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.

正常组织中嵌合结构变异（mSV）的功能影响和细胞背景尚未得到充分研究。利用 Strand-seq，我们对来自 19 名年龄不断增长的人类捐赠者的 1,133 个单细胞基因组进行了测序，并发现了造血干细胞和祖细胞的异质 mSV 景观。虽然 mSV 在一生中不断获得，但我们队列中扩大的亚克隆仅限于 60 岁以上的个体。已经含有 mSV 的细胞更有可能获得额外的体细胞结构变异，包括兆碱基规模的节段非整倍体。利用全面的单细胞微球菌核酸酶消化和测序参考数据，我们对八种造血干细胞和祖细胞进行了高分辨率细胞分型。克隆扩增的 mSV 通过失调多种细胞途径并富集骨髓祖细胞来破坏正常细胞功能。我们的研究结果强调了 mSV 对与衰老造血系统相关的细胞和分子表型的贡献，并为破译正常组织中 mSV、衰老和疾病易感性之间的分子联系奠定了基础。