RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

Keren Yizhak ¹ Francois Aguet ¹ Jaegil Kim ¹ Julian Hess ¹ Kirsten Kubler ^1,2,3 Jonna Grimsby ¹ Ruslana Frazer ¹ Hailei Zhang ¹ Nicholas Haradhvala ^1,2 Daniel Rosebrock ¹ Dimitry Livitz ¹ Xiao Li ¹ Eila Arich-Landkof ^1,2 Noam Shoresh ¹ Chip Stewart ¹ Ayellet Segre ^1,3,4 Philip Branton ⁵ Paz Polak ⁶ Kristin Ardlie ¹ Gad Getz ^1,2,3,7

¹Cancer Program, Broad Institute of Mit and Harvard, USA
²Center for Cancer Research, Massachusetts General Hospital, USA
³Harvard Medical School, Harvard University, USA
⁴Department of Ophthalmology, Massachusetts Eye and Ear, USA
⁵Biorepositories and Biospecimen Research Branch, National Cancer Institute, USA
⁶Oncological Sciences, Mount Sinai Hospital, USA
⁷Department of Pathology, Massachusetts General Hospital

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.