日本理化学研究所的Chikashi Terao和Yoichiro Kamatani团队近日取得一项新成果。他们揭示了日本人群与年龄相关造血克隆的染色体改变。这一研究成果在线发表在2020年6月24日出版的《自然》上。
研究人员根据BioBank Japan数据库中在179,417名日本参与者中检测到的33,250个嵌合染色体嵌合变异，并与英国Biobank类似的数据进行了比较，描述了造血细胞中基因组突变和克隆选择的共享模式和特定人群模式。在长寿的日本人群中，在35.0％超过90岁（例如1.4％）的人中检测到嵌合染色体的改变，这表明这种克隆随着年龄的增长而趋向必然。
日本人和欧洲人在其各自造血克隆突变的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性白血病（在欧洲个体中更常见）和T细胞白血病（在日本个体中更常见）的相对发生率。慢性淋巴细胞性白血病的三种不同突变前体（包括三体性，染色体13q和13q的丢失以及拷贝中性杂合性的丢失）在日本人中的发生率比欧洲人要少2至6倍，这表明在临床明显慢性淋巴细胞白血病发病之前，日本人和欧洲人就对克隆施加了不同的选择压力。在由B和T细胞谱系形成的克隆方面，日本人群和英国人群也表现出很大差异，这预示了这些人群中B和T细胞癌的相对发生率。
研究人员鉴定了六个先前未知的基因座，在这些基因座上的遗传变异易导致嵌合染色体变异，这些变异复制或去除遗传风险等位基因，包括NBN、MRE11和CTU2的大效应稀有变异（优势比为28：91）。研究人员认为对克隆的选择性压力受特定人类种群因素的调节。因此，有必要对来自世界各地的人群进行克隆选择和癌症的进一步基因组表征。
据了解，尚不清楚致癌和衰老生物学受人种因素影响的程度。具有获得性突变的造血克隆随着年龄的增长而增加，并可能导致血液癌。
附：英文原文
Title: Chromosomal alterations among age-related haematopoietic clones in Japan
Author: Chikashi Terao, Akari Suzuki, Yukihide Momozawa, Masato Akiyama, Kazuyoshi Ishigaki, Kazuhiko Yamamoto, Koichi Matsuda, Yoshinori Murakami, Steven A. McCarroll, Michiaki Kubo, Po-Ru Loh, Yoichiro Kamatani
Issue&Volume: 2020-06-24
Abstract: 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.
DOI: 10.1038/s41586-020-2426-2
Source: https://www.nature.com/articles/s41586-020-2426-2
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
