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

Abstract

Most somatic mutations arising during normal development present as low-level in single or multiple tissues depending on the developmental stage and affected organs1-4. However, it remains unclear how the human developmental stages or mutation-carrying organs affect somatic mutations’ features. Here, we performed a systemic and comprehensive analysis of low-level somatic mutations using deep whole-exome sequencing (WES; average read depth: ∼500×) of 498 multiple organ tissues with matched controls from 190 individuals. We found that early-stage mutations shared between multiple organs are lower in number but showed higher allele frequencies than late-stage 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-stage mutations had unique mutational signatures distinct from tumor-originate mutations. Compared with early-stage mutations presenting a clock-like signature across all studied organs or tissues, late-stage mutations show organ, tissue, and cell-type specificity in mutation count, VAFs, and mutational signatures. In particular, analysis of brain somatic mutations shows bimodal occurrence and temporal-lobe-specific mutational signatures. These findings provide new insight into the features of somatic mosaicisms dependent on developmental stages and brain regions.