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RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

2019; American Association for the Advancement of Science; Volume: 364; Issue: 6444 Linguagem: Inglês

10.1126/science.aaw0726

1095-9203

Keren Yizhak, François Aguet, Jaegil Kim, Julian M. Hess, Kirsten Kübler, Jonna Grimsby, Ruslana Frazer, Hailei Zhang, Nicholas J. Haradhvala, Daniel Rosebrock, Dimitri Livitz, Xiao Li, Eila Arich-Landkof, Noam Shoresh, Chip Stewart, Ayellet V. Segrè, Philip A. Branton, Paz Polak, Kristin Ardlie, Gad Getz,

Single-cell and spatial transcriptomics

How somatic mutations accumulate in normal cells is poorly understood. A comprehensive analysis of RNA sequencing data from ~6700 samples across 29 normal tissues revealed multiple somatic variants, demonstrating that macroscopic clones can be found in many normal tissues. We found that sun-exposed skin, esophagus, and lung have a higher mutation burden than other tested tissues, which suggests that environmental factors can promote somatic mosaicism. Mutation burden was associated with both age and tissue-specific cell proliferation rate, highlighting that mutations accumulate over both time and number of cell divisions. Finally, normal tissues were found to harbor mutations in known cancer genes and hotspots. This study provides a broad view of macroscopic clonal expansion in human tissues, thus serving as a foundation for associating clonal expansion with environmental factors, aging, and risk of disease.