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Inherited variation at the epigenetic level: paramutation from the plant to the mouse
Abstract
In contrast with a wide definition of the 'epigenetic variation', including all changes in gene expression that do not result from the alteration of the gene structure, a more restricted class had been defined, initially in plants, under the name 'paramutation'. It corresponds to epigenetic modifications distinct from the regulatory interactions of the cell differentiation pathways, mitotically stable and sexually transmitted with non-Mendelian patterns. This class of epigenetic changes appeared for some time restricted to the plant world, but examples progressively accumulated of epigenetic inheritance in organisms ranging from mice to humans. Occurrence of paramutation in the mouse and possible mechanisms were then established in the paradigmatic case of a mutant phenotype maintained and hereditarily transmitted by wild-type homozygotes. Together with the recent findings in plants indicative of a necessary step of RNA amplification in the reference maize paramutation, the mouse studies point to a new role of RNA, as an inducer and hereditary determinant of epigenetic variation. Given the known presence of a wide range of RNAs in human spermatozoa, as well as a number of unexplained cases of familial disease predisposition and transgenerational maintenance, speculations can be extended to possible roles of RNA-mediated inheritance in human biology and pathology.
... Likewise, in animals, parental influences can be mediated through learning or other mechanisms of developmental plasticity (Avital & Jablonka 2000 ). Recent discoveries in cell biology and development have revealed that the transfer of epigenetic, cytoplasmic, or somatic factors from parents to offspring can influence offspring phenotype (Cuzin et al. 2008, Youngson & Whitelaw 2008). These phenomena do not involve the modification of germline DNA-sequence by environment (see Steele et al. 1998) but, rather, the vertical transmission of factors other than DNA. ...
... However, some variation in epigenetic state is maintained in the germline and transmitted to offspring, resulting in transgenerational epigenetic inheritance (, Youngson & Whitelaw 2008). The molecular mechanisms of transgenerational epigenetic inheritance remain poorly understood (Cuzin et al. 2008, Martin & Zhang 2007, Youngson & Whitelaw 2008). The epigenetic state (epiallele) that is transmitted to offspring may depend on parental genotype , or so-called parental effect genes (Chong et al. 2007, Fitch et al. 1998, Johannes et al. 2008, Youngson & Whitelaw 2008). ...
... Although the sperm transmits relatively little material to the zygote, there is evidence that variation in sperm-borne proteins may affect offspring (see Wilson et al. 2006). Transmission of RNA in eggs or sperm can affect offspring phenotype in many ways, and could play a role in transgenerational epigenetic inheritance (Cuzin et al. 2008, Youngson & Whitelaw 2008). For example, in mice, heterozygous individuals carrying a mutant allele exhibit a spotted phenotype, and both mothers and fathers transmit this phenotype to offspring that are homozygous for the wild-type allele through the gametic transfer of RNA (Rassoulzadegan et al. 2006). ...
Modern evolutionary biology is founded on the Mendelian-genetic model of inheritance, but it is now clear that this model is incomplete. Empirical evi-dence shows that environment (encompassing all external influences on the genome) can impose transgenerational effects and generate heritable varia-tion for a broad array of traits in animals, plants, and other organisms. Such effects can be mediated by the transmission of epigenetic, cytoplasmic, so-matic, nutritional, environmental, and behavioral variation. Building on the work of many authors, we outline a general framework for conceptualizing nongenetic inheritance and its evolutionary implications. This framework shows that, by decoupling phenotypic change from the genotype, nongenetic inheritance can circumvent the limitations of genetic inheritance and thereby influence population dynamics and alter the fitness landscape. The weight of theory and empirical evidence indicates that nongenetic inheritance is a potent factor in evolution that can engender outcomes unanticipated under the Mendelian-genetic model.
... Paramutation-like behaviors have been described for other endogenous and transgenic loci in various plant species (see for review Chandler 2007; Onate-Sanchez and Vicente-Carbajosa 2008; Hollick 2017), including, Arabidopsis endogenous genes and transgenes (Luff et al. 1999;Mittelsten Scheid et al. 2003;Xue et al. 2012;Gao and Zhao 2013;Zheng et al. 2015;Bente et al. 2021), petunia and tomato endogenous genes (Hagemann 1969;van Houwelingen et al. 1999;Gouil et al. 2016;Gouil and Baulcombe 2018), and a tobacco transgene (Khaitová et al. 2011). Paramutation-like phenomena have also been reported in animals (Cuzin et al. 2008;Capovilla et al. 2017;Hollick 2017;Dorador et al. 2022). ...
Paramutation is a transfer of heritable silencing states between interacting endogenous alleles or between endogenous alleles and homologous transgenes. Prior results demonstrated that paramutation occurs at the P1-rr (red pericarp and red cob) allele of the maize p1 (pericarp color 1) gene when exposed to a transgene containing a 1.2-kb enhancer fragment (P1.2) of P1-rr. The paramutable P1-rr allele undergoes transcriptional silencing resulting in a paramutant light-pigmented P1-rr′ state. To define more precisely the sequences required to elicit paramutation, the P1.2 fragment was further subdivided, and the fragments transformed into maize plants and crossed with P1-rr. Analysis of the progeny plants showed that the sequences required for paramutation are located within a ∼600-bp segment of P1.2 and that this segment overlaps with a previously identified enhancer that is present in 4 direct repeats in P1-rr. The paramutagenic segment is transcribed in both the expressed P1-rr and the silenced P1-rr′. Transcription is sensitive to α-amanitin, indicating that RNA polymerase II mediates most of the transcription of this sequence. Although transcription within the paramutagenic sequence was similar in all tested genotypes, small RNAs were more abundant in the silenced P1-rr′ epiallele relative to the expressed P1-rr allele. In agreement with prior results indicating the association of RNA-mediated DNA methylation in p1 paramutation, DNA blot analyses detected increased cytosine methylation of the paramutant P1-rr′ sequences homologous to the transgenic P1.2 subfragments. Together these results demonstrate that the P1-rr enhancer repeats mediate p1 paramutation.
... It was shown that low-copy promoter-associated RNA can be recognized by the antisense strand of siRNA, thus suppressing the corresponding gene [58]. Processes of emergence of RNA-dependent epigenetic modifications were documented in different variants [59]. And just such transcriptome properties could allow "foreign" TF, entering the cell, to shift easily the RNA balance towards the side, unusual for the norm, which is used by the creatron in the brain and gonadal morphons for necessary operations. ...
The current study explored concordance in spouses' perceptions about exercise and how these perceptions predicted observed and self-reported marital functioning using a sample of 64 older married couples. Although couples were similarly motivated to exercise, their views on their physical fitness and potential barriers to exercise were uncorrelated. Dyadic analyses suggested that spouses' exercise perceptions, particularly husbands', were associated with how spouses treated each other during a marital problem-solving task and with their concurrent and future marital satisfaction. Exploring how spouses' views of exercise are related to their marital functioning and for whom these links are most salient may highlight potential opportunities and challenges for those wishing to strengthen couples' individual and relational well-being through exercise.
... Until recently, it was widely accepted that genetic inheritance, i.e. the transmission of the DNA primary sequence between parents and offspring, was the universal mechanism accounting for such resemblance. However, recent progress in cellular and molecular biology has revealed multiple alternative mechanisms for intergenerational transmission, including modification of the DNA nucleotides (Banks et al., 1988;Cubas et al., 1999), chromatin structure (Cavalli & Paro, 1998;Triantaphyllopoulos et al., 2016) or various molecular factors (Díaz & Esponda, 2004;Groothuis et al., 2005;Cuzin et al., 2008) (see Youngson & Whitelaw, 2008 for a review). These empirical discoveries have triggered a renewed interest in already-known macroscopic phenomena, such as maternal effects, environmental correlations or cultural transmission, all contributing to the fact that phenotypes are not solely inherited through the DNA sequence (Bonduriansky & Day, 2009;Jablonka & Raz, 2009). ...
Understanding the importance of non-genetic heredity in the evolutionary process is a major topic in modern evolutionary biology. We modified a classical gene network model by allowing parental transmission of gene expression, and studied its evolutionary properties through individual-based simulations. We identified ontogenetic time (i.e. the time gene networks have to stabilize before being submitted to natural selection) as a crucial factor in determining the evolutionary impact of this phenotypic inheritance. Indeed, fast-developing organisms display enhanced adaptation and greater robustness to mutations when evolving in presence of non-genetic inheritance. In contrast, in our model, long development reduces the influence of the inherited state of the gene network. Non-genetic inheritance thus had a negligible effect on the evolution of gene networks when the speed at which transcription levels reach equilibrium is not constrained. Nevertheless, simulations show that inter-generational transmission of the gene network state negatively affects the evolution of robustness to environmental disturbances for either fast or slow developing organisms. Therefore, these results suggest that the evolutionary consequences of non-genetic inheritance might not be sought only in the way species respond to selection, but also on the evolution of emergent properties (such as environmental and genetic canalization) in complex genetic architectures. This article is protected by copyright. All rights reserved.
... Our previous studies show that exposure to stress in adolescent female rats prior to reproduction leads to trans-generational effects on behavior, stress-related hormone levels, and cortical gene expression and neuronal morphology [32][33][34][35][36]. Others have shown that some environmentally induced epigenetic states can be inherited [37][38][39], a process that appears to be mediated by changes to RNA molecules [40,41]. Here, we asked whether prereproductive stress (PRS) in adolescent female rats would impact editing levels at multiple sites in firstand second-generation offspring. ...
Background:
Adenosine-to-inosine (A-to-I) RNA editing is an epigenetic modification catalyzed by adenosine deaminases acting on RNA (ADARs), and is especially prevalent in the brain. We used the highly accurate microfluidics-based multiplex PCR sequencing (mmPCR-seq) technique to assess the effects of development and environmental stress on A-to-I editing at 146 pre-selected, conserved sites in the rat prefrontal cortex and amygdala. Furthermore, we asked whether changes in editing can be observed in offspring of stress-exposed rats. In parallel, we assessed changes in ADARs expression levels.
Results:
In agreement with previous studies, we found editing to be generally higher in adult compared to neonatal rat brain. At birth, editing was generally lower in prefrontal cortex than in amygdala. Stress affected editing at the serotonin receptor 2c (Htr2c), and editing at this site was significantly altered in offspring of rats exposed to prereproductive stress across two generations. Stress-induced changes in Htr2c editing measured with mmPCR-seq were comparable to changes measured with Sanger and Illumina sequencing. Developmental and stress-induced changes in Adar and Adarb1 mRNA expression were observed but did not correlate with editing changes.
