Journal Article

RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

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

2019

Overview

Somatic cells can accumulate mutations over the course of an individual's lifetime. This generates cells that differ genetically at specific loci within the genome. To explore how this genetic diversity in individuals contributes to disease, Yizhak et al. developed a method to detect mutations from RNA sequencing data (see the Perspective by Tomasetti). Applying this method to Cancer Genome Atlas samples and normal samples from the Genotype-Tissue Expression (GTEx) project generated a tissue-specific study of mutation accumulation. Somatic mutations were detected in nearly all individuals and across many normal human tissues in genomic regions called cancer hotspots and in genes that play a role in cancer. Interestingly, the skin, lung, and esophagus exhibited the most mutations, suggesting that the environment generates many human mutations. Science , this issue p. eaaw0726 ; see also p. 938 “Normal” skin and other human tissues include macroscopic clonal expansions that contain genes associated with cancer risk. 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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Aging / Aging (natural) / Bioaccumulation / Cancer / Cell proliferation / Chromosomes / Clone Cells / Cloning / Deoxyribonucleic acid / DNA / DNA Mutational Analysis - methods / Environmental factors / Environmental Influences / Esophagus / Exposure / Female / Gene expression / Gene sequencing / Genes / Genetic diversity / Genetic drift / Genetics / Genomes / Genotypes / Health risks / Human tissues / Humans / Lesions / Lung cancer / Male / Mosaicism / Mucosa / Mutagens / Mutation / Neoplasms - genetics / Nucleotide sequence / Organ Specificity - genetics / Positive selection / RESEARCH ARTICLE SUMMARY / Ribonucleic acid / Risk assessment / RNA / Sequence Analysis, RNA - methods / Skin / Somatic cells / Tissues / Tumorigenesis / Tumors