Disentangling age-dependent DNA methylation: deterministic, stochastic, and nonlinear

Abstract DNA methylation variability arises due to concurrent genetic and environmental influences. Each of them is a mixture of regular and noisy sources, whose relative contribution has not been satisfactorily understood yet. We conduct a systematic assessment of the age-dependent methylation by t...

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Autores principales:	O. Vershinina, M. G. Bacalini, A. Zaikin, C. Franceschi, M. Ivanchenko
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/76deb4c69ea542838d50cff1a3e90ccc
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spelling	oai:doaj.org-article:76deb4c69ea542838d50cff1a3e90ccc2021-12-02T13:41:00ZDisentangling age-dependent DNA methylation: deterministic, stochastic, and nonlinear10.1038/s41598-021-88504-02045-2322https://doaj.org/article/76deb4c69ea542838d50cff1a3e90ccc2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88504-0https://doaj.org/toc/2045-2322Abstract DNA methylation variability arises due to concurrent genetic and environmental influences. Each of them is a mixture of regular and noisy sources, whose relative contribution has not been satisfactorily understood yet. We conduct a systematic assessment of the age-dependent methylation by the signal-to-noise ratio and identify a wealth of “deterministic” CpG probes (about 90%), whose methylation variability likely originates due to genetic and general environmental factors. The remaining 10% of “stochastic” CpG probes are arguably governed by the biological noise or incidental environmental factors. Investigating the mathematical functional relationship between methylation levels and variability, we find that in about 90% of the age-associated differentially methylated positions, the variability changes as the square of the methylation level, whereas in the most of the remaining cases the dependence is linear. Furthermore, we demonstrate that the methylation level itself in more than 15% cases varies nonlinearly with age (according to the power law), in contrast to the previously assumed linear changes. Our findings present ample evidence of the ubiquity of strong DNA methylation regulation, resulting in the individual age-dependent and nonlinear methylation trajectories, whose divergence explains the cross-sectional variability. It may also serve a basis for constructing novel nonlinear epigenetic clocks.O. VershininaM. G. BacaliniA. ZaikinC. FranceschiM. IvanchenkoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q O. Vershinina M. G. Bacalini A. Zaikin C. Franceschi M. Ivanchenko Disentangling age-dependent DNA methylation: deterministic, stochastic, and nonlinear
description	Abstract DNA methylation variability arises due to concurrent genetic and environmental influences. Each of them is a mixture of regular and noisy sources, whose relative contribution has not been satisfactorily understood yet. We conduct a systematic assessment of the age-dependent methylation by the signal-to-noise ratio and identify a wealth of “deterministic” CpG probes (about 90%), whose methylation variability likely originates due to genetic and general environmental factors. The remaining 10% of “stochastic” CpG probes are arguably governed by the biological noise or incidental environmental factors. Investigating the mathematical functional relationship between methylation levels and variability, we find that in about 90% of the age-associated differentially methylated positions, the variability changes as the square of the methylation level, whereas in the most of the remaining cases the dependence is linear. Furthermore, we demonstrate that the methylation level itself in more than 15% cases varies nonlinearly with age (according to the power law), in contrast to the previously assumed linear changes. Our findings present ample evidence of the ubiquity of strong DNA methylation regulation, resulting in the individual age-dependent and nonlinear methylation trajectories, whose divergence explains the cross-sectional variability. It may also serve a basis for constructing novel nonlinear epigenetic clocks.
format	article
author	O. Vershinina M. G. Bacalini A. Zaikin C. Franceschi M. Ivanchenko
author_facet	O. Vershinina M. G. Bacalini A. Zaikin C. Franceschi M. Ivanchenko
author_sort	O. Vershinina
title	Disentangling age-dependent DNA methylation: deterministic, stochastic, and nonlinear
title_short	Disentangling age-dependent DNA methylation: deterministic, stochastic, and nonlinear
title_full	Disentangling age-dependent DNA methylation: deterministic, stochastic, and nonlinear
title_fullStr	Disentangling age-dependent DNA methylation: deterministic, stochastic, and nonlinear
title_full_unstemmed	Disentangling age-dependent DNA methylation: deterministic, stochastic, and nonlinear
title_sort	disentangling age-dependent dna methylation: deterministic, stochastic, and nonlinear
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/76deb4c69ea542838d50cff1a3e90ccc
work_keys_str_mv	AT overshinina disentanglingagedependentdnamethylationdeterministicstochasticandnonlinear AT mgbacalini disentanglingagedependentdnamethylationdeterministicstochasticandnonlinear AT azaikin disentanglingagedependentdnamethylationdeterministicstochasticandnonlinear AT cfranceschi disentanglingagedependentdnamethylationdeterministicstochasticandnonlinear AT mivanchenko disentanglingagedependentdnamethylationdeterministicstochasticandnonlinear
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Disentangling age-dependent DNA methylation: deterministic, stochastic, and nonlinear

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