Conclusions:
Our findings indicate that mmPCR-seq can accurately detect A-to-I RNA editing in rat brain samples, and confirm previous accounts of a developmental increase in RNA editing rates. Our findings also point to stress in adolescence as an environmental factor that alters RNA editing patterns several generations forward, joining a growing body of literature describing the transgenerational effects of stress.
... Like gene silencing methods, ligand-mediated cis-inhibition can result in phenotypes of varying strengths, as demonstrated by our observation that the severity of SRK cisinhibition depends on the amount of SCR produced in stigma epidermal cells. However, a cis-inhibition strategy has several advantages over conventional gene silencing approaches, which can suffer from off-target effects (Jackson et al., 2003;Scacheri, et al., 2004) and the generation of epigenetic marks that may persist into subsequent generations (Cuzin et al., 2008;Paszkowski and Grossniklaus, 2011;Borges and Martienssen, 2013). By contrast, in cis-inhibition, the interaction between a receptor and its cognate ligand is highly specific, the distribution of the ligand may be controlled by use of cell type-specific promoters, and the suppression of signaling is easily reversed by segregation of the ligandencoding transgene in transgenic progenies. ...
The inhibition of self-pollination in self-incompatible Brassicaceae is based on allele-specific trans-activation of the highly polymorphic S-locus receptor kinase (SRK), which is displayed at the surface of stigma epidermal cells, by its even more polymorphic pollen coat-localized ligand, the S-locus cysteine-rich protein (SCR). In an attempt to achieve constitutive activation of SRK and thus facilitate analysis of self-incompatibility (SI) signaling, we co-expressed an Arabidopsis lyrata SCR variant with its cognate SRK receptor in the stigma epidermal cells of Arabidopsis thaliana plants belonging to the C24 accession, in which expression of SRK and SCR had been shown to exhibit a robust SI response. Contrary to expectation, however, co-expression of SRK and SCR was found to inhibit SRK-mediated signaling and to disrupt the SI response. This phenomenon, called cis-inhibition, is well documented in metazoans but has not as yet been reported for plant receptor kinases. We demonstrate that cis-inhibition of SRK, like its trans-activation, is based on allele-specific interaction between receptor and ligand. We also show that stigma-expressed SCR causes entrapment of its SRK receptor in the endoplasmic reticulum, thus disrupting the proper targeting of SRK to the plasma membrane where the receptor would be available for productive interaction with its pollen coat-derived SCR ligand. Although based on an artificial cis-inhibition system, the results suggest novel strategies of pollination control for the generation of hybrid cultivars and large-scale seed production from hybrid plants in Brassicaceae seed crops, and more generally, for inhibiting cell surface receptor function and manipulating signaling pathways in plants.
Copyright © 2015, Plant Physiology.
... Paramutation, a more restricted class of epigenetic variation, point to a new role of RNA as determinant and inducer of hereditary variation. Strikingly, RNA-mediated non-Mendelian inheritance of an epigenetic change has been demonstrated in the mouse [226] and plants [57]. ...
Recently, the pace of growth in the amount of data sources within Life Sciences has increased exponentially until pose a difficult problem to efficiently manage their integration. The data avalanche we are experiencing may be significant for a turning point in science, with a change of orientation from proprietary to publicly available data and a concomitant acceptance of studies based on the latter. To investigate these issues, a Network of Excellence (EMBRACE) was launched with the aim to integrate the major databases and the most popular bioinformatics software tools. The focus of this thesis is therefore to approach the problem of seamlessly integrating varied data sources and/or distributed research tools.In paper I, we have developed a web service to facilitate allergenicity risk assessment, based on allergen descriptors, in order to characterize proteins with the potential for sensitization and cross-reactivity.In paper II, a web service was developed which uses a lightweight protocol to integrate human endogenous retrovirus (ERV) data within a public genome browser. This new data catalogue and many other publicly available sources were integrated and tested in a bioinformatics-rich client application.In paper III, GeneFinder, a distributed tool for genome-wide association studies, was developed and tested. Useful information based on a particular genomic region can be easily retrieved and assessed.Finally, in paper IV, we developed a prototype pipeline to mine the dog genome for endogenous retroviruses and displaying the transcriptional landscape of these retroviral integrations. Moreover, we further characterized a group that until this point was believed to be primate-specific. Our results also revealed that the dog has been very effective in protecting itself from such integrations.This work integrates different applications in the fields of protein allergology, biotechnology, genome association studies and endogenous retroviruses.
... cytosine DNA-methylation) and histone modifications (e.g. histone tail acetylation) involved in gene regulation (Cuzin et al. 2008;Berger et al. 2009). As a consequence of the different views one might study epigenetics in the original Waddingtonian context by just investigating the non-genetic component of the phenotype, in the modern broad view by investigating gene expression inheritance and from the molecular perspective by investigating for example DNAmethylation. ...
Phenotypic variation within populations is a crucial factor in evolution and is mainly thought to be driven by heritable changes in the base sequence of DNA. Among our domesticated species we find some of the most variable species on earth today. This variety of breeds has appeared during a relatively short evolutionary time, and so far genetic studies have been unable to explain but a small portion of this variation, which indicates more novel mechanisms of inheritance and phenotypic plasticity. The aim of this study was therefore to investigate some of these alternative routes in the chicken, especially focusing on transgenerational effects of environmental challenges on behaviour and gene expression in relation to domestication. In two experiments a chronically unpredictable environment induced phenotypic changes in the parents that were mirrored in the unexposed offspring raised without parental contact. This transmission was especially clear in domesticated birds. A third experiment showed that repeated stress events very early in life could change the developmental program making the birds more resistant to stress later in life. Here, the phenotypic changes were also mirrored in the unexposed offspring and associated with inheritance of gene expression. Epigenetic factors, such as DNA-methylation, could play an important role in the mechanism of these transgenerational effects. A fourth experiment showed that wild types and domesticated chickens differed substantially in their patterns of DNA-methylation, where the domesticated breed had increased amount of promoter DNA-methylation. In line with the previous experiments, this breed also showed increased transmission of methylation marks to their offspring. Conclusively, parental exposure of environmental challenges that introduce changes in behaviour, physiology and gene expression can under both chronic and temporal conditions be heritably programmed in the parent and transmitted to the unexposed offspring. Since heritable epigenetic variation between wild type and domesticated chickens is stable and numerous, it is possible that selection for favourable epigenomes could add another level to the evolutionary processes and therefore might explain some of the rapid changes in the history of the domesticated chicken.
... Furthermore, miRNAs are present in the egg and in the spermatozoa; thus, parental conditions (e.g. disease or oxidative stress status) can be stably inherited for a number of generations (Cuzin, Grandjean & Rassoulzadegan 2008). Indeed, miRNAs are suggested to play a large role in regulating the response to both acute and chronic environmental stress, by programming the cell's gene expression during development to be able to acclimatize to the new environment in the long run (Leung & Sharp 2010). ...
To estimate the impact of urbanization on wild animals, it is important to know how different species, populations and/or individuals deal with and respond to environmental stress. Are more urbanized species adapted to their environment, or do individuals acclimatize over the course of their life? Alternatively, do they simply cope at the expense of other functions? These are three key processes that I will address using two important physiological responses as case traits, namely oxidative stress and inflammation, – which are known to be under genetic control as well as showing great plasticity.
Oxidative stress is a state of more reactive oxidants than antioxidants, which may cause tissue damage linked to disease and senescence. Inflammation, on the other hand, is the response of vascular tissues to harmful stimuli. However, under progressive stimuli, inflammation may also cause tissue destruction and pathology.
Although patterns and strengths of effects are not always clear cut, the often interconnected oxidative stress and inflammation have the potential to be severely affected by urban stressors, thereby mechanistically linking ecology to fitness. Here I discuss five major urban stressors: chemical, noise and artificial night light pollution, disease and diet, and how their individual and combinatory effects may affect these two physiological responses.
To start to disentangle whether physiological responses are a question of evolving, acclimatizing or coping with the urban environment, population genetics along with regulatory mechanisms of gene expression will shed light on the ‘costs’ of urban life and help to understand why some species or genotypes thrive, while others are absent, in urban areas. Single nucleotide polymorphism ( SNP ) has been successful for explaining local adaptation and tolerance towards acute toxic substances. However, for multiple stressors acting in concert, at low chronic exposure, investigations of epigenetic mechanisms regulating gene expression may be more illuminating.
Here I review the pathways by which genetic and epigenetic mechanisms can affect oxidative stress and inflammatory responses in urban environments, thereby affecting overall fitness. By doing so, I identify the major outstanding gaps of knowledge in the interfaces between ecology, toxicology, evolutionary and molecular biology to inform future studies of urban wildlife.
... The Kit locus has been found to be susceptible to paramutations 5,12 . An earlier study reported that an insertional mutation in one Kit allele (a LacZ gene cassette inserted into exon 1 of the Kit gene) caused altered Kit expression from the other allele, leading to a ''white-tail-tip'' (WTT) phenotype in genetically wild type (WT) progeny 12 . ...
Paramutations result from interactions between two alleles at a single locus, whereby one induces a heritable change in the other. Although common in plants, paramutations are rarely studied in animals. Here, we report a new paramutation mouse model, in which the paramutant allele was induced by an insertional mutation and displayed the "white-tail-tip" (WTT) phenotype. The paramutation phenotype could be transmitted across multiple generations, and the breeding scheme (intercrossing vs. outcrossing) drastically affected the transmission efficiency. Paternal (i.e., sperm-borne) RNAs isolated from paramutant mice could induce the paramutation phenotype, which, however, failed to be transmitted to subsequent generations. Maternal miRNAs and piRNAs appeared to have an inhibitory effect on the efficiency of germline transmission of the paramutation. This paramutation mouse model represents an important tool for dissecting the underlying mechanism, which should be applicable to the phenomenon of epigenetic transgenerational inheritance (ETI) in general. Mechanistic insights of ETI will help us understand how organisms establish new heritable epigenetic states during development, or in times of environmental or nutritional stress.
