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. 2018 May 15;14(5):e1007395.
doi: 10.1371/journal.pgen.1007395. eCollection 2018 May.

Distinctive types of postzygotic single-nucleotide mosaicisms in healthy individuals revealed by genome-wide profiling of multiple organs

August Yue Huang  1 , Xiaoxu Yang  1 , Sheng Wang  2   3 , Xianing Zheng  2 , Qixi Wu  4   5 , Adam Yongxin Ye  1   4   6 , Liping Wei  1
Affiliations

Distinctive types of postzygotic single-nucleotide mosaicisms in healthy individuals revealed by genome-wide profiling of multiple organs

August Yue Huang et al. PLoS Genet. .

Abstract

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Identification and validation of pSNMs in 27 organ samples obtained from five individuals.
(A) Genomic landscape of the validated pSNMs. Circos plots from outer to inner represent individuals BBL1100C, BBL11121, BBLC1013, BBLD1005, and BBLD1010, respectively. The Y axis denotes the average minor allele fraction across pSNM-carrying organs of each donor. (B) Correlation of the allele fractions estimated by whole-genome sequencing and targeted ultra-deep resequencing (PASM) of the validated sites. The shape, color, and size of the dots represent the donor and organ type carrying the pSNMs and the site-specific depth of whole-genome sequencing.
Fig 2
Fig 2. Two types of pSNMs revealed by inter- and intra-organ profiles.
(A) Minor allele fractions between different categories of pSNM. The organ-shared pSNMs demonstrated significantly higher allele fractions than the organ-unique pSNMs. (B) Number of pSNMs carried in different organ samples. Red and blue bars denote the organ-shared and organ-unique pSNMs, respectively. An excess of organ-unique pSNMs was observed in the breast sample of BBL11121 and the liver sample of BBLD1005. (C-D) Heatmap of minor allele fractions for pSNMs carried in multiple organ samples of BBLD1005 (C) and BBL11121 (D). Blood samples of two unrelated individuals (ACC1 and ACC4) served as negative controls. The color intensity of each tile represents allele fractions estimated by targeted ultra-depth resequencing. Gray tiles denote sites without sufficient read depth (< 30X). Red and blue bars denote the organ-shared and organ-unique pSNMs, respectively. The majority of organ-unique pSNMs were locally restricted to one or a few physically adjacent organ samples (<1 cm). (E-F) Relative intra-organ similarity of pSNM profiles in BBLD1005 (E) and BBL11121 (F). The originally sequenced samples (liver #9 and breast #9) shared the largest similarity to their physically closest samples.
Fig 3
Fig 3. Distinct genomic characteristics between embryonic and clonal expansion pSNMs.
(A-C) Mutation spectrums in NpG and non-NpG sites for embryonic pSNMs (A), clonal expansion pSNMs in BBLD1005’s liver (B), and clonal expansion pSNMs in BBL11121’s breast (C). Mutation rate was normalized by the total number of sites in the human genome. For embryonic pSNMs, CpG sites showed significantly higher rate of C>T mutations than non-CpG sites. (D) Varied DNA replication timing of the two pSNMs types. The grey line denotes the genomic average. Embryonic pSNMs were enriched in early-replicating regions, whereas clonal expansion pSNMs were enriched in late-replicating regions. (E-G) Proportion of pSNMs locating in open or closed chromatin regions in the HepG2 (E), HMEC (F), and K562 (G) cell-lines. Significantly higher proportions of embryonic pSNMs were observed in transcribed chromatin regions of all three cell types.
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Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 31530092) and the Ministry of Science and Technology of China (2015AA020108). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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