Age-Related Somatic Structural Changes in the Nuclear Genome of Human Blood Cells
Age-Related Somatic Structural Changes in the Nuclear Genome of Human Blood Cells
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DOI：
10.1016/j.ajhg.2011.12.009
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发表时间：
2012-02-10
影响因子：
9.8
通讯作者：
Dumanski, Jan P.
中科院分区：
文献类型：
--
作者：
Forsberg, Lars A.;Rasi, Chiara;Dumanski, Jan P.
结构变异是人类基因组中最常见的个体间遗传差异之一。然而，在正常细胞中从头体细胞结构变异的频率和分布，探索甚少。使用年龄分层队列的318个单卵（MZ）双胞胎和296个单出生的受试者，我们描述了与年龄相关的积累的拷贝数变异的核基因组在体内和频率变化的巨噬细胞和端粒酶范围的变异。在3.4%（9/264）≥ 60岁的受试者中发现了兆碱基范围畸变;这些受试者包括78对MZ双胞胎和108名单胎个体。在81对MZ或180名55岁的单胎受试者中没有观察到此类发现。观察到复发性区域和基因特异性突变，主要是缺失。对43名数据收集间隔7-19年的受试者进行的纵向分析表明，携带结构变化的克隆的积累速率存在相当大的差异。此外，对结构畸变个体的纵向分析表明，外周血中存在畸变细胞克隆的自然自我清除。在三名健康受试者中，我们检测了骨髓增生异常综合征患者的体细胞畸变特征。这里发现的经常性重排是人类血细胞中常见的年龄相关缺陷的候选者。我们预计，这些结果的扩展将允许确定不同体细胞谱系的遗传年龄和估计遗传年龄和实足年龄之间可能存在的个体差异。我们的工作也可能有助于解释与年龄相关的血液中细胞克隆数量减少的原因;这种减少是免疫衰老的标志之一。
Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects >= 60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were 55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.