TY - JOUR
T1 - Characterizing allele- and haplotype-specific copy numbers in single cells with CHISEL
AU - Zaccaria, Simone
AU - Raphael, Benjamin J.
N1 - Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/2
Y1 - 2021/2
N2 - Single-cell barcoding technologies enable genome sequencing of thousands of individual cells in parallel, but with extremely low sequencing coverage (<0.05×) per cell. While the total copy number of large multi-megabase segments can be derived from such data, important allele-specific mutations—such as copy-neutral loss of heterozygosity (LOH) in cancer—are missed. We introduce copy-number haplotype inference in single cells using evolutionary links (CHISEL), a method to infer allele- and haplotype-specific copy numbers in single cells and subpopulations of cells by aggregating sparse signal across hundreds or thousands of individual cells. We applied CHISEL to ten single-cell sequencing datasets of ~2,000 cells from two patients with breast cancer. We identified extensive allele-specific copy-number aberrations (CNAs) in these samples, including copy-neutral LOHs, whole-genome duplications (WGDs) and mirrored-subclonal CNAs. These allele-specific CNAs affect genomic regions containing well-known breast-cancer genes. We also refined the reconstruction of tumor evolution, timing allele-specific CNAs before and after WGDs, identifying low-frequency subpopulations distinguished by unique CNAs and uncovering evidence of convergent evolution.
AB - Single-cell barcoding technologies enable genome sequencing of thousands of individual cells in parallel, but with extremely low sequencing coverage (<0.05×) per cell. While the total copy number of large multi-megabase segments can be derived from such data, important allele-specific mutations—such as copy-neutral loss of heterozygosity (LOH) in cancer—are missed. We introduce copy-number haplotype inference in single cells using evolutionary links (CHISEL), a method to infer allele- and haplotype-specific copy numbers in single cells and subpopulations of cells by aggregating sparse signal across hundreds or thousands of individual cells. We applied CHISEL to ten single-cell sequencing datasets of ~2,000 cells from two patients with breast cancer. We identified extensive allele-specific copy-number aberrations (CNAs) in these samples, including copy-neutral LOHs, whole-genome duplications (WGDs) and mirrored-subclonal CNAs. These allele-specific CNAs affect genomic regions containing well-known breast-cancer genes. We also refined the reconstruction of tumor evolution, timing allele-specific CNAs before and after WGDs, identifying low-frequency subpopulations distinguished by unique CNAs and uncovering evidence of convergent evolution.
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U2 - 10.1038/s41587-020-0661-6
DO - 10.1038/s41587-020-0661-6
M3 - Article
C2 - 32879467
SN - 1087-0156
VL - 39
SP - 207
EP - 214
JO - Nature biotechnology
JF - Nature biotechnology
IS - 2
ER -