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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • DNA Replication Timing
  • Embryonic Development / genetics
  • Female
  • Genome, Human / genetics*
  • Humans
  • Male
  • Middle Aged
  • Mosaicism*
  • Mutation
  • Organ Specificity / genetics
  • Polymorphism, Single Nucleotide*
  • Postmortem Changes
  • Whole Genome Sequencing / methods*
  • Young Adult
  • Zygote / metabolism*

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.