An international team of researchers has published a comprehensive analysis of somatic mutation rates across the human body, offering new insights into how mutations accumulate in normal tissues and vary by cell type, age, and environment. The study, published in Nature, analyzed 3,127 microdissected samples from 941 donors spanning 41 tissue types, making it one of the largest studies to date on tissue-wide somatic mutation patterns.
The research was part of the Human Cell Atlas and utilized whole-genome sequencing to detect somatic single-nucleotide variants (SNVs), indels, copy number changes, and structural variants. The team applied laser-capture microdissection to isolate histologically defined units – such as crypts, ducts, and glands – from fresh-frozen tissues obtained from organ donors of varying ages, from newborns to centenarians.
One of the central findings is that somatic mutation rates vary by over two orders of magnitude between tissues. For example, intestinal crypts accumulated mutations at a rate of approximately 52 SNVs per cell per year, whereas tissues such as cardiac muscle showed much lower mutation rates. The accumulation of mutations was generally linear with age across most tissues, though with variable slopes, suggesting differences in stem cell dynamics and DNA repair efficiency.
Environmental exposures also influenced mutation rates and signatures. For instance, skin and esophageal samples displayed patterns consistent with UV and tobacco-related damage, respectively. In contrast, some tissues, including brain and muscle, showed few exogenous mutational signatures, aligning with their lower cell turnover rates.
The study also reported that many mutations accumulated without evidence of clonal expansion or driver gene selection, although certain tissues – such as endometrium, esophagus, and bladder – showed positive selection for cancer-associated mutations even in the absence of malignancy.
The researchers identified over 70 distinct mutational signatures and observed tissue-specific differences in the prevalence and combination of these signatures. A subset of donors had hypermutated tissues, often due to underlying genetic defects in DNA repair pathways, such as mismatch repair deficiency, even in the absence of a cancer diagnosis.
The findings provide a reference map for somatic mutagenesis in normal human tissues and may aid in distinguishing early neoplastic changes from background mutation accumulation. The authors note that this baseline can help inform studies of cancer development, aging, and regenerative medicine, as well as the interpretation of somatic mutations in non-tumor contexts. Data from the project are expected to contribute to public databases as part of broader efforts to build comprehensive tissue and cell atlases.
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