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.

中文翻译：

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人体的体细胞突变景观

背景健康组织中的体细胞突变会导致衰老、神经变性和癌症的发生，但它们在很大程度上仍未得到表征。结果为了更好地了解体细胞突变的全基因组分布和功能影响，我们利用转录组中包含的基因组信息统一从代表 36 种不同组织的 7500 多个组织样本中调用体细胞突变。该目录包含超过 280,000 个突变，揭示了与基因表达水平和染色质状态相关的组织特异性突变谱的广泛多样性。例如，错配修复基因 MLH1 低表达的肺样本显示出错配修复缺陷的突变特征。此外，我们发现普遍的负选择作用于错义和无义突变，