RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

Abstract

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.

Cell cycle dynamics in the reprogramming of cellular identity

“…Disruption of the stereotypic cell cycle behaviors occurs during aging and alters the clonal composition that collectively comprises a tissue. While this phenomenon was first described for the hematopoietic tissue in the form of clonal hematopoiesis , similar observations have been made in other tissues . As more detailed studies on the cell cycle dynamics of the expanded clones continue to emerge, a significant contribution by these clones to aging and age‐related diseases, such as cancer, is highly anticipated.…”

The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues

“…Somatic variant detection using RNA-seq data is challenging, especially if subclonal mutations with allele fractions as low as 5% are of interest (Yizhak et al, 2019). We therefore developed a highly accurate multi-sample variant calling procedure, which models nucleotide-specific errors, removes germline variants and confounders such as RNA editing sites, and generates a multiindividual, multi-tissue call matrix (3D genotype matrix) by re-genotyping potentially variable sites across thousands of GTEx RNA-seq samples (Figure 1a).…”

DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

“…Since then, numerous studies have evidence in support of this model. For example, cells from old individuals exposed to the environment accumulate abundant mutations (Martincorena et al, 2018;Yizhak et al, 2019) and organisms with defects in DNA repair appear to undergo aspects of accelerated aging, as exemplified by segmental progeroid disorders such as trichothiodystrophy, and Werner, Rothmund-Thompson and Cockayne syndromes, (Carrero et al, 2016;Harkema et al, 2016;Park et al, 1999;Sinclair et al, 1997).…”