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Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing

2019; Cell Press; Volume: 179; Issue: 5 Linguagem: Inglês

10.1016/j.cell.2019.10.026

1097-4172

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 A. Smith, Oleg Golovko, Steven S.S. Poon, Peter Eirew, Farhia Kabeer, Teresa Ruiz de Algara, So Ra Lee, M. Jafar Taghiyar, Curtis Huebner, Jessica Ngo, Tim Hon Man Chan, Spencer Vatrt-Watts, Pascale Walters, Nafis Abrar, Sophia Chan, Matt Wiens, Lauren Martin, R. Wilder Scott, T. Michael Underhill, Elizabeth A. Chavez, Christian Steidl, Daniel Da Costa, Yussanne Ma, Robin Coope, Richard Corbett, Stephen Pleasance, Richard A. Moore, Andrew J. Mungall, Colin Mar, Fergus Cafferty, Karen A. Gelmon, Stephen Chia, Marco A. Marra, Carl L. Hansen, Sohrab P. Shah, Samuel Aparício, Gregory J. Hannon, Giorgia Battistoni, Dario Bressan, Ian G. Cannell, Hannah Casbolt, Cristina Jauset, Tatjana Kovačević, Claire M. Mulvey, Fiona Nugent, Marta Ribes, Isabella Pearsall, Fatime Qosaj, Kirsty Sawicka, Sophia A. Wild, Elena Williams, Samuel Aparício, Emma Laks, Yangguang Li, Ciara H. O’Flanagan, Austin Smith, Teresa Ruíz, Shankar Balasubramanian, Maximillian Lee, Bernd Bodenmiller, Marcel Burger, Laura Kuett, Sandra Tietscher, Jonas Windager, Edward S. Boyden, Shahar Alon, Yi Cui, Amauche Emenari, Dan Goodwin, Emmanouil D. Karagiannis, Anubhav Sinha, Asmamaw T. Wassie, Carlos Caldas, Alejandra Bruna, Maurizio Callari, Wendy Greenwood, Giulia Lerda, Yaniv Lubling, Alastair Marti, Oscar M. Rueda, Abigail Shea, Owen Harris, Robby Becker, Flaminia Grimaldi, Suvi Harris, Sara Lisa Vogl, Johanna A. Joyce, Jean Hausser, Spencer S. Watson, Sorhab Shah, Andrew McPherson, Ignacio Vázquez-Garćıa, Simon Tavaré, Khanh N. Dinh, Eyal Fisher, Russell Kunes, Nicolas A. Walton, Mohammad Al Sa’d, Nick Chornay, A. Dariush, Eduardo Gonzales Solares, Carlos González, A. Yoldaş, Neil S. Millar, Xiaowei Zhuang, Jean Fan, Hsuan Lee, Leonardo Sepulveda Duran, Chenglong Xia, Pu Zheng,

Genomics and Phylogenetic Studies

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.