The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6–9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3–TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5–50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.Analysis of genotyping data for more than 150,000 individuals from the UK Biobank using long-range phase information sheds light on mechanisms of clonal haematopoiesis.

中文翻译：

---

从 8,342 种镶嵌染色体改变中洞察克隆造血

塑造健康个体克隆进化的选择压力在很大程度上是未知的。在这里，我们研究了 8,342 条镶嵌染色体改变，长度从 50 kb 到 249 Mb，我们使用基于相位的计算技术（估计错误发现率，6-9%）在来自 151,202 名英国生物银行参与者的血液来源 DNA 中发现了这些改变。我们发现了六个基因座，在这些基因座上，遗传变异与顺式缺失或杂合性丧失的获得密切相关。在三个这样的位点（MPL、TM2D3-TARSL2 和 FRA10B），我们确定了一个可能的因果变异，它具有高外显率（5-50%）。一个基因座的遗传等位基因似乎影响体细胞突变的概率，而其他三个基因座的等位基因则成为阳性或阴性克隆选择的对象。几种特定的镶嵌染色体改变与未来的血液系统恶性肿瘤密切相关。我们的结果揭示了对人类健康产生广泛影响的克隆扩增的多种途径。使用长程相位信息对来自英国生物银行的 150,000 多人的基因分型数据进行分析，揭示了克隆造血的机制。