Motif-Centered Analyses Elucidate Mutagenic Mechanisms Operating in Normal Human Tissues

Somatic mutations are inevitable in human genomes and can lead to tumorigenesis, yet baseline mutagenesis in non-cancerous normal cells remain poorly understood. Here, we analyzed the mutation profiles of 11,949 normal samples across 25 tissues obtained from whole-genome and whole-exome sequencing datasets. We applied stringent statistical hypothesis for detecting enrichment and enrichment-adjusted Minimal Estimate of Mutation Load (MEML) in trinucleotide motifs preferred by known mutagenic processes. We found several cancer-associated mutational motifs in cancer-free tissues. Samples enriched with C[->]T mutations in nCg motif associated with clock-like spontaneous deamination of meCpG were detected across all tissues. We revealed another clock-like motif, T[->]C substitutions in aTn motif associated with exposure to small epoxides and other SN2 electrophiles, in several tissues. Analyses of UV-associated motifs yCn, nTt, and their sub-motifs revealed UV-mutagenesis only in skin. APOBEC-induced C[->]T and C[->]G mutations in tCw motif were enriched in bladder, lung, small intestine, liver, and breast with preference for APOBEC3A-like mutagenesis in most. Non-cancerous diseased samples showed significantly higher, age-independent accumulation of aTn and nCg motifs compared to healthy tissues. Together, our analyses elucidated several ongoing mutagenic processes in normal human tissues and provided a robust analytical framework for identifying mutagenic sources from somatic mutation catalogues.