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| Item Type: | Article |
|---|---|
| Title: | Cell-type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells |
| Creators Name: | Grimes, K. and Jeong, H. and Amoah, A. and Xu, N. and Niemann, J. and Raeder, B. and Hasenfeld, P. and Stober, C. and Rausch, T. and Benito, E. and Jann, J.C. and Nowak, D. and Emini, R. and Hoenicka, M. and Liebold, A. and Ho, A. and Shuai, S. and Geiger, H. and Sanders, A.D. and Korbel, J.O. |
| Abstract: | 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. |
| Keywords: | Genetic Variation, Hematopoietic Stem Cells, Mosaicism, Single-Cell Analysis, Stem Cells / Metabolism |
| Source: | Nature Genetics |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date: | 28 May 2024 |
| Official Publication: | https://doi.org/10.1038/s41588-024-01754-2 |
| PubMed: | View item in PubMed |
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