... This suggests that small RNA can direct epigenetics differences between two closely related Arabidopsis ecotypes. Other RNA-directed epigenetic natural variations abound in literature (Cuzin et al., 2008;Chandler, 2007;Alleman et al., 2006;Chandler and Stam, 2004). A study revealed that silencing of RNA-directed RNA polymerase 1 (RdR1) makes Nicotiana attenuata highly susceptible to insect herbivores (Pandey et al., 2008). ...
Epigenetics, which generally refers to beyond genetics, began to attract the attention of plant geneticits principally due to many biological phenomena that deviate from basic evolutionary rules and trends. Several studies past and present have attributed gene expression including both qualitative and environmentally influenced morphological changes in plants and crop species to epigenetic related activities such as DNA methylation, histone modifications, non-coding RNA mediated pathways amongst others and show that these epigenetic landmarks can be stably inherited across generations. However, the ‘ghostlike’ nature of these epigenetic activities will otherwise make steady progress in its utilization in agronomy related problems fairly slow. There are still many unknown about the ‘how’ (for example it is well known that the emergence of DNA methylation is mostly affected by growth conditions such as stress but this is not so with random mutational events) before this science can be adequately utilized in the manipulation of quantitatively controlled agronomic traits. Here, we examined the mechanisms as well as showed recent epigenetic inheritance and somaclonal variation related evidences in plant, with emphasis on a number of methylation related fingerprints in crop plants as an epigenetic marker that play key role in phenotypic variations.
... As far as I'm aware, we have very little understanding of the mechanistic basis of how sperm phenotype affects offspring phenotype. There is evidence that RNA in sperm can affect sperm phenotype and this may be the source of the effect (Cuzin et al., 2008;Youngson and Whitelaw, 2008). Alternatively, sperm phenotype may covary with other components of the ejaculate, and the ejaculate rather than the sperm may drive phenotypic changes in the offspring (Bonduriansky and Day, 2009). ...
Traditionally, it has been assumed that sperm are a vehicle for genes and nothing more. As such, the only source of variance in offspring phenotype via the paternal line has been genetic effects. More recently, however, it has been shown that the phenotype or environment of fathers can affect the phenotype of offspring, challenging traditional theory with implications for evolution, ecology and human in vitro fertilisation. Here, I review sources of non-genetic variation in the sperm phenotype and evidence for co-variation between sperm and offspring phenotypes. I distinguish between two environmental sources of variation in sperm phenotype: the pre-release environment and the post-release environment. Pre-release, sperm phenotypes can vary within species according to male phenotype (e.g. body size) and according to local conditions such as the threat of sperm competition. Post-release, the physicochemical conditions that sperm experience, either when freely spawned or when released into the female reproductive tract, can further filter or modify sperm phenotypes. I find evidence that both pre- and post-release sperm environments can affect offspring phenotype; fertilisation is not a new beginning - rather, the experiences of sperm with the father and upon release can drive variation in the phenotype of the offspring. Interestingly, there was some evidence for co-variation between the stress resistance of sperm and the stress resistance of offspring, though more studies are needed to determine whether such effects are widespread. Overall, it appears that environmentally induced covariation between sperm and offspring phenotypes is non-negligible and further work is needed to determine their prevalence and strength.
© 2015. Published by The Company of Biologists Ltd.
... Microinjections of RNA from somatic and germ cells of heterozygotic mice to the wild-type one-cell embryo increased the frequency of the heritable white tail phenotype, whereas wild-type RNA injections of the control embryos showed the mutant phenotype at a low efficacy with inefficient transmission to the progeny (Rassoulzadegan et al., 2006). Moreover, the injection of two miRNAs (miR-221 and -222) that are partially complementary to the Kit RNA was also able to induce the paramutated state in contrast to injection of the variety of other miRNAs tested (Cuzin et al., 2008;Rassoulzadegan et al., 2006). ...
Research efforts during the past decades have provided intriguing evidence suggesting that stressful experiences during pregnancy exert long-term consequences on the future mental wellbeing of both the mother and her baby. Recent human epidemiological and animal studies indicate that stressful experiences in utero or during early life may increase the risk of neurological and psychiatric disorders, arguably via altered epigenetic regulation. Epigenetic mechanisms, such as miRNA expression, DNA methylation, and histone modifications are prone to changes in response to stressful experiences and hostile environmental factors. Altered epigenetic regulation may potentially influence fetal endocrine programming and brain development across several generations. Only recently, however, more attention has been paid to possible transgenerational effects of stress. In this review we discuss the evidence of transgenerational epigenetic inheritance of stress exposure in human studies and animal models. We highlight the complex interplay between prenatal stress exposure, associated changes in miRNA expression and DNA methylation in placenta and brain and possible links to greater risks of schizophrenia, attention deficit hyperactivity disorder, autism, anxiety - or depression-related disorders later in life. Based on existing evidence, we propose that prenatal stress, through the generation of epigenetic alterations, becomes one of the most powerful influences on mental health in later life. The consideration of ancestral and prenatal stress effects on lifetime health trajectories is critical for improving strategies that support healthy development and successful aging.
... Environmental epigenetic transgenerational inheritance (EETI) refers to the phenomenon in which exposure of the gestating mother (F0), along with the developing fetus (F1), to environmental insults, such as endocrine disruptors, toxicants, poor nutrition, etc., causes epimutations that are transmitted to the F3 generation, and beyond, through the germline, in the absence of continued exposure (Cuzin et al., 2008;Gluckman et al., 2007;Skinner, 2011;Skinner and Guerrero-Bosagna, 2009;Whitelaw and Whitelaw, 2008). The Skinner lab first reported, in 2005, that exposure of gestating female rats to vinclozolin, an environmental endocrine disruptor, during the time window (E8.5-E14.5) of global demethylation in the PGCs in the fetal rat gonads (F1) causes a phenotype characterized by increased incidence of adult onset diseases, including disrupted spermatogenesis, prostate or kidney diseases, immune abnormalities, and tumorigenesis, in not only F1 and F2 generations, but also the F3 generation that is never directly exposed to vinclozolin (Anway et al., 2005) (Fig. 2). ...
“Epigenetic Transgenerational Inheritance” (ETI) has been defined as germline (sperm or egg) transmission of epigenetic information between generations in the absence of direct exposures or genetic manipulations. Among reported cases of ETI in mammals, the majority are induced by environmental factors, including environmental toxicants [e.g. agricultural fungicide vinclozolin, plastic additive bisphenol A, pesticide methoxychlor, dioxin, di-(2-ethylhexyl) phthalate, dichlorodiphenyltrichloroethane, and hydrocarbons] and poor nutritional conditions. Although the ETI phenomenon is well established, the underlying mechanism remains elusive. Putative epimutations, including changes in DNA methylation and histone modification patterns have been reported, but it remains unclear how these epimutations are formed in the first place, and how they are memorized in the germline and then get transmitted to subsequent generations. Based on recent advances in our understanding of regulatory noncoding RNAs (ncRNAs), I propose that ncRNAs are involved in ETI, during both the initial epimutation formation and the subsequent germline transmission of epimutations. ncRNAs can function at epigenetic levels by affecting DNA methylation and histone modifications, thereby changing gene transcriptional activities, which can lead to an altered mRNA transcriptome associated with a disease phenotype. Alternatively, novel or altered ncRNA expression can cause dysregulated post-transcriptional regulation, thus directly affecting the mRNA transcriptome and inducing a disease phenotype. Sperm-borne ncRNAs are potential mediators for epigenetic memory across generations, but they alone may not be sufficient for stable transmission of epimutations across generations. Overall, research on ncRNAs in the context of ETI is urgently needed to shed light on the underlying mechanism of ETI.
... Similarly, non-coding RNAs are affected by learning processes but can also mediate phenotypic changes across generations. A fascinating example is paramutations that have been well studied, for example, in plants (Cuzin et al, 2008) but also occur in mammals. In mice, it was found that presence of miR 221 and miR 222 in germ cells was responsible for the transfer of a specific phenotype linked to tail color to the subsequent generation (Rassoulzadegan et al, 2006). ...
Recent data support the view that epigenetic processes play a role in memory consolidation and help to transmit acquired memories even across generations in a Lamarckian manner. Drugs that target the epigenetic machinery were found to enhance memory function in rodents and ameliorate disease phenotypes in models for brain diseases such as Alzheimer's disease, Chorea Huntington, Depression or Schizophrenia. In this review, I will give an overview on the current knowledge of epigenetic processes in memory function and brain disease with a focus on Morbus Alzheimer as the most common neurodegenerative disease. I will address the question whether an epigenetic therapy could indeed be a suitable therapeutic avenue to treat brain diseases and discuss the necessary steps that should help to take neuroepigenetic research to the next level.
... Growing evidence points to interactions with the environment yielding epigenetic alterations in gene expression that lead to transgenerational phenotypes and disease etiologies transmitted to daughter cells throughout many doublings [9]. Of particular interest in this regard are paramutational-like effects described in mice whereby specific miRNAs control gene expression by a germline transmissible, epigenetic mechanism [10], which can result in pathophysiologies such as heritable cardiac hypertrophy [11]. OA disease develops in the context of chondrocytes responding to a stress-associated, proinflammatory environment. ...
Osteoarthritis (OA) is a multifactorial disease subject to the effects of many genes and environmental factors. Alterations in the normal pattern of chondrocyte gene control in cartilage facilitate the onset and progression of OA. Stable changes in patterns of gene expression, not associated with alterations in DNA sequences, occur through epigenetic changes, including DNA methyla-tion, histone modifications, and alterations in chromatin structure, as well as by microRNA (miRNA)-mediated mechanisms. Moreover, the ability of the host to repair damaged cartilage is reflected in alterations in gene control circuits, suggestive of an epigenetic and miRNA-dependent tug-of-war between tissue homeo-stasis and OA disease pathogenesis. Herein, we summa-rize epigenetic and miRNA-mediated mechanisms impacting on OA progression and in this context offer potential therapeutic strategies for OA treatment. What is OA disease and how does it develop? Idiopathic osteoarthritis (OA) is a late-onset, complex disease of the joint, characterized by progressive failure of the extracellular matrix (ECM) of cartilage (Figure 1 and Box 1), with changes in and contributions by the synovium, subchondral bone, and other joint tissues. Risk factors for OA development can be divided into two fun-damental mechanisms related to the adverse effects of trauma on an otherwise normal joint, to normal loading on a maligned joint, or a range of scenarios in between, all resulting in abnormal biomechanics that impact on bio-logical responses. Although tremendous advances have been made in defining OA susceptibility genes, these are merely predictive of risk for disease development, whereas it is the interaction with the environment that determines whether individuals develop the disease. Much has been learned about factors involved in carti-lage degeneration and other joint pathologies from animal models of post-traumatic OA, including transgenic and knockout mice subjected to surgically induced OA disease [1]. Genetic models with abnormal composition and structure of articular cartilage or other joint tissues may develop spontaneous or accelerated OA due to altered
... Sperm-specific RNAs can influence fertilization and early embryo development but may also epigenetically modify the phenotype of the offspring (reviewed in Cuzin et al., 2008;Lalancette et al., 2008a;Johnson et al., 2011a;Hamatani, 2012;Rando, 2012). Following somatic cell nuclear transfer, some pathological changes in the placenta and congenital defects in the fetus as well as in the offspring are observed (reviewed in Shiels et al., 1999;Lanza et al., 2000;Xu and Yang, 2003). ...
