Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type
Abstract Background The lifelong accumulation of somatic mutations underlies age-related phenotypes and cancer. Mutagenic forces are thought to shape the genome of aging cells in a tissue-specific way. Whole genome analyses of somatic mutation patterns, based on both types and genomic distribution o...
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doaj-a0b5804ee3f14ea3ae1dd947efe10ff82020-12-20T12:39:42ZengBMCGenome Biology1474-760X2019-12-0120112210.1186/s13059-019-1892-zWhole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell typeIrene Franco0Hafdis T. Helgadottir1Aldo Moggio2Malin Larsson3Peter Vrtačnik4Anna Johansson5Nina Norgren6Pär Lundin7David Mas-Ponte8Johan Nordström9Torbjörn Lundgren10Peter Stenvinkel11Lars Wennberg12Fran Supek13Maria Eriksson14Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska InstitutetDepartment of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska InstitutetDepartment of Medicine Huddinge, Integrated Cardio Metabolic Center, Karolinska InstitutetScience for Life Laboratory, Department of Physics, Chemistry and Biology, Linköping UniversityDepartment of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska InstitutetScience for Life Laboratory, Department of Cell and Molecular Biology, Uppsala UniversityScience for Life Laboratory, Department of Molecular Biology, Umeå UniversityDepartment of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska InstitutetGenome Data Science, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and TechnologyDepartment of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Division of Transplantation Surgery, Karolinska University HospitalDepartment of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Division of Transplantation Surgery, Karolinska University HospitalDepartment of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Division of Renal Medicine, Karolinska University HospitalDepartment of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Division of Transplantation Surgery, Karolinska University HospitalGenome Data Science, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and TechnologyDepartment of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska InstitutetAbstract Background The lifelong accumulation of somatic mutations underlies age-related phenotypes and cancer. Mutagenic forces are thought to shape the genome of aging cells in a tissue-specific way. Whole genome analyses of somatic mutation patterns, based on both types and genomic distribution of variants, can shed light on specific processes active in different human tissues and their effect on the transition to cancer. Results To analyze somatic mutation patterns, we compile a comprehensive genetic atlas of somatic mutations in healthy human cells. High-confidence variants are obtained from newly generated and publicly available whole genome DNA sequencing data from single non-cancer cells, clonally expanded in vitro. To enable a well-controlled comparison of different cell types, we obtain single genome data (92% mean coverage) from multi-organ biopsies from the same donors. These data show multiple cell types that are protected from mutagens and display a stereotyped mutation profile, despite their origin from different tissues. Conversely, the same tissue harbors cells with distinct mutation profiles associated to different differentiation states. Analyses of mutation rate in the coding and non-coding portions of the genome identify a cell type bearing a unique mutation pattern characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions. Conclusions Our analysis of normal cells from healthy donors identifies a somatic mutation landscape that enhances the risk of tumor transformation in a specific cell population from the kidney proximal tubule. This unique pattern is characterized by high rate of mutation accumulation during adult life and specific targeting of expressed genes and regulatory regions.https://doi.org/10.1186/s13059-019-1892-zSomatic mutationsAgingKidney cancerProximal tubulekidney progenitors |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Irene Franco Hafdis T. Helgadottir Aldo Moggio Malin Larsson Peter Vrtačnik Anna Johansson Nina Norgren Pär Lundin David Mas-Ponte Johan Nordström Torbjörn Lundgren Peter Stenvinkel Lars Wennberg Fran Supek Maria Eriksson |
spellingShingle |
Irene Franco Hafdis T. Helgadottir Aldo Moggio Malin Larsson Peter Vrtačnik Anna Johansson Nina Norgren Pär Lundin David Mas-Ponte Johan Nordström Torbjörn Lundgren Peter Stenvinkel Lars Wennberg Fran Supek Maria Eriksson Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type Genome Biology Somatic mutations Aging Kidney cancer Proximal tubule kidney progenitors |
author_facet |
Irene Franco Hafdis T. Helgadottir Aldo Moggio Malin Larsson Peter Vrtačnik Anna Johansson Nina Norgren Pär Lundin David Mas-Ponte Johan Nordström Torbjörn Lundgren Peter Stenvinkel Lars Wennberg Fran Supek Maria Eriksson |
author_sort |
Irene Franco |
title |
Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type |
title_short |
Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type |
title_full |
Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type |
title_fullStr |
Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type |
title_full_unstemmed |
Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type |
title_sort |
whole genome dna sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type |
publisher |
BMC |
series |
Genome Biology |
issn |
1474-760X |
publishDate |
2019-12-01 |
description |
Abstract Background The lifelong accumulation of somatic mutations underlies age-related phenotypes and cancer. Mutagenic forces are thought to shape the genome of aging cells in a tissue-specific way. Whole genome analyses of somatic mutation patterns, based on both types and genomic distribution of variants, can shed light on specific processes active in different human tissues and their effect on the transition to cancer. Results To analyze somatic mutation patterns, we compile a comprehensive genetic atlas of somatic mutations in healthy human cells. High-confidence variants are obtained from newly generated and publicly available whole genome DNA sequencing data from single non-cancer cells, clonally expanded in vitro. To enable a well-controlled comparison of different cell types, we obtain single genome data (92% mean coverage) from multi-organ biopsies from the same donors. These data show multiple cell types that are protected from mutagens and display a stereotyped mutation profile, despite their origin from different tissues. Conversely, the same tissue harbors cells with distinct mutation profiles associated to different differentiation states. Analyses of mutation rate in the coding and non-coding portions of the genome identify a cell type bearing a unique mutation pattern characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions. Conclusions Our analysis of normal cells from healthy donors identifies a somatic mutation landscape that enhances the risk of tumor transformation in a specific cell population from the kidney proximal tubule. This unique pattern is characterized by high rate of mutation accumulation during adult life and specific targeting of expressed genes and regulatory regions. |
topic |
Somatic mutations Aging Kidney cancer Proximal tubule kidney progenitors |
url |
https://doi.org/10.1186/s13059-019-1892-z |
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