Mechanisms of Non-Genetic Inheritance and Psychiatric Disorders

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.

Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress

“…Notably, perturbations such as parental stress, malnutrition, infection, or advanced age have been associated with an increased incidence of neurodevelopmental disease in offspring (1), and alterations in their hypothalamic-pituitary-adrenal (HPA) stress axis response may be central to increased disease predisposition (2,3). Studies in diverse animal models have demonstrated similar outcomes, particularly that of offspring HPA axis dysregulation, following either maternal or paternal stress exposure (4-7); yet mechanisms by which parental lifetime stress experience modify offspring development and adult phenotypes remain unclear.…”

Neurodevelopment and the Origins of Brain Disorders

“…Toth (2015) reviews recent, intriguing research on intergenerational, non-genetic transmission of epigenetic information that alters brain development and impacts risk for mental illness. He presents the current evidence for the impact of the prenatal environment on such transmission, delineates the limitations of this work, and maps out the potential for future studies in animal models and in humans.…”

Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment

“…Maternal effects on fetal development have been explored in other mouse models related to autism, but these studies have focused on environmental stressors that impact the prenatal environment (Bronson and Bale, 2014;Malkova et al, 2012). Recent studies related to mood and anxiety have indicated that genetic factors may also influence neurodevelopment by altering maternal physiology during pregnancy (Toth, 2014). Interestingly, maternal genotype effects on fetal development have been reported in offspring of 5-HT 1A and TPH1 null mice (Cote et al, 2007;Gleason et al, 2010).…”