Abstract
BackgroundSomatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet they remain largely uncharacterized.ResultsTo gain a better understanding of the genome-wide distribution and functional impact of somatic mutations, we leverage the genomic information contained in the transcriptome to uniformly call somatic mutations from over 7500 tissue samples, representing 36 distinct tissues. This catalog, containing over 280,000 mutations, reveals a wide diversity of tissue-specific mutation profiles associated with gene expression levels and chromatin states. For example, lung samples with low expression of the mismatch-repair gene MLH1 show a mutation signature of deficient mismatch repair. In addition, we find pervasive negative selection acting on missense and nonsense mutations, except for mutations previously observed in cancer samples, which are under positive selection and are highly enriched in many healthy tissues.ConclusionsThese findings reveal fundamental patterns of tissue-specific somatic evolution and shed light on aging and the earliest stages of tumorigenesis.
Highlights
Somatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet they remain largely uncharacterized
Pioneering work on somatic evolution in cancer has led to the characterization of cancer driver genes [2] and mutation signatures [3]; the interplay between chromatin, nuclear architecture, carcinogens, and the mutational landscape [4,5,6,7]; the evolutionary forces acting on somatic mutations [8,9,10,11]; and clinical implications of somatic mutations [12]
We observed that genes whose expression is associated with mutation load in several tissues are enriched in DNA repair, autophagy, immune response, cellular transport, cell adhesion, and viral processes, and while these functions have been implicated in mutagenesis in cancer [31,32,33], our results highlight how expression variation of these genes associates with mutational variation in healthy tissues
Summary
Somatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet they remain largely uncharacterized. Somatic mutations have been far less studied in healthy human tissues than in cancer. Somatic mutations have been characterized in tissues like the skin [15], brain [16, 17], esophagus [18, 19], and colon [20]. These studies confirmed that cells harboring certain mutations expand clonally, and the number of clonal populations—as well as the total number of somatic mutations—increases with age. A more comprehensive understanding of somatic mutations across the human body has been limited by the small number of tissues studied to date
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