1. Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing
- Author
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Edward S. Boyden, Elizabeth A. Chavez, Steven S.S. Poon, Robby Becker, Wendy Greenwood, M Jafar Taghiyar, Peter Eirew, Maximillian Lee, Carl L. Hansen, Hans Zahn, Sohrab P. Shah, Mohammad Al Sa’d, Jonas Windager, Maia A. Smith, Lauren Martin, Hsuan Lee, Matt Wiens, So Ra Lee, A. Dariush, Oleg Golovko, Fergus Cafferty, Sorhab Shah, Russell Kunes, Owen Harris, Nick Chornay, Jean Fan, Samuel Aparicio, Marco A. Marra, Shankar Balasubramanian, Stephen Chia, Andrew McPherson, Farhia Kabeer, Samantha Leung, Sophia A Wild, Neil Millar, Claire Mulvey, Shahar Alon, Giorgia Battistoni, Leonardo Sepulveda Duran, Anubhav Sinha, Khanh N. Dinh, Viktoria Bojilova, Yi Cui, Nafis Abrar, Sophia Chan, Yussanne Ma, Austin Smith, Marcel Burger, Jean Hausser, Eduardo Gonzales Solares, Maurizio Callari, Bernd Bodenmiller, Dario Bressan, Aybuke Kupcu Yoldas, Tehmina Masud, Adi Steif, Colin Mar, Abigail Shea, Gregory J. Hannon, Yangguang Li, Timothy M. Chan, Christian Steidl, Cydney B. Nielsen, Flaminia Grimaldi, Eyal Fisher, Daniel J. Da Costa, Tatjana Kovacevic, Carlos Gonzalez-Fernandez, Beixi Wang, Spencer Watson, Sandra Tietscher, Teresa Ruiz, Ignacio Vázquez-García, Jessica Ngo, Amauche Emenari, Pu Zheng, Kirsty Sawicka, Carlos Caldas, Asmamaw T Wassie, Daniel Lai, Chenglong Xia, Oscar M. Rueda, Robin J.N. Coope, Andrew J. Mungall, Fiona Nugent, Marta Paez Ribes, Karen A. Gelmon, Stephen Pleasance, Simon Tavaré, Pascale Walters, Teresa Ruiz de Algara, Ciara H. O'Flanagan, Curtis Huebner, Emma Laks, T. Michael Underhill, Jazmine Brimhall, Alastair Marti, Justina Biele, R. Wilder Scott, Diljot Grewal, Fatime Qosaj, Richard D. Moore, Dan Goodwin, Laura Kuett, Nicolas A. Walton, Suvi Harris, Emmanouil D. Karagiannis, Cristina Jauset, Elena Williams, Isabella Pearsall, Sara Vogl, Alejandra Bruna, Yaniv Lubling, Jerome Ting, Ian G. Cannell, Xiaowei Zhuang, Richard Corbett, Hannah Casbolt, Giulia Lerda, Johanna A. Joyce, and Spencer Vatrt-Watts
- Subjects
Genome instability ,DNA Replication ,Male ,tumor evolution ,Genotype ,Cell Survival ,Genomics ,Computational biology ,Biology ,Genome ,Polymorphism, Single Nucleotide ,Article ,General Biochemistry, Genetics and Molecular Biology ,DNA sequencing ,03 medical and health sciences ,Mice ,0302 clinical medicine ,copy number ,Cell Line, Tumor ,tumor heterogeneity ,Animals ,Chromosomes, Human ,Humans ,Cell Shape ,Phylogeny ,030304 developmental biology ,cancer genomics ,0303 health sciences ,Genome, Human ,Cell Cycle ,DNA replication ,High-Throughput Nucleotide Sequencing ,Cell cycle ,genomic instability ,Aneuploidy ,Diploidy ,single cell ,Clone Cells ,Mutation ,DNA Transposable Elements ,Female ,Ploidy ,Single-Cell Analysis ,030217 neurology & neurosurgery - Abstract
Summary 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., Graphical Abstract, Highlights • Scaled method and resource of > 50K single-cell whole genomes from diverse cell types • Clonal merging can resolve clone specific mutations to single-nucleotide level • Image analysis of single cells permits correlation of morphology and genome features • Clonal replication states and rare aneuploidy patterns of single cells measured, A high-throughput method for amplication-free single-cell whole-genome sequencing can be scaled up to analyze tens of thousands of cells from different tissues and clinical sample types and identifies replication states, aneuploidies, and subclonal mutations.
- Published
- 2018