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| Item Type: | Article |
|---|---|
| Title: | Functional analysis of structural variants in single cells using Strand-seq |
| Creators Name: | Jeong, H., Grimes, K., Rauwolf, K.K., Bruch, P.M., Rausch, T., Hasenfeld, P., Benito, E., Roider, T., Sabarinathan, R., Porubsky, D., Herbst, S.A., Erarslan-Uysal, B., Jann, J.C., Marschall, T., Nowak, D., Bourquin, J.P., Kulozik, A.E., Dietrich, S., Bornhauser, B., Sanders, A.D. and Korbel, J.O. |
| Abstract: | Somatic structural variants (SVs) are widespread in cancer, but their impact on disease evolution is understudied due to a lack of methods to directly characterize their functional consequences. We present a computational method, scNOVA, which uses Strand-seq to perform haplotype-aware integration of SV discovery and molecular phenotyping in single cells by using nucleosome occupancy to infer gene expression as a readout. Application to leukemias and cell lines identifies local effects of copy-balanced rearrangements on gene deregulation, and consequences of SVs on aberrant signaling pathways in subclones. We discovered distinct SV subclones with dysregulated Wnt signaling in a chronic lymphocytic leukemia patient. We further uncovered the consequences of subclonal chromothripsis in T cell acute lymphoblastic leukemia, which revealed c-Myb activation, enrichment of a primitive cell state and informed successful targeting of the subclone in cell culture, using a Notch inhibitor. By directly linking SVs to their functional effects, scNOVA enables systematic single-cell multiomic studies of structural variation in heterogeneous cell populations. |
| Keywords: | Cell Line, Chromothripsis, Gene Rearrangement, Genomic Structural Variation, Leukemia, Neoplasms |
| Source: | Nature Biotechnology |
| ISSN: | 1087-0156 |
| Publisher: | Nature Publishing Group |
| Volume: | 41 |
| Number: | 6 |
| Page Range: | 832-844 |
| Date: | June 2023 |
| Official Publication: | https://doi.org/10.1038/s41587-022-01551-4 |
| PubMed: | View item in PubMed |
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