Distinctive types of postzygotic single-nucleotide mosaicisms in healthy individuals revealed by genome-wide profiling of multiple organs
Distinctive types of postzygotic single-nucleotide mosaicisms in healthy individuals revealed by genome-wide profiling of multiple organs
复制标题
通过多个器官的全基因组分析揭示健康个体中独特类型的合子后单核苷酸嵌合体
DOI：
10.1371/journal.pgen.1007395
复制
发表时间：
2018-05-01
期刊：
影响因子：
4.5
通讯作者：
Wei, Liping
中科院分区：
文献类型：
--
作者：
Huang, August Yue;Yang, Xiaoxu;Wei, Liping
合子后单核苷酸嵌合体（pSNM）已在肿瘤中得到广泛研究，并已知在肿瘤发生中发挥关键作用。然而，健康人类正常器官中 pSNM 的模式和起源仍然很大程度上未知。通过全基因组测序和超深扩增子重测序，我们从 5 个健康捐赠者的 27 个死后器官样本中鉴定并验证了 164 个 pSNM。突变等位基因比例范围为 1.0% 至 29.7%。器官间和器官内比较揭示了两种不同类型的 pSNM，其中大约一半起源于早期胚胎发生期间（胚胎 pSNM），其余的更可能是由最近发生的克隆扩增事件引起的（克隆扩增 pSNM）。与克隆扩增 pSNM 相比，胚胎 pSNM 的 C>T 突变比例更高，CpG 位点突变率更高。我们观察到这两种类型的 pSNM 之间的复制时间存在差异，胚胎和克隆扩增 pSNM 分别富集于早期和晚期复制区域。胚胎 pSNM 数量的增加位于开放染色质状态和胚胎转录的拓扑关联域中。我们的研究结果为正常人类发育过程中合子后嵌合的起源和空间分布提供了新的见解。
Postzygotic single-nucleotide mosaicisms (pSNMs) have been extensively studied in tumors and are known to play critical roles in tumorigenesis. However, the patterns and origin of pSNMs in normal organs of healthy humans remain largely unknown. Using whole-genome sequencing and ultra-deep amplicon re-sequencing, we identified and validated 164 pSNMs from 27 postmortem organ samples obtained from five healthy donors. The mutant allele fractions ranged from 1.0% to 29.7%. Inter-and intra-organ comparison revealed two distinctive types of pSNMs, with about half originating during early embryogenesis (embryonic pSNMs) and the remaining more likely to result from clonal expansion events that had occurred more recently (clonal expansion pSNMs). Compared to clonal expansion pSNMs, embryonic pSNMs had higher proportion of C>T mutations with elevated mutation rate at CpG sites. We observed differences in replication timing between these two types of pSNMs, with embryonic and clonal expansion pSNMs enriched in early-and late-replicating regions, respectively. An increased number of embryonic pSNMs were located in open chromatin states and topologically associating domains that transcribed embryonically. Our findings provide new insights into the origin and spatial distribution of postzygotic mosaicism during normal human development.