德国欧洲分子生物学实验室Lars M. Steinmetz小组使用联合多组单细胞DNA-RNA测序对基因组变异进行功能表型分析。相关论文于2025年9月1日发表于国际顶尖学术期刊《自然—方法学》杂志上。

课题组开发了单细胞DNA-RNA测序（SDR-seq），可以同时分析多达480个基因组DNA位点和基因，从而准确测定编码和非编码变异的合子性以及相关基因的表达变化。利用SDR-seq，该课题组人员将编码和非编码变异与人类诱导多能干细胞中不同的基因表达联系起来。

此外，该研究团队证明在原发性B细胞淋巴瘤样本中，具有较高突变负担的细胞表现出升高的B细胞受体信号传导和致瘤基因表达。SDR-seq提供了一个强大的平台来剖析由遗传变异编码的调控机制，促进他们对基因表达调控及其对疾病的影响的理解。

研究人员表示，遗传变异（包括编码和非编码）可以影响基因功能和表达，驱动疾病机制，如癌症进展。低效率的精确编辑工具阻碍了内源性遗传变异的系统研究，再加上在单细胞分辨率下自信地将基因型与基因表达联系起来的技术限制。

附：英文原文

Title: Functional phenotyping of genomic variants using joint multiomic single-cell DNA–RNA sequencing

Author: Lindenhofer, Dominik, Bauman, Julia R., Hawkins, John A., Fitzgerald, Donnacha, Yildiz, Umut, Jung, Haeyeon, Korosteleva, Anastasiia, Marttinen, Mikael, Kueblbeck, Moritz, Zaugg, Judith B., Noh, Kyung-Min, Dietrich, Sascha, Huber, Wolfgang, Stegle, Oliver, Steinmetz, Lars M.

Issue&Volume: 2025-09-01

Abstract: Genetic variants (both coding and noncoding) can impact gene function and expression, driving disease mechanisms such as cancer progression. The systematic study of endogenous genetic variants is hindered by inefficient precision editing tools, combined with technical limitations in confidently linking genotypes to gene expression at single-cell resolution. We developed single-cell DNA–RNA sequencing (SDR-seq) to simultaneously profile up to 480 genomic DNA loci and genes in thousands of single cells, enabling accurate determination of coding and noncoding variant zygosity alongside associated gene expression changes. Using SDR-seq, we associate coding and noncoding variants with distinct gene expression in human induced pluripotent stem cells. Furthermore, we demonstrate that in primary B cell lymphoma samples, cells with a higher mutational burden exhibit elevated B cell receptor signaling and tumorigenic gene expression. SDR-seq provides a powerful platform to dissect regulatory mechanisms encoded by genetic variants, advancing our understanding of gene expression regulation and its implications for disease.

DOI: 10.1038/s41592-025-02805-0

Source: https://www.nature.com/articles/s41592-025-02805-0