TY  - JOUR
AU  - Grimes, Karen
AU  - Jeong, Hyobin
AU  - Amoah, Amanda
AU  - Xu, Nuo
AU  - Niemann, Julian
AU  - Raeder, Benjamin
AU  - Hasenfeld, Patrick
AU  - Stober, Catherine
AU  - Rausch, Tobias
AU  - Benito, Eva
AU  - Jann, Johann-Christoph
AU  - Nowak, Daniel
AU  - Emini, Ramiz
AU  - Hoenicka, Markus
AU  - Liebold, Andreas
AU  - Ho, Anthony
AU  - Shuai, Shimin
AU  - Geiger, Hartmut
AU  - Sanders, Ashley D
AU  - Korbel, Jan
TI  - Cell-type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells.
JO  - Nature genetics
VL  - 56
IS  - 6
SN  - 1061-4036
CY  - London
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DKFZ-2024-01148
SP  - 1134-1146
PY  - 2024
N1  - #LA:B480# / 2024 Jun;56(6):1134-1146
AB  - The functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single-cell genomes from 19 human donors of increasing age, and discovered the heterogeneous mSV landscapes of hematopoietic stem and progenitor cells. While mSVs are continuously acquired throughout life, expanded subclones in our cohort are confined to individuals >60. Cells already harboring mSVs are more likely to acquire additional somatic structural variants, including megabase-scale segmental aneuploidies. Capitalizing on comprehensive single-cell micrococcal nuclease digestion with sequencing reference data, we conducted high-resolution cell-typing for eight hematopoietic stem and progenitor cells. Clonally expanded mSVs disrupt normal cellular function by dysregulating diverse cellular pathways, and enriching for myeloid progenitors. Our findings underscore the contribution of mSVs to the cellular and molecular phenotypes associated with the aging hematopoietic system, and establish a foundation for deciphering the molecular links between mSVs, aging and disease susceptibility in normal tissues.
LB  - PUB:(DE-HGF)16
C6  - pmid:38806714
DO  - DOI:10.1038/s41588-024-01754-2
UR  - https://inrepo02.dkfz.de/record/290531
ER  -