Motif-Centered Analyses Reveal Universal and Tissue-Specific Mutagenic Mechanisms Operating in the Human Body.

Area of Science:

• Genomics
• Cancer Research
• Molecular Biology

Background:

• Somatic mutations are fundamental to human genome evolution and cancer development.
• Understanding baseline mutagenesis in normal, non-cancerous cells is crucial but remains poorly characterized.

Purpose of the Study:

• To analyze mutation profiles in a large cohort of normal human tissues to identify ongoing mutagenic processes.
• To establish a robust framework for detecting and attributing sources of somatic mutations in healthy tissues.

Main Methods:

• Analysis of whole-genome and whole-exome sequencing data from 11,949 normal samples across 25 tissues.
• Application of statistical hypothesis testing and Minimal Estimate of Mutation Load (MEML) to detect enriched trinucleotide motifs.
• Comparison of mutation patterns between healthy and non-cancerous diseased tissues.

Main Results:

• Identified cancer-associated mutational motifs, including clock-like C→T (nCg) and T→C (aTn) substitutions, present in various normal tissues.
• UV-associated mutagenesis (yCn, nTt) was exclusively detected in skin samples.
• APOBEC-induced mutations (C→T, C→G in tCw) were enriched in bladder, lung, liver, breast, and small intestine, with a preference for APOBEC3A.
• Diseased non-cancerous tissues showed higher, age-independent accumulation of aTn and nCg motifs compared to healthy tissues.

Conclusions:

• Elucidated several active mutagenic processes occurring in normal human tissues.
• Provided a validated analytical framework for identifying mutagenic signatures from somatic mutation data.
• Highlighted differences in mutation accumulation between healthy and diseased non-cancerous tissues.