BACKGROUND Spermatozoa are highly differentiated, transcriptionally inert cells characterized by a compact nucleus with minimal cytoplasm.
Nevertheless they contain a suite of unique RNAs that are delivered to oocyte upon fertilization. They are likely integrated
as part of many different processes including genome recognition, consolidation-confrontation, early embryonic development
and epigenetic transgenerational inherence. Spermatozoal RNAs also provide a window into the developmental history of each
sperm thereby providing biomarkers of fertility and pregnancy outcome which are being intensely studied.
... Indeed, studying the threedimensional configuration of chromatin in humans has shown that these types of interactions are not uncommon (Lieberman-Aiden et al., 2009). Moreover, it has been hypothesised that, given the large quantity of RNAs present in human sperm, this type of epigenetic mechanism could underlie a number of heritable human diseases and may explain some unusual inheritance patterns (Cuzin et al., 2008;Kiani and Rassoulzadegan, 2013). ...
... A further example of a molecular mechanism is that of paramutation, which consists in the interaction between two alleles at a single locus. This can induce permanent epigenetic changes in organisms from maize to mice (Chandler, 2007(Chandler, , 2010Cuzin et al. 2008;Sidorenko et al. 2009;Arteaga-Vazquez et al. 2010;Erhard & Hollick, 2011). ...
New Findings
What is the topic of this review?
Have recent experimental findings in evolutionary biology concerning the transmission of inheritance opened the way to a reintegration of physiology with evolutionary biology?
What advances does it highlight?
The answer is yes, and that this requires a new synthesis between evolutionary theory and experimental physiology.
The ‘Modern Synthesis’ (Neo‐Darwinism) is a mid‐20th century gene‐centric view of evolution, based on random mutations accumulating to produce gradual change through natural selection. Any role of physiological function in influencing genetic inheritance was excluded. The organism became a mere carrier of the real objects of selection, its genes. We now know that genetic change is far from random and often not gradual. Molecular genetics and genome sequencing have deconstructed this unnecessarily restrictive view of evolution in a way that reintroduces physiological function and interactions with the environment as factors influencing the speed and nature of inherited change. Acquired characteristics can be inherited, and in a few but growing number of cases that inheritance has now been shown to be robust for many generations. The 21st century can look forward to a new synthesis that will reintegrate physiology with evolutionary biology.
... Dysregulation of these complex gene regulatory networks plays a significant role in the pathogenesis of common neurodegenerative disease such as Alzheimer's disease (AD), Parkinson disease (PD), Huntington disease (HD), and amyotrophic lateral sclerosis (ALS; Akbarian et al., 1995b;Hideyama et al., 2012). In eukaryotes, a unifying theme in all of these genetic diseases is alterations in RNA regulation at multiple levels, including transcriptional changes, RNA editing (Burns et al., 1997;Emeson and Singh, 2001;Bass, 2002;Blow et al., 2006;Beal et al., 2007;Barraud and Allain, 2012), post-transcriptional gene silencing (Mette et al., 2000;Pal-Bhadra et al., 2002;Matzke et al., 2007;Carthew and Sontheimer, 2009;Ghildiyal and Zamore, 2009), X chromosome dosage compensation (Yang and Kuroda, 2007;Kanduri et al., 2009;Fedoriw et al., 2012), germ cell reprogramming (Migicovsky and Kovalchuk, 2011;Guibert et al., 2012), and para-mutation (Chandler, 2007;Cuzin et al., 2008; Figure 1). ...
RNA editing is an alteration in the primary nucleotide sequences resulting from a chemical change in the base. RNA editing is observed in eukaryotic mRNA, transfer RNA, ribosomal RNA, and non-coding RNAs (ncRNA). The most common RNA editing in the mammalian central nervous system is a base modification, where the adenosine residue is base-modified to inosine (A to I). Studies from ADAR (adenosine deaminase that act on RNA) mutants in Caenorhabditis elegans, Drosophila, and mice clearly show that the RNA editing process is an absolute requirement for nervous system homeostasis and normal physiology of the animal. Understanding the mechanisms of editing and findings of edited substrates has provided a better knowledge of the phenotype due to defective and hyperactive RNA editing. A to I RNA editing is catalyzed by a family of enzymes knows as ADARs. ADARs modify duplex RNAs and editing of duplex RNAs formed by ncRNAs can impact RNA functions, leading to an altered regulatory gene network. Such altered functions by A to I editing is observed in mRNAs, microRNAs (miRNA) but other editing of small and long ncRNAs (lncRNAs) has yet to be identified. Thus, ncRNA and RNA editing may provide key links between neural development, nervous system function, and neurological diseases. This review includes a summary of seminal findings regarding the impact of ncRNAs on biological and pathological processes, which may be further modified by RNA editing. NcRNAs are non-translated RNAs classified by size and function. Known ncRNAs like miRNAs, smallRNAs (smRNAs), PIWI-interacting RNAs (piRNAs), and lncRNAs play important roles in splicing, DNA methylation, imprinting, and RNA interference. Of note, miRNAs are involved in development and function of the nervous system that is heavily dependent on both RNA editing and the intricate spatiotemporal expression of ncRNAs. This review focuses on the impact of dysregulated A to I editing and ncRNAs in neurodegeneration.
... Studies indicate that epigenetic changes can be inherited via the germline as well as somatically, resulting in the intergenerational non-genomic inheritance of epigenetic states Crews et al. 2007;Cuzin et al. 2008;Jablonka & Raz 2009;Pentinat et al. 2010;Skinner et al. 2008;Stouder & Paoloni-Giacobino 2010;Walker & Gore 2011). It was once believed that genome-wide epigenetic reprogramming during gametogenesis and early embryogenesis would erase epigenetic modifications acquired during the life of the animal in order to restore the totipotency of the fertilized egg (i.e., the ability of fetal stem cells to become any cell type) (Allegrucci et al. 2005). ...
My response is divided into four sections: (1) is devoted to a potpourri of commentaries that are essentially in agreement with the substance of my target article (with one exception); in (2) I address, in response to one of the commentaries, several issues relating to the use of candidate gene association studies in behavior genetics (in particular those proposing a specific G × E interaction); in (3) I provide a detailed response to several defenses of the twin study methodology; and in (4) I conclude with several reflections on that methodology and the conception of human nature it has fostered.
... Studies indicate that epigenetic changes can be inherited via the germline as well as somatically, resulting in the intergenerational non-genomic inheritance of epigenetic states Crews et al. 2007;Cuzin et al. 2008;Jablonka & Raz 2009;Pentinat et al. 2010;Skinner et al. 2008;Stouder & Paoloni-Giacobino 2010;Walker & Gore 2011). It was once believed that genome-wide epigenetic reprogramming during gametogenesis and early embryogenesis would erase epigenetic modifications acquired during the life of the animal in order to restore the totipotency of the fertilized egg (i.e., the ability of fetal stem cells to become any cell type) (Allegrucci et al. 2005). ...
Critically significant parental effects in behavioral genetics may be partly understood as a consequence of maternal brain structure and function of caregiving systems recently studied in humans as well as rodents. Key parental brain areas regulate emotions, motivation/reward, and decision making, as well as more complex social-cognitive circuits. Additional key environmental factors must include socioeconomic status and paternal brain physiology. These have implications for developmental and evolutionary biology as well as public policy.
... Studies indicate that epigenetic changes can be inherited via the germline as well as somatically, resulting in the intergenerational non-genomic inheritance of epigenetic states Crews et al. 2007;Cuzin et al. 2008;Jablonka & Raz 2009;Pentinat et al. 2010;Skinner et al. 2008;Stouder & Paoloni-Giacobino 2010;Walker & Gore 2011). It was once believed that genome-wide epigenetic reprogramming during gametogenesis and early embryogenesis would erase epigenetic modifications acquired during the life of the animal in order to restore the totipotency of the fertilized egg (i.e., the ability of fetal stem cells to become any cell type) (Allegrucci et al. 2005). ...
Against the opinion that DNA as program is not sufficiently explanatory, we maintain that the cellular machinery is entirely computational, and we identify the crucial notion of the interpreter that expresses the gene with the minimal gene set. Epigenetics research does not so much need paradigm shifts as the unraveling of an exceedingly complex computational machine.
... Studies indicate that epigenetic changes can be inherited via the germline as well as somatically, resulting in the intergenerational non-genomic inheritance of epigenetic states Crews et al. 2007;Cuzin et al. 2008;Jablonka & Raz 2009;Pentinat et al. 2010;Skinner et al. 2008;Stouder & Paoloni-Giacobino 2010;Walker & Gore 2011). It was once believed that genome-wide epigenetic reprogramming during gametogenesis and early embryogenesis would erase epigenetic modifications acquired during the life of the animal in order to restore the totipotency of the fertilized egg (i.e., the ability of fetal stem cells to become any cell type) (Allegrucci et al. 2005). ...
Several new molecular findings and concepts furnish evidence in support of gene-environment interdependence, challenging some of the current tenets and basic statistics of behavioral genetics. I, however, argue that (1) some of the expectations evoked by "neogenomics" are contradicted by findings; and (2) while epigenetic and gene expression effects are complex, they can to some extent be incorporated into "classical" behavioral genetics modeling.
