Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden.
Am J Hum Genet. 2012 Feb 10;90(2):217-28. doi: 10.1016/j.ajhg.2011.12.009. Epub 2012 Feb 2.
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.
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，正常细胞中新生体结构变异的频率和分布尚未得到充分探索。我们使用年龄分层的 318 对同卵双胞胎（MZ）和 296 名单胎受试者队列，描述了体内核基因组中与年龄相关的拷贝数变异的积累情况，以及兆碱基和千碱基范围变异的频率变化。在≥60 岁的受试者中（264 名受试者中有 9 名）发现了兆碱基范围的异常；这些受试者包括 78 对 MZ 双胞胎和 108 名单胎个体。在≤55 岁的 81 对 MZ 双胞胎或 180 名单胎个体中没有观察到这种发现。观察到了与区域和基因特异性相关的、频繁发生的突变，主要是缺失。对 43 名数据采集间隔 7-19 年的受试者的纵向分析表明，携带结构变化的克隆积累率存在相当大的差异。此外，对存在结构异常的个体的纵向分析表明，异常细胞克隆从外周血中自然消除。在 3 名健康受试者中，我们检测到了具有骨髓增生异常综合征特征的体细胞异常。这里发现的反复重排是人类血液细胞中常见的与年龄相关缺陷的候选者。我们预计这些结果的扩展将能够确定不同体细胞谱系的遗传年龄，并估计遗传年龄和实际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血液中细胞克隆数量随年龄减少的原因；这种减少是免疫衰老的标志之一。
