Cancer progression is driven by both somatic copy number aberrations (CNAs) and chromatin remodeling, yet little is known about the interplay between these two classes of events in shaping the clonal diversity of cancers. We present Alleloscope, a method for allele-specific copy number estimation that can be applied to single-cell DNA- and/or transposase-accessible chromatin-sequencing (scDNA-seq, ATAC-seq) data, enabling combined analysis of allele-specific copy number and chromatin accessibility. On scDNA-seq data from gastric, colorectal and breast cancer samples, with validation using matched linked-read sequencing, Alleloscope finds pervasive occurrence of highly complex, multiallelic CNAs, in which cells that carry varying allelic configurations adding to the same total copy number coevolve within a tumor. On scATAC-seq from two basal cell carcinoma samples and a gastric cancer cell line, Alleloscope detected multiallelic copy number events and copy-neutral loss-of-heterozygosity, enabling dissection of the contributions of chromosomal instability and chromatin remodeling to tumor evolution.
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The patient scDNA-seq and linked-read sequencing data generated for this study are available under dbGAP identifier phs001711. The scATAC-seq dataset is available in the National Institute of Health’s Sequence Read Archive (SRA) repository under accession PRJNA674903. There are no restrictions on data availability or use. The other patient scDNA-seq data were obtained from dbGAP under accession phs001818.v3.p1 (ref. 27) and phs001711 (ref. 12). The cell line scDNA-seq dataset was from the SRA under accession PRJNA498809. The public scATAC-seq data and WES data were obtained from the SRA under accession PRJNA532774 (ref. 25) and PRJNA533341 (ref. 31).
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The work is supported by the National Institutes of Health (grant nos. P01HG00205ESH to B.T.L., S.M.G. and H.P.J., 5R01-HG006137-07 and 1U2CCA233285-01 to C-Y.W. and to N.R.Z., 1R35HG011292-01 to B.T.L.). Additional support to H.P.J. came from the Research Scholar grant no. RSG-13-297-01-TBG from the American Cancer Society, Clayville Foundation and the Gastric Cancer Foundation. Additional support to N.R.Z. came from 1R01GM125301-01, 1P01CA210944-01 and The Mark Foundation for Cancer Research.
The authors declare no competing interests.
Peer review information Nature Biotechnology thanks Stephen Chanock and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Wu, CY., Lau, B.T., Kim, H.S. et al. Integrative single-cell analysis of allele-specific copy number alterations and chromatin accessibility in cancer. Nat Biotechnol (2021). https://doi.org/10.1038/s41587-021-00911-w