Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, PA, USA.
Department of Statistics, University of Pennsylvania, Philadelphia, PA, USA.
Nat Biotechnol. 2021 Oct;39(10):1259-1269. doi: 10.1038/s41587-021-00911-w. Epub 2021 May 20.
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.
癌症的进展是由体细胞拷贝数异常（CNAs）和染色质重塑共同驱动的，但人们对这两类事件在塑造癌症克隆多样性方面的相互作用知之甚少。我们提出了 Alleloscope 方法，这是一种用于等位基因特异性拷贝数估计的方法，可以应用于单细胞 DNA 和/或转座酶可及染色质测序（scDNA-seq、ATAC-seq）数据，从而能够对等位基因特异性拷贝数和染色质可及性进行联合分析。在来自胃、结直肠和乳腺癌样本的 scDNA-seq 数据上，通过与匹配的链接读取测序进行验证，Alleleoscope 发现了普遍存在的高度复杂的多等位基因 CNA，其中携带不同等位基因构型的细胞在肿瘤内共同进化，从而增加相同的总拷贝数。在来自两个基底细胞癌样本和一个胃癌细胞系的 scATAC-seq 上，Alleleoscope 检测到多等位基因拷贝数事件和拷贝中性杂合性丢失，从而能够剖析染色体不稳定性和染色质重塑对肿瘤进化的贡献。
