Abstract
Inheritance is typically associated with the Mendelian transmission of information from parents to offspring by alleles (DNA sequence). However, empirical data clearly suggest that traits can be acquired from ancestors by mechanisms that do not involve genetic alleles, referred to as non-genetic inheritance. Information that is non-genetically transmitted across generations includes parental experience and exposure to certain environments, but also parental mutations and polymorphisms, because they can change the parental ‘intrinsic’ environment. Non-genetic inheritance is not limited to the first generation of the progeny, but can involve the grandchildren and even further generations. Non-genetic inheritance has been observed for multiple traits including overall development, cardiovascular risk and metabolic symptoms, but this review will focus on the inheritance of behavioral abnormalities pertinent to psychiatric disorders. Multigenerational non-genetic inheritance is often interpreted as the transmission of epigenetic marks, such as DNA methylation and chromatin modifications, via the gametes (transgenerational epigenetic inheritance). However, information can be carried across generations by a large number of bioactive substances, including hormones, cytokines, and even microorganisms, without the involvement of the gametes. We reason that this broader definition of non-genetic inheritance is more appropriate, especially in the context of psychiatric disorders, because of the well-recognized role of parental and early life environmental factors in later life psychopathology. Here we discuss the various forms of non-genetic inheritance in humans and animals, as well as rodent models of psychiatric conditions to illustrate possible mechanisms.
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Acknowledgements
This work was supported by US National Institute of Mental Health grant 1RO1MH080194, 5R01MH058669 and 5R01MH086883 to MT.
Glossary
(some definitions may differ from those used in other reviews)
Inheritance. The process by which phenotypes (traits or characters) are passed from parents to offspring.
Non-genetic inheritance. Inheritance is typically associated with genetic or Mendelian inheritance. However, traits can be passed from parents to offspring via mechanisms that do not involve the DNA sequence. Therefore, inheritance is a broader term that includes non-genetic mechanisms of inheritance.
Gamete. A mature male or female germ cell that fuses with a gamete of the opposite sex during fertilization.
Epigenetic marks/signatures. In addition to the DNA sequence, gene expression information is embedded in additional layers on the DNA, termed epigenetic marks/signatures. Cells acquire epigenetic marks during their development. Epigenetic marks include chemical modifications of the DNA and secondary modifications in histones. Small RNAs are also often viewed as epigenetic signals/signatures because, a priori, any mechanism that provides regulatory information to a genome could be considered epigenetic. In contrast to the DNA sequence, epigenetic marks are malleable by the environment and their changes by the environment can significantly alter the cellular phenotype. In fact, it is believed that adaptation to the environment, learning, and many environmentally related processes involve changes in the epigenetic state of alleles.
Epialleles. Alleles those are identical in sequence, but different in epigenetic modifications.
Non-genetic inheritance via the gametes. A form of non-genetic inheritance that is mediated by the gametes without the involvement of DNA sequence. As epigenetic marks in the gametes are believed to carry the information from parents to offspring, this mechanism is also referred to as ‘transgenerational epigenetic inheritance’. However, any biological compound within or associated with the gametes, excluding the DNA sequence, may serve as a carrier of non-genetic information.
Gestational and early postnatal non-genetic inheritance. A process that involves the transfer of traits from the mother to offspring during gestation, or from the parents to the offspring during the early postnatal period, which typically spans from birth to weaning. It is also called ‘maternal/parental programming’. Mother/father information transfer can occur via the immune system, metabolites, and the microbiome, but also through social/behavioral interaction.
Multigenerational non-genetic effects. The acquisition and propagation of novel phenotypes across multiple generations that are not genetically based.
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Toth, M. Mechanisms of Non-Genetic Inheritance and Psychiatric Disorders. Neuropsychopharmacol 40, 129–140 (2015). https://doi.org/10.1038/npp.2014.127
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DOI: https://doi.org/10.1038/npp.2014.127
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