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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 
 PLOS GENETICS, Vol.18(9) : e1010404, 2022-09 
Journal Title
Issue Date
Exome Sequencing ; Gene Frequency ; Humans ; Mosaicism* ; Mutation ; Neoplasms* / genetics
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 clone-forming 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.
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1. College of Medicine (의과대학) > Dept. of Biomedical Systems Informatics (의생명시스템정보학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hoon Chul(강훈철) ORCID logo https://orcid.org/0000-0002-3659-8847
Kim, Dong Seok(김동석)
Kim, Sangwoo(김상우) ORCID logo https://orcid.org/0000-0001-5356-0827
Sim, Nam Suk(심남석)
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