The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with advancing age and can lead to blood cancers 1 – 10 . Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal mosaic chromosomal alterations that we detected in 179,417 Japanese participants in the BioBank Japan cohort and compared with analogous data from the UK Biobank. In this long-lived Japanese population, mosaic chromosomal alterations were detected in more than 35.0% (s.e.m., 1.4%) of individuals older than 90 years, which suggests that such clones trend towards inevitability with advancing age. Japanese and European individuals exhibited key differences in the genomic locations of mutations in their respective haematopoietic clones; these differences predicted the relative rates of chronic lymphocytic leukaemia (which is more common among European individuals) and T cell leukaemia (which is more common among Japanese individuals) in these populations. Three different mutational precursors of chronic lymphocytic leukaemia (including trisomy 12, loss of chromosomes 13q and 13q, and copy-neutral loss of heterozygosity) were between two and six times less common among Japanese individuals, which suggests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent chronic lymphocytic leukaemia. Japanese and British populations also exhibited very different rates of clones that arose from B and T cell lineages, which predicted the relative rates of B and T cell cancers in these populations. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN , MRE11 and CTU2 (odds ratio, 28–91). We suggest that selective pressures on clones are modulated by factors that are specific to human populations. Further genomic characterization of clonal selection and cancer in populations from around the world is therefore warranted. Population-specific patterns of genomic mutations and selection of haematopoietic clones in Japanese and European participants predict the divergent rates of chronic lymphocytic leukaemia and T cell leukaemia in these populations.

中文翻译：

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日本年龄相关造血克隆的染色体改变

肿瘤发生和衰老的生物学在多大程度上受到区分人群的因素的影响尚不清楚。具有获得性突变的造血克隆随着年龄的增长而变得普遍，并可能导致血癌 1 – 10 。在这里，我们根据我们在 BioBank Japan 队列的 179,417 名日本参与者中检测到的 33,250 种常染色体嵌合染色体改变，并与来自英国 Biobank 的类似数据进行比较，描述了造血细胞中基因组突变和克隆选择的共享和群体特异性模式。在这个长寿的日本人群中，超过 35.0% (sem, 1.4%) 的 90 岁以上个体检测到镶嵌染色体改变，这表明随着年龄的增长，这种克隆趋于不可避免。日本和欧洲个体在其各自的造血克隆中的突变基因组位置上表现出关键差异；这些差异预测了这些人群中慢性淋巴细胞白血病（在欧洲人中更常见）和 T 细胞白血病（在日本人中更常见）的相对发病率。慢性淋巴细胞白血病的三种不同突变前体（包括 12 三体、染色体 13q 和 13q 缺失以及拷贝中性杂合性缺失）在日本个体中的发生率低 2 到 6 倍，这表明日本和欧洲人群在早在临床上明显的慢性淋巴细胞性白血病发展之前就对克隆施加了选择性压力。日本和英国人群也表现出非常不同的来自 B 和 T 细胞谱系的克隆率，这预测了这些人群中 B 和 T 细胞癌的相对发病率。我们确定了六个先前未描述的基因座，在这些基因座上，遗传变异易于发生重复或去除遗传风险等位基因的镶嵌染色体改变，包括 NBN 、 MRE11 和 CTU2 的大效应罕见变异（优势比，28-91）。我们建议对克隆的选择压力受特定于人群的因素的调节。因此，有必要对来自世界各地的人群中的克隆选择和癌症进行进一步的基因组表征。