... Studies indicate that epigenetic changes can be inherited via the germline as well as somatically, resulting in the intergenerational non-genomic inheritance of epigenetic states Crews et al. 2007;Cuzin et al. 2008;Jablonka & Raz 2009;Pentinat et al. 2010;Skinner et al. 2008;Stouder & Paoloni-Giacobino 2010;Walker & Gore 2011). It was once believed that genome-wide epigenetic reprogramming during gametogenesis and early embryogenesis would erase epigenetic modifications acquired during the life of the animal in order to restore the totipotency of the fertilized egg (i.e., the ability of fetal stem cells to become any cell type) (Allegrucci et al. 2005). ...
The science of genetics is undergoing a paradigm shift. Recent discoveries, including the activity of retrotransposons, the extent of copy number variations, somatic and chromosomal mosaicism, and the nature of the epigenome as a regulator of DNA expressivity, are challenging a series of dogmas concerning the nature of the genome and the relationship between genotype and phenotype. According to three widely held dogmas, DNA is the unchanging template of heredity, is identical in all the cells and tissues of the body, and is the sole agent of inheritance. Rather than being an unchanging template, DNA appears subject to a good deal of environmentally induced change. Instead of identical DNA in all the cells of the body, somatic mosaicism appears to be the normal human condition. And DNA can no longer be considered the sole agent of inheritance. We now know that the epigenome, which regulates gene expressivity, can be inherited via the germline. These developments are particularly significant for behavior genetics for at least three reasons: First, epigenetic regulation, DNA variability, and somatic mosaicism appear to be particularly prevalent in the human brain and probably are involved in much of human behavior; second, they have important implications for the validity of heritability and gene association studies, the methodologies that largely define the discipline of behavior genetics; and third, they appear to play a critical role in development during the perinatal period and, in particular, in enabling phenotypic plasticity in offspring. I examine one of the central claims to emerge from the use of heritability studies in the behavioral sciences, the principle of minimal shared maternal effects, in light of the growing awareness that the maternal perinatal environment is a critical venue for the exercise of adaptive phenotypic plasticity. This consideration has important implications for both developmental and evolutionary biology.
... It is becoming obvious that some epigenetic modifications are heritable (Cavalli and Paro 1999; Goldberg et al. 2007), although the mechanism by which this transmission is achieved remains unknown (Cuzin et al. 2008). The main challenge for geneticists is to understand the impact of this epigenetic code. ...
All genomes contain, to agreater or lesser extent, sequences that do not seem to be beneficial.
The most preeminent group consists of transposable elements (TEs). These repeated DNA sequences have asignificant
influence on genome dynamics and evolution. One of the main challenges facing modern molecular evolution
is to understand and measure their impact on evolution. The aim of this paper is to establish the relevance
and contribution of population studies, as well as the species comparative approaches, to understanding
the dynamics of TEs. Most of the examples cited concern the species Drosophila
melanogaster, since this is one of the genetic key-model organisms, for which an enormous amount
of data has been collected over aperiod of 100 years of genetic research, and which represents agenus
for which the genomes of 12 species have been sequenced.
... Similarly, when male rodents are fed a high-fat or low-protein diet, their offspring exhibit severe metabolic defects, which are possibly caused by altered DNA methylation of specific metabolic genes [7,8]. In addition, several other transgenerational phenomena have been reported in various species, such as paramutation in plants and tumor suscepibility in Drosophila [9,10]. In their recent publication, Greer et al. [2] extend the transgenerational phenotype to lifespan. ...
A recent study reported that longevity in Caenorhabditits elegans can be inherited over several generations. This is probably achieved through the following epigenetic mechanism: inherited demethylated histones at some central loci, such as miRNA, transcription factors or signaling regulators affect the expression of certain genes leading to the longevity phenotype.
... The putative information transfer from fathers to offspring could be accomplished through any of several mechanisms suggested for establishment and transfer of paternal signal(s) via the sperm, involving gene methylation, paramutation, microRNA [Cuzin et al., 2008;Filkowski et al., 2009], remodelling of chromatin and nucleus structure [De Boer et al., 2010], histones [Ruden and Lu, 2008], and exogenous DNA or RNA [Sciamanna et al., 2009]. Both DNA methylation and chromatin remodeling were directly implicated in a study of epigenetic reprogramming in mice [Chong et al., 2007]. ...
Both gene methylation changes and genetic instability have been noted in offspring of male rodents exposed to radiation or chemicals, but few specific gene targets have been established. Previously, we identified the gene for ribosomal RNA, rDNA, as showing methylation change in sperm of mice treated with the preconceptional carcinogen, chromium(III) chloride. rDNA is a critical cell growth regulator. Here, we investigated the effects of paternal treatments on rDNA in offspring tissue. A total of 93 litters and 758 offspring were obtained, permitting rigorous mixed-effects models statistical analysis of the results. We show that the offspring of male mice treated with Cr(III) presented increased methylation in a promoter sequence of the rDNA gene, specifically in lung. Furthermore polymorphic variants of the multi-copy rDNA genes displayed altered frequencies indicative of structural changes, as a function of both tissue type and paternal treatments. Organismal effects also occurred: some groups of offspring of male mice treated with either Cr(III) or its vehicle, acidic saline, compared with those of untreated mice, had altered average body and liver weights and levels of serum glucose and leptin. Males treated directly with Cr(III) or acidic saline presented serum hormone changes consistent with a stress response. These results establish for the first time epigenetic and genetic instability effects in a gene of central physiological importance, in offspring of male mice exposed preconceptionally to chemicals, possibly related to a stress response in these males.
... Growing evidence points to interactions with the environment yielding epigenetic alterations in gene expression that lead to transgenerational phenotypes and disease etiologies transmitted to daughter cells throughout many doublings [9]. Of particular interest in this regard are paramutational-like effects described in mice whereby specific miRNAs control gene expression by a germline transmissible, epigenetic mechanism [10], which can result in pathophysiologies such as heritable cardiac hypertrophy [11]. OA disease develops in the context of chondrocytes responding to a stress-associated, proinflammatory environment. ...
Osteoarthritis (OA) is a multifactorial disease subject to the effects of many genes and environmental factors. Alterations in the normal pattern of chondrocyte gene control in cartilage facilitate the onset and progression of OA. Stable changes in patterns of gene expression, not associated with alterations in DNA sequences, occur through epigenetic changes, including DNA methylation, histone modifications, and alterations in chromatin structure, as well as by microRNA (miRNA)-mediated mechanisms. Moreover, the ability of the host to repair damaged cartilage is reflected in alterations in gene control circuits, suggestive of an epigenetic and miRNA-dependent tug-of-war between tissue homeostasis and OA disease pathogenesis. Herein, we summarize epigenetic and miRNA-mediated mechanisms impacting on OA progression and in this context offer potential therapeutic strategies for OA treatment.
All genomes contain, to a greater or lesser extent, sequences that do not seem to be beneficial. The most preeminent group consists of transposable elements (TEs). These repeated DNA sequences have a significant influence on genome dynamics and evolution. One of the main challenges facing modern molecular evolution is to understand and measure their impact on evolution. The aim of this paper is to establish the relevance and contribution of population studies, as well as the species comparative approaches, to understanding the dynamics of TEs. Most of the examples cited concern the species Drosophila melanogaster, since this is one of the genetic key-model organisms, for which an enormous amount of data has been collected over a period of 100 years of genetic research, and which represents a genus for which the genomes of 12 species have been sequenced.
Background: Epidermolysis bullosa simplex is a hereditary skin disorder caused by mutations in several genes such as KRT5 and KRT14 . Skin fragility in basal keratinocytes presence regions led to the cytolysis of epidermis and blistering. Aim of this study was to detect the molecular defects in KRT5 and KRT14 genes hot spots in patients with clinical suspicion of EBS and investigation of their probable genotype-phenotype correlations.
Methods: Exons 1 and 6-7 of KRT5 and exons 1 and 4-7 of KRT14 amplification and mutation detection were performed by polymerase chain reaction and Sanger sequencing, respectively. Novel variants pathogenicity evaluated by bioinformatics tools.
Results: Nine important variants detected in seven different patients within 6 Iranian families affected by Epidermolysis bullosa simplex, of which four variants were novel. Three patients had a mottled pigmentation phenotype [G96D (p.Gly96Asp) and F97I (p.Phe97Ile) in KRT5 ]. One of them showed a Dowling–Meara phenotype [A417P (p.Ala417Pro) and E477D (p.Glu477Asp) in KRT5 ] and another had a Koebner type phenotype [R397I (p.Arg397Ile) and Q444* (p.Gln444Ter) in KRT5 ]. A novel variant [G92E (p.Gly92Glu) in KRT5 ] in a double heterozygous state with a challenging variant [A413T (p.Ala413Thr) in KRT14 ] identified in one patient with Koebner type phenotype. Also, a previously reported mutation [I377T (p.Ile377Thr) in KRT14 gene] identified in this study.
Conclusion: The results of molecular data analysis showed that the most severe phenotypes were associated with mutations in highly conserved regions. In some cases, different inheritance modes were observed.
L’identification de l’information génétique comme support de l’hérédité a accordé aux gènes une importance majeure dans l’étude de l’évolution et des mécanismes permettant la mise en place des caractères. Cependant, les processus permettant à une variation génétique de se traduire en variation phénotypique sont complexes et leur identification est centrale pour la compréhension de l’évolution.On parle de relation génotype-phénotype pour désigner la fonction qui relie l’espace des gènes à celui des caractères. Étudier les propriétés de cette relation permet d’identifier des mécanismes pouvant altérer les trajectoires évolutives et améliorer notre compréhension de l’évolution de systèmes vivants. Je défends notamment l’intérêt d’étudier mécanistiquement les processus par lesquels une variation génétique donne naissance à une variation phénotypique, et emploie, pour ce faire, un modèle de réseau de régulation transcriptionnelle.Ici, j’étudie les effets d’une information environnementale sur la relation génotype-phénotype et ses propriétés (notamment sa canalisation, sa robustesse à des perturbations génétiques ou environnementales). Pour ce faire, l’évolution de réseaux de régulation simulés est étudiée en présence d’un gène senseur de l’environnement ou d’une forme d’hérédité non génétique.Ce manuscrit débute par une discussion générale de l’intérêt des approches par modélisation, notamment pour l’étude de phénomènes complexes. Enfin, les résultats obtenus sont présentés en regard des discussions sur la nécessité d’une « synthèse évolutive étendue » pour décrire le processus évolutif d’une manière difficilement accessible par une approche gène-centrée.
