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Cell-type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells

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...

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Main Authors: Grimes, Karen (Author) , Jeong, Hyobin (Author) , Amoah, Amanda (Author) , Xu, Nuo (Author) , Niemann, Julian (Author) , Raeder, Benjamin (Author) , Hasenfeld, Patrick (Author) , Stober, Catherine (Author) , Rausch, Tobias (Author) , Benito, Eva (Author) , Jann, Johann-Christoph (Author) , Nowak, Daniel (Author) , Emini, Ramiz (Author) , Hoenicka, Markus (Author) , Liebold, Andreas (Author) , Ho, Anthony Dick (Author) , Shuai, Shimin (Author) , Geiger, Hartmut (Author) , Sanders, Ashley D. (Author) , Korbel, Jan Oliver (Author)
Format: Article (Journal)
Language:English
Published: June 2024
In: Nature genetics
Year: 2024, Volume: 56, Issue: 6, Pages: 1134-1146
ISSN:1546-1718
DOI:10.1038/s41588-024-01754-2
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41588-024-01754-2
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41588-024-01754-2
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Author Notes:Karen Grimes, Hyobin Jeong, Amanda Amoah, Nuo Xu, Julian Niemann, Benjamin Raeder, Patrick Hasenfeld, Catherine Stober, Tobias Rausch, Eva Benito, Johann-Christoph Jann, Daniel Nowak, Ramiz Emini, Markus Hoenicka, Andreas Liebold, Anthony Ho, Shimin Shuai, Hartmut Geiger, Ashley D. Sanders & Jan O. Korbel
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Summary: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.
Item Description:Online veröffentlicht: 28. Mai 2024
Gesehen am 29.01.2025
Physical Description:Online Resource
ISSN:1546-1718
DOI:10.1038/s41588-024-01754-2

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