德国欧洲分子生物学实验室Jan O. Korbel等研究人员合作揭示造血干细胞和祖细胞中马赛克结构变异的细胞类型特异性后果。相关论文发表在2024年5月28日出版的《自然—遗传学》杂志上。
利用Strand-seq技术，研究人员对19名年龄不断增长的人类捐献者的1133个单细胞基因组进行了测序，发现了造血干细胞和祖细胞中异质性的马赛克结构变体（mSV）景观。虽然mSV在人的一生中会不断获得，但在研究人员的队列中，扩增的亚克隆仅限于年龄大于60岁的个体。已经携带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蛋白核酸酶消化和测序参考数据，研究人员对八个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通过失调多种细胞通路和富集髓系祖细胞，破坏了正常的细胞功能。这些发现强调了mSV对与造血系统衰老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。
据介绍，人们对正常组织中mSV的功能影响和细胞背景研究不足。
附：英文原文
Title: Cell-type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells
Author: Grimes, Karen, Jeong, Hyobin, Amoah, Amanda, Xu, Nuo, Niemann, Julian, Raeder, Benjamin, Hasenfeld, Patrick, Stober, Catherine, Rausch, Tobias, Benito, Eva, Jann, Johann-Christoph, Nowak, Daniel, Emini, Ramiz, Hoenicka, Markus, Liebold, Andreas, Ho, Anthony, Shuai, Shimin, Geiger, Hartmut, Sanders, Ashley D., Korbel, Jan O.
Issue&Volume: 2024-05-28
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.
来源：科学网
原标题：研究揭示造血干细胞和祖细胞中马赛克结构变异的细胞类型特异性后果
作者：小柯机器人