Ma Tianxing, Li Haochen, Zhang Xuegong
MOE Key Laboratory of Bioinformatics, Bioinformatics Division, BNRIST and Department of Automation, Tsinghua University, Beijing 100084, China.
School of Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China.
Gene. 2022 Jun 30;829:146520. doi: 10.1016/j.gene.2022.146520. Epub 2022 Apr 20.
eQTL studies are essential for understanding genomic regulation. The effects of genetic variations on gene regulation are cell-type-specific and cellular-context-related, so studying eQTLs at a single-cell level is crucial. The ideal solution is to use both mutation and expression data from the same cells. However, the current technology of such paired data in single cells is still immature. We present a new method, eQTLsingle, to discover eQTLs only with single-cell RNA-seq (scRNA-seq) data, without genomic data. It detects mutations from scRNA-seq data and models gene expression of different genotypes with the zero-inflated negative binomial (ZINB) model to find associations between genotypes and phenotypes at the single-cell level. On a glioblastoma and gliomasphere scRNA-seq dataset, eQTLsingle discovered hundreds of cell-type-specific tumor-related eQTLs, most of which cannot be found in bulk eQTL studies. Detailed analyses on examples of the discovered eQTLs revealed important underlying regulatory mechanisms. eQTLsingle is a uniquely powerful tool for utilizing the vast scRNA-seq resources for single-cell eQTL studies, and it is available for free academic use at https://github.com/horsedayday/eQTLsingle.
表达数量性状基因座（eQTL）研究对于理解基因组调控至关重要。基因变异对基因调控的影响具有细胞类型特异性且与细胞环境相关，因此在单细胞水平研究eQTL至关重要。理想的解决方案是使用来自同一细胞的突变和表达数据。然而，目前单细胞中此类配对数据的技术仍不成熟。我们提出了一种新方法eQTLsingle，仅利用单细胞RNA测序（scRNA-seq）数据来发现eQTL，而无需基因组数据。它从scRNA-seq数据中检测突变，并使用零膨胀负二项式（ZINB）模型对不同基因型的基因表达进行建模，以在单细胞水平上找到基因型与表型之间的关联。在胶质母细胞瘤和胶质瘤球scRNA-seq数据集上，eQTLsingle发现了数百个细胞类型特异性的肿瘤相关eQTL，其中大部分在批量eQTL研究中无法找到。对发现的eQTL实例进行的详细分析揭示了重要的潜在调控机制。eQTLsingle是利用大量scRNA-seq资源进行单细胞eQTL研究的独特强大工具，可在https://github.com/horsedayday/eQTLsingle上免费用于学术用途。