DNA methylation at cytosines followed by guanines, CpGs, forms one of the multiple layers of epigenetic mechanisms controlling and modulating gene expression through chromatin structure. It closely interacts with histone modifications and chromatin remodeling complexes to form the local genomic and higher-order chromatin landscape. DNA methylation is essential for proper mammalian development, crucial for imprinting and plays a role in maintaining genomic stability. DNA methylation patterns are susceptible to change in response to environmental stimuli such as diet or toxins, whereby the epigenome seems to be most vulnerable during early life. Changes of DNA methylation levels and patterns have been widely studied in several diseases, especially cancer, where interest has focused on biomarkers for early detection of cancer development, accurate diagnosis, and response to treatment, but have also been shown to occur in many other complex diseases. Recent advances in epigenome engineering technologies allow now for the large-scale assessment of the functional relevance of DNA methylation. As a stable nucleic acid-based modification that is technically easy to handle and which can be analyzed with great reproducibility and accuracy by different laboratories, DNA methylation is a promising biomarker for many applications.
To date, the impact of the evo-devo “revolution” has been almost entirely restricted to the morphological domain—discussions of the role of contingency and development in the evolution of morphological traits being commonplace. In contrast, very little attention has been paid to contingency and development in the evolution of behavioural traits. This observation leads one to ask if there is any in-principle reason why this is the case. In this chapter, I respond to this question by motivating the application of the conceptual toolkit from evo-devo to the behavioural domain. I argue that there is evidence from inheritance of behaviour through social learning that demonstrates that development plays an important causal role in the evolution of behavioural traits. Furthermore, this evidence is as strong as, if not stronger than, analogous evidence used to motivate the evo-devo approach in the morphological domain. On these grounds, we should be just as willing to engage in the evo-devo research program when considering the evolution of behavioural traits as we are when considering the evolution of morphological traits.
Plants undergo various epigenetic modifications throughout their lifespan, directly affecting gene expression in the current and subsequent generation. Plant epigenetic changes include DNA methylation and histone modification. Non-coding RNA activity has also been shown to play an important role in regulating translation and transcription. In plants, epigenetic changes are involved in regulating many biological phenomena, including silencing of transgenes and transposons, regulation of imprinting, and development. In this chapter, molecular mechanisms of epigenetic modification and transgenerational inheritance of epigenetic marks in plants are reviewed. Recent reports of biotic or abiotic stress-induced transgenerational epigenetic inheritance are presented, and epigenetic inheritance mediated by small molecules are discussed.
The realization that epigenetic changes caused by extrinsic factors can be transmitted from an exposed founder to its progeny and subsequent generations in a wide range of taxons has generated great interest and debate. Such inherited changes may reflect much broader adjustments in phenotype that permit species to adapt to environment changes without altering their genetic blueprint. The phenomenon is often called transgenerational transmission, although the term is often inappropriately used, particularly in mammals. While such inheritance has been inferred to occur in humans, proving that it does so is impractical. Accordingly, most studies have been performed in animal models, particularly rodents. However, the case for epigenetic inheritance has only rarely been proven. Many studies have failed to follow descendants for the required number of generations to ensure effects are not manifested by direct encounter with germlines of F1 and F2 offspring. Mode of inheritance, whether through the female of male germline, has not usually been established, and, in general, we are far from understanding what groups of genes are affected. What is most lacking is a feasible mechanism for explaining the perpetuated response. Although altered gene expression in descendants is often associated with altered chromatin states, DNA methylation or histone protein modifications, this begs the question of how this information is passed through the germline and directed to re-occur in descendants. Most likely candidates for ensuring cross-generational transmission are RNA molecules that can bind DNA of particular target genes sequences and direct necessary chromatin structure changes to affect gene expression.
Alga is an informal name that refers to a diverse group of photosynthetic eukaryotes that have a polyphyletic origin in the tree of life. Although genomics has provided powerful tools for understanding the evolution of algal photosynthesis many issues remain unresolved. These include explaining the intermingling of plastid-lacking taxa such as ciliates and oomycetes among plastid-containing groups of chromalveolates. Does this pattern reflect a single ancient endosymbiosis in the chromalveolate ancestor followed by independent plastid losses or multiple secondary endosymbioses? Here we review current knowledge about chromalveolate evolution and phylogeny with a focus on secondary and tertiary endosymbiosis and survey recent genome-wide analyses to assess the potentially broad and lasting impacts of plastid transfer on eukaryote evolution. We assess the evidence for ‘footprints’ of photosynthetic pasts that remain even when the plastid is lost. These data comprise remnant algal genes in the nucleus of plastid-lacking taxa that have putatively originated via intracellular gene transfer from the former endosymbiont. We also provide a survey of recent work done in the field of protein import (i.e., via translocons) into chromalveolate and other plastids derived from secondary endoysmbiosis. We contrast the similarities and differences between primary and secondary plastid protein import machineries and speculate on the key innovations that led to their establishment. And finally, we take a careful look at the remarkable case of sea slug (Elysia chlorotica) kleptoplasty and photosynthesis and review recent work aimed at explaining this phenomenon in different metazoa. In particular, we critically assess support for the hypothesis that sea slug photosynthesis is explained by massive horizontal gene transfer (HGT) from the genome of the captured alga.
The field of autonomous vehicle control (AVC) is a rapidly growing one which promises improved performance, autonomy, comfort and safety for future’s intelligent transportation systems (ITS). In this paper, the objective is to present and demonstrate a cognitive modular approach for adaptive cruise control of autonomous/driverless vehicles by exploiting similarities between signal processing mechanisms and system architectures in control systems and the animal brain. To demonstrate the effectiveness of the proposed cognitive cruise control approach, numerical results from a case study with a realistic vehicle model is provided in this paper.
Genomic imprinting is a parent-of-origin phenomenon whereby gene expression is restricted to the allele inherited from either the maternal or paternal parent. It has been described from flowering plants and eutherian mammals and may have evolved due to parental conflicts over resource allocation. In mammals, imprinted genes are responsible for ensuring correct rates of embryo development and for preventing parthenogenesis. The molecular basis of imprinting depends upon the presence of differential epigenetic marks on the alleles inherited from each parent, although in plants the exact mechanisms that control imprinting are still unclear in many cases. Recent studies have identified large numbers of candidate imprinted genes from Arabidopsis thaliana and other plants (see Chap. 7 by Köhler and colleagues elsewhere in this volume) providing the tools for more thorough investigation into how imprinted gene networks (IGNs) are regulated. Analysis of genomic imprinting in animals has revealed important information on how IGNs are regulated during development, which often involves intermediate levels of imprinting. In some instances, small but significant changes in the degree of parental bias in gene expression have been linked to developmental traits, livestock phenotypes, and human disease. As some of the imprinted genes recently reported from plants show differential rather than complete (binary) imprinting, there is a clear need for tools that can quantify the degree of allelic expression bias occurring at a transcribed locus. In this chapter, we describe the use of Quantification of Allele-Specific Expression by Pyrosequencing(®) (QUASEP) as a tool suitable for this challenge. We describe in detail the factors which ensure that a Pyrosequencing(®) assay will be suitable for giving robust QUASEP and the problems which may be encountered during the study of imprinted genes by Pyrosequencing(®), with particular reference to our work in A. thaliana and in cattle. We also discuss some considerations with respect to the statistical analysis of the resulting data. Finally, we provide a brief overview of the future possibility of adapting Pyrosequencing(®) for analyzing other aspects of imprinting including the analysis of methylated regions.
The understanding of epigenetic mechanisms is necessary for assessing the potential impacts of epigenetics on plant growth, development and reproduction, and ultimately for the response of these factors to evolutionary pressures and crop breeding programs. This volume highlights the latest in laboratory and bioinformatic techniques used for the investigation of epigenetic phenomena in plants. Such techniques now allow genome-wide analyses of epigenetic regulation and help to advance our understanding of how epigenetic regulatory mechanisms affect cellular and genome function. To set the scene, we begin with a short background of how the field of epigenetics has evolved, with a particular focus on plant epigenetics. We consider what has historically been understood by the term "epigenetics" before turning to the advances in biochemistry, molecular biology, and genetics which have led to current-day definitions of the term. Following this, we pay attention to key discoveries in the field of epigenetics that have emerged from the study of unusual and enigmatic phenomena in plants. Many of these phenomena have involved cases of non-Mendelian inheritance and have often been dismissed as mere curiosities prior to the elucidation of their molecular mechanisms. In the penultimate section, consideration is given to how advances in molecular techniques are opening the doors to a more comprehensive understanding of epigenetic phenomena in plants. We conclude by assessing some opportunities, challenges, and techniques for epigenetic research in both model and non-model plants, in particular for advancing understanding of the regulation of genome function by epigenetic mechanisms.
A recent study by Greer et al. in the nematode C. elegans has shown transgenerational epigenetic inheritance of longevity in the descendants of worms deficient for subunits of a complex responsible for histone H3 lysine 4 trimethylation (H3K4me3). In this commentary, we discuss the implications of this epigenetic memory of longevity and the potential mechanisms underlying this phenomenon. The transgenerational inheritance of longevity could result from heritable depletion of H3K4me3 at particular aging-regulating gene loci that would only be progressively replenished. The epigenetic memory of longevity could also be explained by the transgenerational transmission of other molecules, for example other proteins or non-coding RNAs. The discovery of an epigenetic memory of longevity in worms raises the intriguing possibility that environmental cues modulating longevity in ancestors might affect subsequent generations in a non-Mendelian manner. Another remaining intriguing question is whether transgenerational inheritance of longevity also exists in other species, including mammals.
Women hold political beliefs that differ systematically from those of men, a phenomenon scholars call “gender gaps.” The collective opinions of women tend to favor social welfare policies and spending on these policies. Far from being inconsequential, empirical research indicates that these gender gaps in political preferences create gender gaps in vote choice and party identification. Yet despite the political importance of gender gaps in political preferences, scholars still have much to learn about how these gaps have changed over time and what factors may increase the size of these gaps. I use the 2008 American National Election Studies and the 2000 and 2004 National Annenberg Election Studies data to explore the origins of gender gaps in an area in which gaps have been increasing over time: social policy. I test hypotheses drawn from fields such as evolutionary biology, political science, psychology, and sociology. The results provide evidence that feminist consciousness, gender role socialization, and political knowledge play the greatest role in the formation of gender gaps on questions about social policy.
