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Epigenetics and individuality: from concepts to causality across timescales

Nature Reviews Genetics volume 26, pages 406–423 (2025)Cite this article

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Abstract

Traditionally, differences among individuals have been divided into genetic and environmental causes. However, both types of variation can underlie regulatory changes in gene expression — that is, epigenetic changes — that persist across cell divisions (developmental differentiation) and even across generations (transgenerational inheritance). Increasingly, epigenetic variation among individuals is recognized as an important factor in human diseases and ageing. Moreover, non-genetic inheritance can lead to evolutionary changes within populations that differ from those expected by genetic inheritance alone. Despite its importance, causally linking epigenetic variation to phenotypic differences across individuals has proven difficult, particularly when epigenetic variation operates independently of genetic variation. New genomic approaches are providing unprecedented opportunity to measure and perturb epigenetic variation, helping to elucidate the role of epigenetic variation in mediating the genotype–phenotype map. Here, we review studies that have advanced our understanding of how epigenetic variation contributes to phenotypic differences between individuals within and across generations, and provide a unifying framework that allows historical and mechanistic perspectives to more fully inform one another.

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Fig. 1: Epigenetics and the genotype–phenotype map through the lens of individuals.
Fig. 2: Epigenetic regulation of phenotypic plasticity across species.
Fig. 3: Mechanisms of transgenerational epigenetic effects in C. elegans.
Fig. 4: A classic example of within-generation epigenetic and phenotypic diversity with transgenerational epigenetic inheritance through the maternal line.
Fig. 5: Heritable epigenetic variation influences evolutionary dynamics.

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Acknowledgements

The authors thank members of the Phillips Lab for helpful discussions. The authors work is supported with funding from the National Institutes of Health to A.K.W. (F32 GM146402) and P.C.P. (R35 GM131838).

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  1. Institute of Ecology and Evolution, University of Oregon, Eugene, OR, USA

    Amy K. Webster & Patrick C. Phillips

  2. Department of Biological Science, Florida State University, Tallahassee, FL, USA

    Amy K. Webster

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Webster, A.K., Phillips, P.C. Epigenetics and individuality: from concepts to causality across timescales. Nat Rev Genet 26, 406–423 (2025). https://doi.org/10.1038/s41576-024-00804-z

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