Clonally expanded blood cells that contain somatic mutations (clonal haematopoiesis) are commonly acquired with age and increase the risk of blood cancer 1 – 9 . The blood clones identified so far contain diverse large-scale mosaic chromosomal alterations (deletions, duplications and copy-neutral loss of heterozygosity (CN-LOH)) on all chromosomes 1 , 2 , 5 , 6 , 9 , but the sources of selective advantage that drive the expansion of most clones remain unknown. Here, to identify genes, mutations and biological processes that give selective advantage to mutant clones, we analysed genotyping data from the blood-derived DNA of 482,789 participants from the UK Biobank 10 . We identified 19,632 autosomal mosaic chromosomal alterations and analysed these for relationships to inherited genetic variation. We found 52 inherited, rare, large-effect coding or splice variants in 7 genes that were associated with greatly increased vulnerability to clonal haematopoiesis with specific acquired CN-LOH mutations. Acquired mutations systematically replaced the inherited risk alleles (at MPL ) or duplicated them to the homologous chromosome (at FH , NBN , MRE11 , ATM , SH2B3 and TM2D3 ). Three of the genes ( MRE11 , NBN and ATM ) encode components of the MRN–ATM pathway, which limits cell division after DNA damage and telomere attrition 11 – 13 ; another two ( MPL and SH2B3 ) encode proteins that regulate the self-renewal of stem cells 14 – 16 . In addition, we found that CN-LOH mutations across the genome tended to cause chromosomal segments with alleles that promote the expansion of haematopoietic cells to replace their homologous (allelic) counterparts, increasing polygenic drive for blood-cell proliferation traits. Readily acquired mutations that replace chromosomal segments with their homologous counterparts seem to interact with pervasive inherited variation to create a challenge for lifelong cytopoiesis. Analysis of blood-derived DNA from participants in the UK Biobank demonstrates that clonal expansions of acquired copy-neutral loss of heterozygosity mutations act on inherited alleles along a chromosome arm by modifying their allelic dosages.

中文翻译：

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单基因和多基因遗传成为克隆选择的工具

含有体细胞突变（克隆性造血）的克隆扩增血细胞通常随着年龄的增长而获得，并增加患血癌的风险 1 – 9 。迄今为止鉴定的血液克隆在所有染色体 1、2、5、6、9 上都包含各种大规模镶嵌染色体改变（缺失、重复和拷贝中性杂合性丢失 (CN-LOH)），但选择优势的来源推动大多数克隆扩张的原因仍然未知。在这里，为了识别为突变克隆提供选择性优势的基因、突变和生物学过程，我们分析了来自英国生物银行 10 的 482,789 名参与者的血液衍生 DNA 的基因分型数据。我们确定了 19,632 个常染色体嵌合染色体改变，并分析了这些改变与遗传遗传变异的关系。我们发现了 52 个遗传的、罕见的、7 个基因中的大效应编码或剪接变体与特定获得性 CN-LOH 突变的克隆造血易感性大大增加有关。获得性突变系统地替换了遗传风险等位基因（在 MPL 处）或将它们复制到同源染色体（在 FH、NBN、MRE11、ATM、SH2B3 和 TM2D3 处）。其中三个基因（MRE11、NBN 和 ATM）编码 MRN-ATM 通路的成分，在 DNA 损伤和端粒磨损后限制细胞分裂 11 – 13 ；另外两个（MPL 和 SH2B3）编码调节干细胞自我更新的蛋白质 14 – 16 。此外，我们发现整个基因组的 CN-LOH 突变倾向于导致具有等位基因的染色体片段，这些等位基因促进造血细胞的扩增以取代其同源（等位基因）对应物，增加血细胞增殖性状的多基因驱动。容易获得的用同源对应物替换染色体片段的突变似乎与普遍的遗传变异相互作用，从而为终生细胞生成带来挑战。对来自英国生物银行参与者的血液衍生 DNA 的分析表明，获得性拷贝中性杂合性突变丢失的克隆扩增通过改变其等位基因剂量作用于染色体臂上的遗传等位基因。