La compréhension de l’hérédité a considérablement progressé ces 20 dernières années. L’étude des maladies monogéniques a fortement contribué à nous éclairer sur le fonctionnement des gènes et le récent décryptage du génome humain sur son organisation. Les connaissances ont évolué et modifié notre vision de l’hérédité : à l’heure actuelle, les lois de Mendel appliquées aux maladies monogéniques ne suffisent plus à expliquer la transmission de nos caractères. Les régulations du génome et ses interactions, y compris l’impact de l’environnement, démontrent la complexité de la transmission de nos traits et les modulations précises à la fois acquises et héréditaires qui en résultent pour chaque individu. Par ailleurs, la génétique humaine est insuffisamment connue des médecins et biologistes et n’a pas une place suffisante dans l’enseignement médical. Cet article a pour objectif non pas de décrire les pathologies héréditaires mais de rappeler quelques notions essentielles des mécanismes de transmission. La génétique ayant une place de plus en plus importante en médecine, il nous semble important de connaître ces principes, les consultants étant amenés à poser des questions au médecin non spécialiste et le médecin ou le biologiste confrontés de plus en plus à ces questions se trouvent fréquemment dans la difficulté pour y répondre.
It is worthy to supplement Charney with two historical issues: (1) There were two rival trends in the rebirth of genetic thought in the 1960s: the universal and the variation related. This traditional duality suggested that heredity cannot be equated with genetic determinism. (2) The classical debates and reinterpretation of adoption/twin studies in the 1980s regarding intelligence suggested that the environment had a more active role in unfolding the genetic program.
Traditional lay perceptions of genetics are plagued with essentialist biases leading to some unfortunate consequences. Changes in the scientific understanding of heredity in general, and in genotype-phenotype relationships more specifically, provide a vital basis for shifting public understanding of genetics. Facilitating postgenomic literacy among the public has the potential to have translational implications in diminishing deleterious attitudes, beliefs, and behaviors.
Complex silencing mechanisms in plants and other kingdoms target transposons, repeat sequences, invasive viral nucleic acids and transgenes, but also endogenous genes and genes involved in paramutation. Paramutation occurs in a heterozygote when a transcriptionally active allele heritably adopts the epigenetic state of a transcriptionally and/or post-transcriptionally repressed allele. P1-rr and its silenced epiallele P1-pr, which encode a Myb-like transcription factor mediating pigmentation in floral organs of Zea mays, differ in their cytosine methylation pattern and chromatin structure at a complex enhancer site. Here, we tested whether P1-pr is able to heritably silence its transcriptionally active P1-rr allele in a heterozygote and whether DNA methylation is associated with the establishment and maintenance of P1-rr silencing. We found that P1-pr participates in paramutation as the repressing allele and P1-rr as the sensitive allele. Silencing of P1-rr is highly variable compared to the inducing P1-pr resulting in a wide range of gene expression. Whereas cytosine methylation at P1-rr is negatively correlated with transcription and pigment levels after segregation of P1-pr, methylation lags behind the establishment of the repressed p1 gene expression. We propose a model in which P1-pr paramutation is triggered by changing epigenetic states of transposons immediately adjacent to a P1-rr enhancer sequence. Considering the vast amount of transposable elements in the maize genome close to regulatory elements of genes, numerous loci could undergo paramutation-induced allele silencing, which could also have a significant impact on breeding agronomically important traits.
Background
Gene Regulation and EpigeneticsTrans-Generational Epigenetic TransmissionImplications and Conclusions
References
In the mouse, the Kit receptor and its ligand, the stem cell factor (SCF), are encoded at the W/Kit and Steel loci, respectively. The Kit/SCF transduction pathway is involved in promoting cellular migration, proliferation and/or survival of melanoblasts, hematopoietic progenitors and primordial germ cells. Furthermore, a functional Kit/SCF pathway is required for the development of interstitial cells of Cajal (ICC) in the small intestine. Whereas all c-kit-expressing cells in embryogenesis were not identified, previous studies clearly demonstrated that the c-kit expression pattern extends well beyond cells known to be affected by W mutations. To investigate further Kit function, we specifically marked the c-kit-expressing cells and followed their fate during embryogenesis. A mutation was introduced by gene targeting at the W/Kit locus in mouse embryonic stem cells. The lacZ reporter gene was inserted into the first exon of c-kit, thus creating a null allele, called WlacZ.
The lacZ expression reflects normal expression of the c-kit gene in WlacZ/+ embryos. The comparison of the patterns of lacZ-expressing cells between WlacZ/+ and WlacZ/WlacZ embryos allowed us to detect where and when melanoblasts, primordial germ cells and hematopoietic progenitors failed to survive in the absence of Kit. We also observed that ICC express c-kit during embryogenesis. ICC are found identically in WlacZ/+ and WlacZ/WlacZ embryos. Therefore, ICC do not depend on Kit expression during embryogenesis. These results indicate that the function of the c-kit gene is only required for the postnatal development of the ICC.
Unexpected sites of c-kit expression were uncovered in embryos, including endothelial, epithelial and endocrine cells. None of these cells are dependent on Kit expression for their migration, proliferation and/or survival during embryogenesis. Nevertheless, we assume that the Kit/SCF pathway could be involved in the growth of transformed endothelial, epithelial and endocrine cells.
High efficiencies of recombination between LoxP elements were initially recorded when the Cre recombinase was expressed in meiotic spermatocytes. However, it was unexpectedly found that LoxP recombination fell to very low values at the second generation of mice expressing Cre during meiosis. The inability of the LoxP elements to serve as recombination substrates was correlated with cytosine methylation, initially in LoxP and transgene sequences, but later extending for distances of at least several kilobases into chromosomal sequences. It also affected the allelic locus, implying a transfer of structural information between alleles similar to the transvection phenomenon described in Drosophila. Once initiated following Cre-LoxP interaction, neither cis-extension nor transvection of the methylated state required the continuous expression of Cre, as they occurred both in germinal and somatic cells and in the fraction of the offspring that had not inherited the Sycp1-Cre transgene. Therefore, these processes depend on a physiological mechanism of establishment and extension of an epigenetic state, for which they provide an experimental model.
Hypertrophic growth is a risk factor for mortality in heart diseases. Mechanisms are lacking for this global increase in RNA and protein per cell, which underlies hypertrophy. Hypertrophic signals cause phosphorylation of the RNA polymerase II C-terminal domain, required for transcript elongation. RNA polymerase II kinases include cyclin-dependent kinases-7 (Cdk7) and Cdk9, components of two basal transcription factors. We report activation of Cdk7 and -9 in hypertrophy triggered by signaling proteins (Galphaq, calcineurin) or chronic mechanical stress. Only Cdk9 was activated by acute load or, in culture, by endothelin. A preferential role for Cdk9 was shown in RNA polymerase II phosphorylation and growth induced by endothelin, using pharmacological and dominant-negative inhibitors. All four hypertrophic signals dissociated 7SK small nuclear RNA, an endogenous inhibitor, from cyclin T-Cdk9. Cdk9 was limiting for cardiac growth, shown by suppressing its inhibitor (7SK) in culture and preventing downregulation of its activator (cyclin T1) in mouse myocardium.Note: In the AOP version of this article, the numbering of the author affiliations was incorrect. This has now been fixed, and the affiliations appear correctly online and in print.
In mammals, imprinted genes have parent-of-origin-specific patterns of DNA methylation that cause allele-specific expression. At Rasgrf1 (encoding RAS protein-specific guanine nucleotide-releasing factor 1), a repeated DNA element is needed to establish methylation and expression of the active paternal allele. At Igf2r (encoding insulin-like growth factor 2 receptor), a sequence called region 2 is needed for methylation of the active maternal allele. Here we show that replacing the Rasgrf1 repeats on the paternal allele with region 2 allows both methylation and expression of the paternal copy of Rasgrf1, indicating that sequences that control methylation can function ectopically. Paternal transmission of the mutated allele also induced methylation and expression in trans of the normally unmethylated and silent wild-type maternal allele. Once activated, the wild-type maternal Rasgrf1 allele maintained its activated state in the next generation independently of the paternal allele. These results recapitulate in mice several features in common with paramutation described in plants.
Paramutation is a widespread epigenetic phenomenon that was first described in pea and then extensively studied in maize, whereby combining two specific alleles results in a heritable change in the expression of one of the alleles. Far from being restricted to endogenous plant genes, paramutation-like interactions have been described in several kingdoms, in which they can occur between homologous transgenes or between transgenes and homologous endogenous genes at allelic or non-allelic positions. In this review, we discuss potential mechanisms underlying paramutation, compare paramutation to several other trans-sensing phenomena, and speculate on the potential roles and evolutionary implications of these intriguing homology-sensing mechanisms.
Transgenerational effects of maternal nutrition or other environmental 'exposures' are well recognised, but the possibility of exposure in the male influencing development and health in the next generation(s) is rarely considered. However, historical associations of longevity with paternal ancestors' food supply in the slow growth period (SGP) in mid childhood have been reported. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we identified 166 fathers who reported starting smoking before age 11 years and compared the growth of their offspring with those with a later paternal onset of smoking, after correcting for confounders. We analysed food supply effects on offspring and grandchild mortality risk ratios (RR) using 303 probands and their 1818 parents and grandparents from the 1890, 1905 and 1920 Overkalix cohorts, northern Sweden. After appropriate adjustment, early paternal smoking is associated with greater body mass index (BMI) at 9 years in sons, but not daughters. Sex-specific effects were also shown in the Overkalix data; paternal grandfather's food supply was only linked to the mortality RR of grandsons, while paternal grandmother's food supply was only associated with the granddaughters' mortality RR. These transgenerational effects were observed with exposure during the SGP (both grandparents) or fetal/infant life (grandmothers) but not during either grandparent's puberty. We conclude that sex-specific, male-line transgenerational responses exist in humans and hypothesise that these transmissions are mediated by the sex chromosomes, X and Y. Such responses add an entirely new dimension to the study of gene-environment interactions in development and health.
