Landscape of human protein-coding somatic mutations across tissues and individuals

Although somatic mutations are fundamentally important to human biology, disease, and aging, many outstanding questions remain about their rates, spectrum, and determinants in apparently healthy tissues. Here, we performed high-coverage exome sequencing on 265 samples from 14 GTEx donors sampled for a median of 17.5 tissues per donor (spanning 46 total tissues). Using a novel probabilistic method tailored to the unique structure of our data, we identified 8,470 somatic variants. We leverage our compendium of somatic mutations to quantify the burden of deleterious somatic variants among tissues and individuals, identify molecular features such as chromatin accessibility that exhibit significantly elevated somatic mutation rates, provide novel biological insights into mutational mechanisms, and infer developmental trajectories based on patterns of multi-tissue somatic mosaicism. Our data provides a high-resolution portrait of somatic mutations across genes, tissues, and individuals.