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      Determinants of telomere length across human tissues

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          Abstract

          Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.

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          Most cited references35

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          Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.

          Cristian Tomasetti, Bert Vogelstein (2015)
          Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue's homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes. Copyright © 2015, American Association for the Advancement of Science.
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            Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention

            Cristian Tomasetti, Lu Li, Bert Vogelstein (2017)
            Cancers are caused by mutations that may be inherited, induced by environmental factors, or result from DNA replication errors (R). We studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries throughout the world. The data revealed a strong correlation (median = 0.80) between cancer incidence and normal stem cell divisions in all countries, regardless of their environment. The major role of R mutations in cancer etiology was supported by an independent approach, based solely on cancer genome sequencing and epidemiological data, which suggested that R mutations are responsible for two-thirds of the mutations in human cancers. All of these results are consistent with epidemiological estimates of the fraction of cancers that can be prevented by changes in the environment. Moreover, they accentuate the importance of early detection and intervention to reduce deaths from the many cancers arising from unavoidable R mutations.
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              The telomere syndromes.

              Mary Armanios, Elizabeth H Blackburn (2012)
              There has been mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders. Their manifestations encompass common disease states such as idiopathic pulmonary fibrosis and bone marrow failure. Although these disorders seem to be clinically diverse, collectively they comprise a single syndrome spectrum defined by the short telomere defect. Here we review the manifestations and unique genetics of telomere syndromes. We also discuss their underlying molecular mechanisms and significance for understanding common age-related disease processes.
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                Author and article information

                Contributors
                Kathryn Demanelis: (View ORCID Profile)
                Meytal Chernoff: (View ORCID Profile)
                Lin Tong: (View ORCID Profile)
                Chenan Zhang: (View ORCID Profile)
                Mekala Sabarinathan: (View ORCID Profile)
                Hannah Lin: (View ORCID Profile)
                Eduardo Ramirez: (View ORCID Profile)
                Meritxell Oliva: (View ORCID Profile)
                Sarah Kim-Hellmuth: (View ORCID Profile)
                Barbara E. Stranger: (View ORCID Profile)
                Tsung-Po Lai: (View ORCID Profile)
                Abraham Aviv: (View ORCID Profile)
                Kristin G. Ardlie: (View ORCID Profile)
                François Aguet: (View ORCID Profile)
                Jennifer A. Doherty: (View ORCID Profile)
                Muhammad G. Kibriya: (View ORCID Profile)
                Brandon L. Pierce: (View ORCID Profile)
                Journal
                Title: Science
                Abbreviated Title: Science
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Print): 0036-8075
                ISSN (Electronic): 1095-9203
                Publication date Created: September 10 2020
                Publication date Created: September 11 2020
                Publication date (Electronic): September 10 2020
                Publication date (Print): September 11 2020
                Volume: 369
                Issue: 6509
                Page: eaaz6876
                Affiliations
                [1 ]Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
                [2 ]Section of Genetic Medicine, Department of Medicine, Institute for Genomics and Systems Biology, Center for Data Intensive Science, University of Chicago, Chicago, IL, USA.
                [3 ]New York Genome Center, New York, NY, USA.
                [4 ]Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.
                [5 ]Department of Systems Biology, Columbia University, New York, NY, USA.
                [6 ]Center for Genetic Medicine, Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
                [7 ]Center of Human Development and Aging, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA.
                [8 ]Broad Institute of MIT and Harvard, Cambridge, MA, USA.
                [9 ]Department of Human Genetics, University of Chicago, Chicago, IL, USA.
                [10 ]University of Chicago Comprehensive Cancer Center, Chicago, IL, USA.
                [11 ]Department of Medicine, University of Chicago, Chicago, IL, USA.
                [12 ]Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
                Article
                DOI: 10.1126/science.aaz6876
                PubMed ID: 32913074
                SO-VID: 2a3385ce-4505-4de2-9b79-9e59bb4f74a4
                Copyright © © 2020
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                https://www.sciencemag.org/about/science-licenses-journal-article-reuse

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