There is increasing evidence in both plants and animals that epigenetic marks are not always cleared between generations. Incomplete erasure at genes associated with a measurable phenotype results in unusual patterns of inheritance from one generation to the next, termed transgenerational epigenetic inheritance. The Agouti viable yellow (A(vy)) allele is the best-studied example of this phenomenon in mice. The A(vy) allele is the result of a retrotransposon insertion upstream of the Agouti gene. Expression at this locus is controlled by the long terminal repeat (LTR) of the retrotransposon, and expression results in a yellow coat and correlates with hypomethylation of the LTR. Isogenic mice display variable expressivity, resulting in mice with a range of coat colours, from yellow through to agouti. Agouti mice have a methylated LTR. The locus displays epigenetic inheritance following maternal but not paternal transmission; yellow mothers produce more yellow offspring than agouti mothers. We have analysed the DNA methylation in mature gametes, zygotes, and blastocysts and found that the paternally and maternally inherited alleles are treated differently. The paternally inherited allele is demethylated rapidly, and the maternal allele is demethylated more slowly, in a manner similar to that of nonimprinted single-copy genes. Interestingly, following maternal transmission of the allele, there is no DNA methylation in the blastocyst, suggesting that DNA methylation is not the inherited mark. We have independent support for this conclusion from studies that do not involve direct analysis of DNA methylation. Haplo-insufficiency for Mel18, a polycomb group protein, introduces epigenetic inheritance at a paternally derived A(vy) allele, and the pedigrees reveal that this occurs after zygotic genome activation and, therefore, despite the rapid demethylation of the locus.
Paramutation is a heritable epigenetic modification induced in plants by cross-talk between allelic loci. Here we report a similar modification of the mouse Kit gene in the progeny of heterozygotes with the null mutant Kit(tm1Alf) (a lacZ insertion). In spite of a homozygous wild-type genotype, their offspring maintain, to a variable extent, the white spots characteristic of Kit mutant animals. Efficiently inherited from either male or female parents, the modified phenotype results from a decrease in Kit messenger RNA levels with the accumulation of non-polyadenylated RNA molecules of abnormal sizes. Sustained transcriptional activity at the postmeiotic stages--at which time the gene is normally silent--leads to the accumulation of RNA in spermatozoa. Microinjection into fertilized eggs either of total RNA from Kit(tm1Alf/+) heterozygotes or of Kit-specific microRNAs induced a heritable white tail phenotype. Our results identify an unexpected mode of epigenetic inheritance associated with the zygotic transfer of RNA molecules.
In female mammals, one of the two X chromosomes is converted from the active euchromatic state into inactive heterochromatin during early embryonic development. This process, known as X-chromosome inactivation, results in the transcriptional silencing of over a thousand genes and ensures dosage compensation between the sexes. Here, we discuss the possible mechanisms of action of the Xist transcript, a remarkable noncoding RNA that triggers the X-inactivation process and also seems to participate in setting up the epigenetic marks that provide the cellular memory of the inactive state. So far, no functional protein partners have been identified for Xist RNA, but different lines of evidence suggest that it may act at multiple levels, including nuclear compartmentalization, chromatin modulation, and recruitment of Polycomb group proteins.
Site-specific methylation of cytosines is a key epigenetic mark of vertebrate DNA. While a majority of the methylated residues are in the symmetrical (meC)pG:Gp(meC) configuration, a smaller, but significant fraction is found in the CpA, CpT and CpC asymmetric (non-CpG) dinucleotides. CpG methylation is reproducibly maintained by the activity of the DNA methyltransferase 1 (Dnmt1) on the newly replicated hemimethylated substrates (meC)pG:GpC. On the other hand, establishment and hereditary maintenance of non-CpG methylation patterns have not been analyzed in detail. We previously reported the occurrence of site- and allele-specific methylation at both CpG and non-CpG sites. Here we characterize a hereditary complex of non-CpG methylation, with the transgenerational maintenance of three distinct profiles in a constant ratio, associated with extensive CpG methylation. These observations raised the question of the signal leading to the maintenance of the pattern of asymmetric methylation. The complete non-CpG pattern was reinstated at each generation in spite of the fact that the majority of the sperm genomes contained either none or only one methylated non-CpG site. This observation led us to the hypothesis that the stable CpG patterns might act as blueprints for the maintenance of non-CpG DNA methylation. As predicted, non-CpG DNA methylation profiles were abrogated in a mutant lacking Dnmt1, the enzymes responsible for CpG methylation, but not in mutants defective for either Dnmt3a or Dnmt2.
The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.
The genetic and environmental components in 15 common cancers were estimated using the nationwide Swedish Family-Cancer Database. Tetrachoric correlations were used to describe similarity in cancer liability among family members. Structural equation modeling was used to derive estimates of the importance of genetic and environmental effects. Statistically significant estimates of proportion of cancer susceptibility, accounted for by genetic effects, were obtained for all studied cancers except for leukemia. The estimate was highest in thyroid cancer (53%), followed by tumors at endocrine glands (28%), testis (25%), breast (25%), cervix (22%), melanoma (21%), colon (13%), nervous system (12%), rectum (12%), non-Hodgkin lymphoma (10%), lung (8%), kidney (8%), urinary bladder (7%), stomach (1%) and leukemia (1%). The estimates of shared environmental effects ranged from 0% (cervix) to 15% (stomach). The childhood shared environmental effects were most important in testicular cancer (17%), stomach cancer (13%) and cervix in situ (13%). Our results indicate that environment has a principal causative role in cancer at all studied sites except for thyroid. The relatively large effect of heritability in cancer at some sites, on the other hand, indicates that even though susceptibility genes have been described at many cancer sites, they are likely to explain only part of the genetic effects.
Our increased knowledge of epigenetic reprogramming supports the idea that epigenetic marks are not always completely cleared between generations. Incomplete erasure at genes associated with a measurable phenotype can result in unusual patterns of inheritance from one generation to the next. It is also becoming clear that the establishment of epigenetic marks during development can be influenced by environmental factors. In combination, these two processes could provide a mechanism for a rapid form of adaptive evolution.
The majority of cellular and molecular andrologists endorse the view that the sperm is a vessel for transporting the paternal genome to the waiting egg and nothing more. Any requirement for additional spermatozoal components that enter the ooplasm apart from the paternal centriole and the soluble egg-activating factor is generally dismissed. Many studies, however, have reported RNAs in ejaculate spermatozoa and we now know that mRNAs are delivered to the egg on fertilisation. The function and utility of sperm mRNA remains essentially unexplored. Here, we examine the controversy surrounding spermatozoal mRNA carriage, the evidence refuting its presence as an artefact and how spermatozoal mRNA is leading us to suspect that, quite apart from its undoubted diagnostic potential, it might have an important role in the establishment and maintenance of a viable paternal genome.
Wild progeny from intercrosses of pyridoxine mutants have been found in tetrads showing irregular segregation of one or the other of the mutants. [1] These wild types therefore appear not to be true recombinants arising from crossing over between the mutant genes. Earlier, individuals of the genotypes expected to result from two- or three-strand double crossovers involving the regions adjacent to the locus of a pyridoxine mutant had been obtained with surprisingly high frequency from marked crosses between this mutant and its wild allele. [2] Since the frequency was very nearly that with which wild offspring were obtained from intercrosses, the possibility was considered that the apparent double-crossover recombinants might be due not to ordinary crossing over but to the mechanism which operates in the intercross. That these apparent recombinants also are found to accompany abnormal segregation is shown by the experiments reported here.
Paramutation is an allele-dependent transfer of epigenetic information, which results in the heritable silencing of one allele by another. Paramutation at the b1 locus in maize is mediated by unique tandem repeats that communicate in trans to establish and maintain meiotically heritable transcriptional silencing. The mop1 (mediator of paramutation1) gene is required for paramutation, and mop1 mutations reactivate silenced Mutator elements. Plants carrying mutations in the mop1 gene also stochastically exhibit pleiotropic developmental phenotypes. Here we report the map-based cloning of mop1, an RNA-dependent RNA polymerase gene (RDRP), most similar to the RDRP in plants that is associated with the production of short interfering RNA (siRNA) targeting chromatin. Nuclear run-on assays reveal that the tandem repeats required for b1 paramutation are transcribed from both strands, but siRNAs were not detected. We propose that the mop1 RDRP is required to maintain a threshold level of repeat RNA, which functions in trans to establish and maintain the heritable chromatin states associated with paramutation.
Noncoding RNA has long been proposed to control gene expression via sequence-specific interactions with regulatory regions. Here, we review the role of noncoding RNA in heterochromatic silencing and in the silencing of transposable elements (TEs), unpaired DNA in meiosis, and developmentally excised DNA. The role of cotranscriptional processing by RNA interference and by other mechanisms is discussed, as well as parallels with RNA silencing in imprinting, paramutation, polycomb silencing, and X inactivation. Interactions with regulatory sequences may well occur, but at the RNA rather than at the DNA level.
Paramutation is the epigenetic transfer of information from one allele of a gene to another to establish a state of gene expression that is heritable for generations. RNA has recently emerged as a prominent mediator of this remarkable phenomenon in both maize and mice.
Non-coding RNAs (ncRNAs) with gene regulatory functions are starting to be seen as a common feature of mammalian gene regulation with the discovery that most of the transcriptome is ncRNA. The prototype has long been the Xist ncRNA, which induces X-chromosome inactivation in female cells. However, a new paradigm is emerging--the silencing of imprinted gene clusters by long ncRNAs. Here, we review models by which imprinted ncRNAs could function. We argue that an Xist-like model is only one of many possible solutions and that imprinted ncRNAs could provide the better model for understanding the function of the new class of ncRNAs associated with non-imprinted mammalian genes.
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Chandler VL: Paramutation: RNA-mediated instructions passed across generations. Cell 2007, 23:641-645. The most recent review of the experimental evidences for RNA-mediated inheritance comparing the plant and the mouse systems.
Chromatin conversations: mechanisms and implications of paramutation
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Chandler VL, Stam M: Chromatin conversations: mechanisms and implications of paramutation. Nat Rev Genet 2004, 5:532-544.
Les phé nomè nes de barrage chez Podospora anserina
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The controversy, potential and roles of spermatozoal RNA An up-to-date summary of the observation of the human sperm RNA and speculations on its possible functions
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Miller D, Ostermeier GC, Krawetz SA: The controversy, potential and roles of spermatozoal RNA. Trends Mol Med 2005, 11:156-163. An up-to-date summary of the observation of the human sperm RNA and speculations on its possible functions.
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