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Somatic mutations in aging and disease

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Abstract  

Time always leaves its mark, and our genome is no exception. Mutations in the genome of somatic cells were first hypothesized to be the cause of aging in the 1950s, shortly after the molecular structure of DNA had been described. Somatic mutation theories of aging are based on the fact that mutations in DNA as the ultimate template for all cellular functions are irreversible. However, it took until the 1990s to develop the methods to test if DNA mutations accumulate with age in different organs and tissues and estimate the severity of the problem. By now, numerous studies have documented the accumulation of somatic mutations with age in normal cells and tissues of mice, humans, and other animals, showing clock-like mutational signatures that provide information on the underlying causes of the mutations. In this review, we will first briefly discuss the recent advances in next-generation sequencing that now allow quantitative analysis of somatic mutations. Second, we will provide evidence that the mutation rate differs between cell types, with a focus on differences between germline and somatic mutation rate. Third, we will discuss somatic mutational signatures as measures of aging, environmental exposure, and activities of DNA repair processes. Fourth, we will explain the concept of clonally amplified somatic mutations, with a focus on clonal hematopoiesis. Fifth, we will briefly discuss somatic mutations in the transcriptome and in our other genome, i.e., the genome of mitochondria. We will end with a brief discussion of a possible causal contribution of somatic mutations to the aging process.

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Funding

This study was financially supported by the National Natural Science Foundation of China grant 82172461 to J.V.; NIH grants AG017242, AG047200, AG038072, ES029519, HL145560, and AG056278 to J.V.; DOD grant BC180689P1 to J.V.; and the Glenn Foundation for Medical Research to J.V.

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  1. Peijun Ren and Jie Zhang contributed equally to this work.

Authors and Affiliations

  1. Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Peijun Ren, Jie Zhang & Jan Vijg

  2. Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Jan Vijg

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  1. Peijun Ren
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  2. Jie Zhang
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Contributions

J.V. and P.R. conceived of topic area. J.V. and P.R. wrote the initial draft of the manuscript. J.Z. drew the figures. J.V. reviewed and edited the manuscript; all authors commented on previous versions of the manuscript. All authors approved the manuscript for publication. We acknowledge the Bioinformatics Core in the Center for Single-Cell Omics (CSCOmics), Shanghai Jiao Tong University School of Medicine, for providing assistance with interpreting the bioinformatics and computational genomics aspects of this review.

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Correspondence to Peijun Ren or Jan Vijg.

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J.V. is co-founder of SingulOmics Corp. and MutagenTech Inc. The remaining authors declare no competing interests.

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Ren, P., Zhang, J. & Vijg, J. Somatic mutations in aging and disease. GeroScience (2024). https://doi.org/10.1007/s11357-024-01113-3

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