Analysis of low-level somatic mosaicism reveals stage and tissue-specific mutational features in human development

Ja Hye Kim, Shinwon Hwang, Hyeonju Son, Dongsun Kim, Il Bin Kim, Myeong Heui Kim, Nam Suk Sim, Dong Seok Kim, Yoo Jin Ha, Junehawk Lee, Hoon Chul Kang, Jeong Ho Lee, Sangwoo Kim

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1 Citation (Scopus)


Most somatic mutations that arise during normal development are present at low levels in single or multiple tissues depending on the developmental stage and affected organs. However, the effect of human developmental stages or mutations of different organs on the features of somatic mutations is still unclear. Here, we performed a systemic and comprehensive analysis of low-level somatic mutations using deep whole-exome sequencing (average read depth ∼500×) of 498 multiple organ tissues with matched controls from 190 individuals. Our results showed that early clone-forming mutations shared between multiple organs were lower in number but showed higher allele frequencies than late cloneforming mutations [0.54 vs. 5.83 variants per individual; 6.17% vs. 1.5% variant allele frequency (VAF)] along with less nonsynonymous mutations and lower functional impacts. Additionally, early and late clone-forming mutations had unique mutational signatures that were distinct from mutations that originated from tumors. Compared with early clone-forming mutations that showed a clock-like signature across all organs or tissues studied, late clone-forming mutations showed organ, tissue, and cell-type specificity in the mutation counts, VAFs, and mutational signatures. In particular, analysis of brain somatic mutations showed a bimodal occurrence and temporal-lobe-specific signature. These findings provide new insights into the features of somatic mosaicism that are dependent on developmental stage and brain regions.

Original languageEnglish
Article numbere1010404
JournalPLoS Genetics
Issue number9
Publication statusPublished - 2022 Sept 19

Bibliographical note

Publisher Copyright:
Copyright © 2022 Kim et al.

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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