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Somatic mutations in single human cardiomyocytes reveal age-associated DNA damage and widespread oxidative genotoxicity

Authors :
Sangita Choudhury
August Yue Huang
Junho Kim
Zinan Zhou
Katherine Morillo
Eduardo A. Maury
Jessica W. Tsai
Michael B. Miller
Michael A. Lodato
Sarah Araten
Nazia Hilal
Eunjung Alice Lee
Ming Hui Chen
Christopher A. Walsh
Source :
Nature Aging. 2:714-725
Publication Year :
2022
Publisher :
Springer Science and Business Media LLC, 2022.

Abstract

The accumulation of somatic DNA mutations over time is a hallmark of aging in many dividing and nondividing cells but has not been studied in postmitotic human cardiomyocytes. Using single-cell whole-genome sequencing, we identified and characterized the landscape of somatic single-nucleotide variants (sSNVs) in 56 single cardiomyocytes from 12 individuals (aged from 0.4 to 82 years). Cardiomyocyte sSNVs accumulate with age at rates that are faster than in many dividing cell types and nondividing neurons. Cardiomyocyte sSNVs show distinctive mutational signatures that implicate failed nucleotide excision repair and base excision repair of oxidative DNA damage, and defective mismatch repair. Since age-accumulated sSNVs create many damaging mutations that disrupt gene functions, polyploidization in cardiomyocytes may provide a mechanism of genetic compensation to minimize the complete knockout of essential genes during aging. Age-related accumulation of cardiac mutations provides a paradigm to understand the influence of aging on cardiac dysfunction.

Details

ISSN :
26628465
Volume :
2
Database :
OpenAIRE
Journal :
Nature Aging
Accession number :
edsair.doi.dedup.....a31bdf78d75e273ff9d5821a56da4178
Full Text :
https://doi.org/10.1038/s43587-022-00261-5