrt-Watts, Pascale Walters, Nafis Abrar, Sophia Chan, Matt Wiens, Lauren Martin, R. Wilder Scott, T. Michael Underhill, Elizabeth Chavez, Christian Steidl, Daniel Da Costa, Yussanne Ma, Robin J.N. Coope, Richard Corbett, Stephen Pleasance, Richard Moore, Andrew J. Mungall, Colin Mar, Fergus Cafferty, Karen Gelmon, Stephen Chia,The CRUK IMAXT Grand Challenge Team, Marco A. Marra, Carl Hansen, Sohrab P. Shah, Samuel Aparicio
Issue&Volume: 2019/11/14
Abstract: 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.
DOI: 10.1016/j.cell.2019.10.026
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31176-6