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 cancers1,2,3,4,5,6,7,8,9,10. 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.
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A table for mosaic events detected in the current study is available as Supplementary Data 1. The BBJ genotype is available from the Japanese Genotype-phenotype Archive (JGA; http://trace.ddbj.nig.ac.jp/jga/index_e.html) under accession code JGAD00000000123. Individual-level linkage of mosaic events can be provided by the BBJ project upon request (https://biobankjp.org/english/index.html).
All computational codes are available upon request from the corresponding authors (although they are not immediately portable to other computing environments). A standalone software implementation (MoChA) of the algorithm used to call mCAs is available at https://github.com/freeseek/mocha.
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We thank the staff of the BBJ for collecting and managing samples and clinical information. This study was funded by the BioBank Japan project, which was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese Government and AMED under grant numbers 17km0305002 and 18km0605001. This research was conducted using the UK Biobank Resource under application no. 19808. P.-R.L. was supported by NIH grant DP2 ES030554, a Burroughs Wellcome Fund Career Award at the Scientific Interfaces, the Next Generation Fund at the Broad Institute of MIT and Harvard, a Glenn Foundation for Medical Research and AFAR Grants for Junior Faculty award, and a Sloan Research Fellowship.
The authors declare no competing interests.
Peer review information Nature thanks Paul Scheet, George Vassiliou and John Witte for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Mean age and sex of carriers of specific mCA types (defined by chromosome and copy number) with at least 100 carriers in the 179,417 participants. Marker sizes are proportional to mCA frequencies. Data are mean ± s.e.m. Numeric data are provided in Supplementary Table 7.
Extended Data Fig. 2 Comparable chromosomal coverage by heterozygous genotypes in the BBJ and UKB data.
Average numbers of heterozygous genotyped sites (averaged across individuals) in each 1-Mb region of the genome for the BBJ and UKB genotyping arrays. hets, heterozygous sites.
Relative frequencies of estimated CN-LOH breakpoint locations in the BBJ and UKB data. Breakpoints were smoothed over ±2 Mb to enable plotting of frequency curves, which were rescaled to 1.
Extended Data Fig. 4 Quantile–quantile plots of mosaic events with significant associations demonstrate that there is no inflation of association statistics.
Quantile–quantile plots of results for mosaic events with significant associations. Analysis results of Fisher’s exact test (two-sided, nominal P values) using 173,599 participants are shown. We defined the following hits as hit loci: 42–49 Mb at chromosome 1 (1p CN-LOH), 88–94 Mb at chromosome 8 (8q CN-LOH), 92–96 Mb at chromosome 11 (11q CN-LOH), 88–90 Mb at chromosome 16 (16q CN-LOH), 23–26 Mb and 100–103 Mb at chromosome 14 (cis association of 14q CN-LOH), 4–6 Mb at chromosome 9 (9p CN-LOH), 0–2 Mb at chromosome 5 (trans association of 14q CN-LOH) and 1–3 Mb at chromosome 7 (trans association of chromosome 15 gain).
a–i, Associations of inherited variants with 8q CN-LOH (a), 11q CN-LOH (b), 16q CN-LOH (c), chromosome 15 gain (d), 1p CN-LOH (e), 9p CN-LOH (f) and 14q CN-LOH (g–i) are shown for regions containing the NBN, MRE11, CTU2, MAD1L1, MPL, JAK2, NEDD8–TINF2, DLK1 and TERT loci, respectively. a–c, e, Loci are rare cis associations. f–h, Loci are common cis associations. d, i, Loci are trans associations. a–d, g–i, Loci are in previously unreported regions. Purple points indicate lead variants. Other variants are colour-coded according to the linkage disequilibrium r2 with lead variants. The TCL1A variant that significantly associated with 14q CN-LOH allelic imbalance is not shown here because it did not significantly associate with 14q CN-LOH risk. Analysis results of Fisher’s exact test (two-sided, nominal P values) using 173,599 participants are shown.
Schematics show the patterns of selection or elimination of inherited variants by CN-LOH events. Asterisks indicate risk alleles. For the TCL1A locus, which did not significantly associate with the presence of 14q CN-LOH, we depict TCL1A as a gene for which CN-LOH mutations select an allele.
We identified 185 individuals who carried multiple CN-LOH clones on a single chromosome. a, Multiple clones were observed in at least one individual for all chromosomes except chromosomes 18, 20 and 22. The plots show phased BAF deviations (y axis) as a function of chromosome position (x axis) for the individual with the largest clone per chromosome (among all individuals with multiple CN-LOH clones on that chromosome). Coloured horizontal lines of different colours indicate distinct BAF deviations corresponding to overlapping CN-LOH events. b, The number of participants carrying multiple CN-LOH clones on a single chromosome is shown for each chromosomal arm.
a, Risk of mortality from various causes conferred by presence of an mCA at >1% cell fraction. Leukaemia, malignant lymphoma and multiple myeloma are subdivisions of blood cancer. Cardiovascular mortality includes deaths from coronary artery disease and ischaemic stroke. b, Risk of leukaemia mortality conferred by specific mCAs (grouped by chromosomal location and copy-number change) reaching Bonferroni-corrected significance. c, Risk of leukaemia mortality conferred by mosaic status stratified by mosaic cell fraction. d, Risk of leukaemia mortality conferred by mosaic status stratified by mosaic cell fraction and number of mosaic events detected (one versus two or more). All analyses were restricted to individuals with no previous cancer diagnosis and were corrected for age, sex, smoking status and genotyping array (Methods). Data are hazard ratio or odds ratio and 95% confidence intervals. Numeric data are provided in Supplementary Tables 24–27. Results using 86,546 participants are indicated. Cox proportional hazard models (two-sided) were used for a, b and d. A Cochran–Mantel–Haenszel test was used for c.
This file contains Supplementary Notes 1-8, which include descriptions of detailed methods and data interpretation, Supplementary References and Supplementary Tables 1-28.
This file contains a table of anonymized individual-level mosaic events in detail.
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Terao, C., Suzuki, A., Momozawa, Y. et al. Chromosomal alterations among age-related haematopoietic clones in Japan. Nature 584, 130–135 (2020). https://doi.org/10.1038/s41586-020-2426-2