RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

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 G. Ardlie; Gad Getz

doi:10.1126/science.aaw0726

RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

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 G. Ardlie, Gad Getz

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	eaaw0726
Journal	Science
Volume	364
Issue number	6444
DOIs	https://doi.org/10.1126/science.aaw0726
State	Published - 7 Jun 2019
Externally published	Yes

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/science.aaw0726

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Yizhak, K., Aguet, F., Kim, J., Hess, J. M., Kübler, K., Grimsby, J., Frazer, R., Zhang, H., Haradhvala, N. J., Rosebrock, D., Livitz, D., Li, X., Arich-Landkof, E., Shoresh, N., Stewart, C., Segrè, A. V., Branton, P. A., Polak, P., Ardlie, K. G., & Getz, G. (2019). RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science, 364(6444), Article eaaw0726. https://doi.org/10.1126/science.aaw0726

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title = "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.",

author = "Keren Yizhak and Fran{\c c}ois Aguet and Jaegil Kim and Hess, {Julian M.} and Kirsten K{\"u}bler and Jonna Grimsby and Ruslana Frazer and Hailei Zhang and Haradhvala, {Nicholas J.} and Daniel Rosebrock and Dimitri Livitz and Xiao Li and Eila Arich-Landkof and Noam Shoresh and Chip Stewart and Segr{\`e}, {Ayellet V.} and Branton, {Philip A.} and Paz Polak and Ardlie, {Kristin G.} and Gad Getz",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. The title Science is a registered trademark of AAAS.",

year = "2019",

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doi = "10.1126/science.aaw0726",

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Yizhak, K, Aguet, F, Kim, J, Hess, JM, Kübler, K, Grimsby, J, Frazer, R, Zhang, H, Haradhvala, NJ, Rosebrock, D, Livitz, D, Li, X, Arich-Landkof, E, Shoresh, N, Stewart, C, Segrè, AV, Branton, PA, Polak, P, Ardlie, KG & Getz, G 2019, 'RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues', Science, vol. 364, no. 6444, eaaw0726. https://doi.org/10.1126/science.aaw0726

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T1 - RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

AU - Yizhak, Keren

AU - Aguet, François

AU - Kim, Jaegil

AU - Hess, Julian M.

AU - Kübler, Kirsten

AU - Grimsby, Jonna

AU - Frazer, Ruslana

AU - Zhang, Hailei

AU - Haradhvala, Nicholas J.

AU - Rosebrock, Daniel

AU - Livitz, Dimitri

AU - Li, Xiao

AU - Arich-Landkof, Eila

AU - Shoresh, Noam

AU - Stewart, Chip

AU - Segrè, Ayellet V.

AU - Branton, Philip A.

AU - Polak, Paz

AU - Ardlie, Kristin G.

AU - Getz, Gad

N1 - Publisher Copyright: © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. The title Science is a registered trademark of AAAS.

PY - 2019/6/7

Y1 - 2019/6/7

N2 - 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.

AB - 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.

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RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

Abstract

ASJC Scopus subject areas

UN SDGs

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