Nongenetic inheritance and transgenerational epigenetics

doi:10.1016/j.molmed.2014.12.004

Trends in Molecular Medicine

Volume 21, Issue 2, February 2015, Pages 134-144

https://doi.org/10.1016/j.molmed.2014.12.004 Get rights and content

Highlights

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Evidence from plants, animal, and human epidemiological studies has provided significant evidence for nongenetic multigenerational transmission of phenotypic responses to ancestral experiences.
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It is important to distinguish multigenerational exposures of either fetus or germline from bona fide transgenerational gamete-mediated nongenetic transmission.
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Epigenetic modifications such as DNA methylation, chromatin modification, and noncoding RNAs are involved.
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True transgenerational epigenetic transmission could possibly establish new stable traits in response to ancestral experience.

The idea that inherited genotypes define phenotypes has been paramount in modern biology. The question remains, however, whether stable phenotypes could be also inherited from parents independently of the genetic sequence per se. Recent data suggest that parental experiences can be transmitted behaviorally, through in utero exposure of the developing fetus to the maternal environment, or through either the male or female germline. The challenge is to delineate a plausible mechanism. In the past decade it has been proposed that epigenetic mechanisms are involved in multigenerational transmission of phenotypes and transgenerational inheritance. The prospect that ancestral experiences are written in our epigenome has immense implications for our understanding of human behavior, health, and disease.

Section snippets

Evidence for nongenetic multigenerational transmission of parental experience

New adaptive phenotypes can emerge as a result of natural selection of genetic variants. Natural selection is highly inefficient and slow in responding to immediate environmental challenges. It is well known that physiological systems can respond and adapt to new changes in real time, but the question remains whether there are nongenetic processes that could establish stable phenotypes and whether these can be inherited through germline transmission across generations. Biological examples have

Epigenetic mechanisms as possible mediators of responses to the environment

Epigenetics refers to mechanisms of long-term or stable regulation of gene expression programs that do not involve a change in gene sequences. Differences in epigenetic programming between different tissues in the same individual, or in the same tissue between different individuals, can result in alteration in gene expression programming that could cause phenotypic differences in the absence of a genetic difference 13, 14, 15, 16. The idea that epigenetic variance could create phenotypic

Non-gamete mediated multigenerational transmission of parental experience and its epigenetic underpinning

If multigenerational transmission of ancestral experiential memory evolved to increase survival and fitness, such a mechanism should be able to modulate phenotypes crucial for survival, such as reproduction, mate selection, diet and feeding habits, and flight from threat. It is plausible then that nongenetic inheritance would function at different timescales depending on the nature of the ancestral experience. Maintaining plasticity in response to dynamic environments requires

Gamete-mediated multigenerational transmission of parental experience

Exposure of either male or female gametes could change their epigenetic state and lead to phenotypic changes in the offspring that develop from these gametes (Figure 1). Although the main focus to date has been on the effect of gestational exposure of gametes, spermatogenesis continues throughout adult life, and it is therefore possible that preconception adult paternal experience might have an impact on the offspring. The question is whether these exposures are limited to chemical exposures or

Gamete-mediated transgenerational inheritance of ancestral behavioral, toxic, and addictive experiences

There is increasing evidence for nongenetic gamete-mediated transgenerational inheritance of responses to several types of paternal experiences, including diet, stressful and adverse social experiences, and exposure to toxins and drugs of addiction, which is mediated via inheritance of epigenetic states. There is also new evidence of transgenerational transmission of ancestral experience of organ injury (Box 4).

Concluding remarks and future perspectives

Many questions remain regarding the strength and significance of transgenerational phenotypes and further replication is required. Particularly important is estimating how widespread transgenerational nongenetic inheritance is in humans. There are lingering doubts about whether stable transgenerational effects are truly epigenetic, or whether they are genetic differences that are misconstrued as nongenetic inheritance. With accumulating evidence, confidence in this process is increasing.

Acknowledgments

Work in laboratory of M.S. was funded by the Canadian Institute of Health Research and the Sackler Program in Psychobiology and Epigenetics at McGill University.

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Trends in Molecular Medicine

ReviewSpecial Issue: Nurturing the Next GenerationNongenetic inheritance and transgenerational epigenetics

Highlights

Section snippets

Evidence for nongenetic multigenerational transmission of parental experience

Epigenetic mechanisms as possible mediators of responses to the environment

Non-gamete mediated multigenerational transmission of parental experience and its epigenetic underpinning

Gamete-mediated multigenerational transmission of parental experience

Gamete-mediated transgenerational inheritance of ancestral behavioral, toxic, and addictive experiences

Concluding remarks and future perspectives

Acknowledgments

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Trends Biochem. Sci.

Curr. Opin. Struct. Biol.

J. Biol. Chem.

Cell

Curr. Opin. Cell Biol.

Cell

Cell

Cell

Dev. Cell

Mol. Cell. Endocrinol.

Embryological aspects of inducible morphological defenses in Daphnia

J. Morphol.

Transgenerational epigenetic inheritance: how important is it?

Nat. Rev. Genet.

Male-line transgenerational responses in humans

Hum. Fertil.

Sex-specific, male-line transgenerational responses in humans

Eur. J. Hum. Genet.

Obesity in young men after famine exposure in utero and early infancy

N. Engl. J. Med.

Persistent epigenetic differences associated with prenatal exposure to famine in humans

Proc. Natl. Acad. Sci. U.S.A.

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BJOG

Epigenetic programming by maternal behavior

Nat. Neurosci.

Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring

Endocrinology

The (dual) origin of epigenetics

Cold Spring Harb. Symp. Quant. Biol.

Epigenetics: a historical overview

Epigenetics

Epigenetics: an overview

Dev. Genet.

The changing concept of epigenetics

Ann. N. Y. Acad. Sci.

Canalization of development and genetic assimilation of acquired characters

Nature

The early-life social environment and DNA methylation

Clin. Genet.

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Science

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Methylation of DNA

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The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain

Science

Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification

Nature

Review
Special Issue: Nurturing the Next Generation
Nongenetic inheritance and transgenerational epigenetics