TY  - JOUR
AU  - Lindenhofer, Dominik
AU  - Bauman, Julia R
AU  - Hawkins, John Andrew
AU  - Fitzgerald, Donnacha
AU  - Yildiz, Umut
AU  - Jung, Haeyeon
AU  - Korosteleva, Anastasiia
AU  - Marttinen, Mikael
AU  - Kueblbeck, Moritz
AU  - Zaugg, Judith B
AU  - Noh, Kyung-Min
AU  - Dietrich, Sascha
AU  - Huber, Wolfgang
AU  - Stegle, Oliver
AU  - Steinmetz, Lars M
TI  - Functional phenotyping of genomic variants using joint multiomic single-cell DNA-RNA sequencing.
JO  - Nature methods
VL  - nn
SN  - 1548-7091
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DKFZ-2025-01824
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40890552
DO  - DOI:10.1038/s41592-025-02805-0
UR  - https://inrepo02.dkfz.de/record/304284
ER  -