A body map of somatic mutagenesis in morphologically normal human tissues

Area of Science:

• Genomics
• Cell Biology
• Human Physiology

Background:

• Somatic mutations accumulate in normal tissues, contributing to aging and disease.
• Understanding mutation patterns in healthy tissues is crucial for disease etiology.

Purpose of the Study:

• To comprehensively analyze somatic mutations and clonal expansions in morphologically normal human tissues.
• To map the spatial distribution and characteristics of somatic clones across various organs.

Main Methods:

• Genomic analysis of 1,737 normal tissue biopsies from 9 organs across 5 donors.
• Identification and characterization of somatic mutations, copy number alterations, and mutational signatures.
• Reconstruction of spatial somatic clonal architecture at sub-millimeter resolution.

Main Results:

• Somatic mutation accumulation and clonal expansions are widespread in normal human tissues, with variable extents.
• Somatic copy number alterations are rare, except in the esophagus and cardia.
• Ubiquitous endogenous mutational processes (SBS1, SBS5) and donor-specific exogenous processes were identified.
• Macroscopic clones were observed in the esophagus and cardia, while microscopic, independently evolving clones were found in the colon, rectum, and duodenum.

Conclusions:

• A detailed body map of somatic mutations and clonal expansions within an individual was generated.
• Tissue-specific differences in clonal expansion and mutation patterns were observed.
• The study provides insights into the landscape of somatic genetic variation in normal human tissues.