Haplotype-aware analysis of somatic copy number variations from single -cell transcriptomes
Haplotype-aware analysis of somatic copy number variations from single -cell transcriptomes
复制标题
DOI：
10.1038/s41587-022-01468-y
复制
发表时间：
2022-09-26
影响因子：
46.9
通讯作者：
Kharchenko, Peter, V
中科院分区：
文献类型：
--
作者：
Gao, Teng;Soldatov, Ruslan;Kharchenko, Peter, V
Numbat 整合表达、等位基因和单倍型信息来检测 scRNA-seq 中的拷贝数变异。基因组不稳定性和转录程序的异常改变在癌症中都发挥着重要作用。单细胞 RNA 测序 (scRNA-seq) 有潜力在一次检测中研究肿瘤异质性的遗传和非遗传来源。在这里，我们提出了一种计算方法 Numbat，它将从基于群体的定相中获得的单倍型信息与等位基因和表达信号相结合，以增强 scRNA-seq 中拷贝数变异的检测。 Numbat 利用亚克隆之间的进化关系来迭代推断单细胞拷贝数谱和肿瘤克隆系统发育。对包括多发性骨髓瘤、胃癌、乳腺癌和甲状腺癌在内的 22 个肿瘤样本的分析表明，Numbat 可以重建肿瘤拷贝数谱并精确识别肿瘤微环境中的恶性细胞。我们鉴定了具有与肿瘤进展和治疗耐药性相关的转录特征的遗传亚群。 Numbat 既不需要样本匹配的 DNA 数据，也不需要先验的基因分型，并且适用于广泛的实验环境和癌症类型。
Numbat integrates expression, allele and haplotype information to detect copy number variations in scRNA-seq.Genome instability and aberrant alterations of transcriptional programs both play important roles in cancer. Single-cell RNA sequencing (scRNA-seq) has the potential to investigate both genetic and nongenetic sources of tumor heterogeneity in a single assay. Here we present a computational method, Numbat, that integrates haplotype information obtained from population-based phasing with allele and expression signals to enhance detection of copy number variations from scRNA-seq. Numbat exploits the evolutionary relationships between subclones to iteratively infer single-cell copy number profiles and tumor clonal phylogeny. Analysis of 22 tumor samples, including multiple myeloma, gastric, breast and thyroid cancers, shows that Numbat can reconstruct the tumor copy number profile and precisely identify malignant cells in the tumor microenvironment. We identify genetic subpopulations with transcriptional signatures relevant to tumor progression and therapy resistance. Numbat requires neither sample-matched DNA data nor a priori genotyping, and is applicable to a wide range of experimental settings and cancer types.