利用体细胞突变进行克隆追踪可以探索人类疾病中的克隆动态。在这里，我们对具有遗传性核糖体病Shwachman-Diamond综合征的10个个体的323个造血系列进行了全基因组测序，以重建造血系统谱系。在约30%的系列中，我们发现了互斥的TP53、EIF6、RPL5、RPL22、PRPF8基因的突变，以及增加SBDS和EFL1基因剂量的染色体7和15异常。目标基因突变在子宫内开始，导致克隆扩张的大量出现，其中仅有少数造血干细胞谱系（平均8个，范围1-24个）在8个个体（范围为4-100%的克隆度）中贡献了约50%的造血系列，直到年轻成年时期。疾病转化期间的快速克隆扩张与双等位点的TP53突变和增加的突变负担相关。我们的研究凸显了p53依赖的核仁监控通路中的交叉体细胞突变如何抵消胚系核糖体病的有害影响，但也增加了TP53突变癌症演化的机会。© 2023. Springer Nature Limited.

Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.© 2023. Springer Nature Limited.