基因突变在生物体的一生中不断积累。虽然人体中的体细胞单核苷酸变异已得到很好的表征，但正常组织中大型染色体改变的模式和后果仍然很大程度上未知。在这里，我们对来自基因型-组织表达项目的 948 名健康个体的嵌合染色体改变 (mCA) 进行了全组织调查，通过单倍型定相增强了基于 RNA 的等位基因不平衡估计。我们发现大约四分之一的人至少在一个组织中携带克隆扩增的 mCA，其发病率与年龄密切相关。 mCA 的患病率和全基因组模式在不同组织类型之间差异很大，表明组织特异性诱变暴露和选择压力。正常肾上腺和垂体中的 mCA 景观与这些组织产生的肿瘤中的 mCA 景观相似，而食道和皮肤则不然。总之，我们的研究结果表明，mCA 在正常人体组织中广泛出现，与年龄相关，与肿瘤发生有着复杂的联系。© 2023。作者获得 Springer Nature America, Inc. 的独家许可。

Genetic mutations accumulate in an organism's body throughout its lifetime. While somatic single-nucleotide variants have been well characterized in the human body, the patterns and consequences of large chromosomal alterations in normal tissues remain largely unknown. Here, we present a pan-tissue survey of mosaic chromosomal alterations (mCAs) in 948 healthy individuals from the Genotype-Tissue Expression project, augmenting RNA-based allelic imbalance estimation with haplotype phasing. We found that approximately a quarter of the individuals carry a clonally-expanded mCA in at least one tissue, with incidence strongly correlated with age. The prevalence and genome-wide patterns of mCAs vary considerably across tissue types, suggesting tissue-specific mutagenic exposure and selection pressures. The mCA landscapes in normal adrenal and pituitary glands resemble those in tumors arising from these tissues, whereas the same is not true for the esophagus and skin. Together, our findings show a widespread age-dependent emergence of mCAs across normal human tissues with intricate connections to tumorigenesis.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.