Non-genetic Inheritance Research Articles

How stabilizing selection and nongenetic inheritance combine to shape the evolution of phenotypic plasticity.

Relatively little is known about whether and how nongenetic inheritance interacts with selection to impact the evolution of phenotypic plasticity. Here, we empirically evaluated how stabilizing selection and a common form of nongenetic inheritance-maternal environmental effects-jointly influence the evolution of phenotypic plasticity in natural populations of spadefoot toads. We compared populations that previous fieldwork has shown to have evolved conspicuous plasticity in resource-use phenotypes ("resource polyphenism") with those that, owing to stabilizing selection favouring a narrower range of such phenotypes, appear to have lost this plasticity. We show that: (a) this apparent loss of plasticity in nature reflects a condition-dependent maternal effect and not a genetic loss of plasticity, that is "genetic assimilation," and (b) this plasticity is not costly. By shielding noncostly plasticity from selection, nongenetic inheritance generally, and maternal effects specifically, can preclude genetic assimilation from occurring and consequently impede adaptive (genetic) evolution.

A quantitative genetic analysis of life-history traits and lifetime reproductive success in reintroduced Chinook salmon

Reintroductions are widely implemented as a means of reestablishing wild populations and genetic parentage methods can be used in concert with these efforts to monitor and evaluate efficacy. In addition to understanding demographic outcomes, reconstructed pedigrees, when combined with phenotypic data, can provide insight into the adaptive potential of reintroduced individuals. Here, we examined the heritability and evolvability of life-history traits and lifetime reproductive success in two threatened Chinook salmon populations undergoing reintroduction to historical habitats above dams in Oregon, USA, using previously-developed multigenerational genetic pedigrees. All of the examined life-history traits: length-at-maturity, age-at-maturity, and arrival timing to the spawning grounds, and lifetime reproductive success exhibited significant narrow-sense heritabilities and evolvabilities. There was also a detectable influence of parental effects (i.e., paternal or maternal effects) on life-history trait variation, suggesting that in addition to genetic effects, nongenetic inheritance mechanisms are influencing life-history diversity in the populations. Additionally, our analyses revealed evidence of natural selection on the date of reintroduction, although the form and intensity of selection differed between the two populations; the forms of selection also point to the potential for phenotype-environment mismatch under some conditions. Overall, our results suggest that these threatened Chinook salmon populations exhibit significant adaptive potential, a factor that should be important to the longer-term success of recovery efforts.

Oxidative Stress and Cancer.

Cancer is considered a major cause of death worldwide. The etiology of cancer is linked to environmental and genetic inheritance causes. Approximately 90 percent of all human cancers have an environmental cause (non-genetic inheritance) predominantly through lifestyle choices (smoking, diet, UV radiation) while the remaining due to infections and chemical exposure. Cancer is a multistage process that involves mutational changes and uncontrolled cell proliferation. Research has firmly established a causal and contributory role of oxidative stress and oxidative damage in cancer initiation and progression. The purpose of this article is to review the role that oxidative stress and reactive oxygen species play in the development of cancer. Both endogenous and exogenous sources of reactive oxygen species result in increased oxidative stress in the cell. Excess reactive oxygen fumed can result in damage to and modification of cellular macromolecules most importantly genomic DNA that can produce mutations. In addition, oxidative stress modulates gene expression of downstream targets involved in DNA repair, cell proliferation and antioxidants. The modulation of gene expression by oxidative stress occurs in part through activation or inhibition of transcription factors and second messengers. The role of single nuclear polymorphism for oxidative DNA repair and enzymatic antioxidants is important in determining the potential human cancer risk. oxidative stress and the resulting oxidative damage are important contributors to the formation and progression of cancer.

Non-genetic inheritance via the male germline in mammals.

Numerous studies in humans and in animal models have demonstrated that exposure to adverse environmental conditions in early life results in long-term structural and functional changes in an organism, increasing the risk of cardiometabolic, neurobehavioural and reproductive disorders in later life. Such effects are not limited to the first generation offspring but may be transmitted to a second or a number of subsequent generations, through non-genomic mechanisms. While the transmission of ‘programmed’ effects through the maternal line could occur as a consequence of multiple influences, for example, altered maternal physiology, the inheritance of effects through the male line is more difficult to explain and there is much interest in a potential role for transgenerational epigenetic inheritance. In this review, we will discuss the mechanisms by which induced effects may be transmitted through the paternal lineage, with a particular focus on the role of epigenetic inheritance.This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.

Nongenetic inheritance of increased Cd tolerance in a field Gammarus fossarum population: Parental exposure steers offspring sensitivity

While the phenomenon of increased population tolerance to environmental contaminants has been widely reported for aquatic animal species living in contaminated ecosystems, the question of the nature of the tolerance, i.e., genetic adaptation or phenotypic plasticity, has not yet been studied to the same degree and remains under debate when explaining the variability of toxicological sensitivity among field populations. The occurrence of both processes challenges the ecological risk assessment (ERA) of chemicals, questioning the relevance of toxicity assessment procedures based on bioassays employing organisms from naive reference populations. Nonetheless, given that genetic adaptation and phenotypic acclimation are based on different mechanisms, with different persistence periods over time when exposure is stopped, gaining insight into the mechanism of tolerance to contaminants of field populations is a major concern for ERA. In this context, this study aimed to test whether genetic adaptation underlies the tolerance to cadmium (Cd) in a field Gammarus fossarum population identified in a previous study. Breeding and exposure experiments conducted in laboratory conditions revealed that: (1) first and second cohorts of neonates produced from field-collected parents present an increased Cd tolerance, which is explained by a reduction of between-brood variability of Cd sensitivity with an absence of sensitive broods compared to two reference populations rather than by the existence of more tolerant individuals; and (2) Cd tolerance was no longer evident for broods of the third cohort produced by these breeders when maintained under Cd-free conditions in the laboratory. Hence, this study drew the striking conclusion that the observation of Cd tolerance inheritance within the field population studied does not demonstrate genetic adaptation, but it results from an effect of parental exposure inducing transgenerational plasticity, which deeply influences the variability of population sensitivity. To our knowledge, this study is only the second report of increased tolerance to contaminants in a field population explicitly attributed to the phenomenon of transgenerational acclimation.

Testing the generality of non-genetic inheritance.

A study in Cell examines the pervasiveness of a classic form of non-genetic inheritance involving transposable element DNA methylation in mice. It reports that non-genetic inheritance is likely to be the exception rather than the rule across other loci genome-wide.

Les troubles psychiques, conséquences d’un traumatisme vécu et/ou hérité ? Regard critique sur les recherches chez l’homme s’intéressant aux facteurs transgénérationnels.

The last quarter-century has witnessed a growing interest into attempts to identify determinants in the aetiologies of mental disorders. Evidence indicates complex aetiologies involving numerous (and interacting) genetic and environmental factors. Findings from empirical investigations relying on surrogate measures of genetic risk (i.e., family history of mental disorders) and aggregate heritability (i.e., twin pairs) argued for a strong influence of heritable components/genetic vulnerability. First attempts to obtain evidence from studies making use of molecular genetics sparked excitement in the scientific community. Initially, the field generated a bulk of largely irreproducible results, furthermore occluded by selective reporting of positive findings and lack of replication attempts with adequate power. These early difficulties gave rise to unprecedented collaboration and replicable findings in the area of psychiatric genetics. Epidemiological research into environmental factors in psychiatry has yielded consistent findings over decades, and identified several (proxy) environmental risk factors associated with mental disorders. These comprise childhood trauma, immigration and minority status, urbanicity, cannabis use, and obstetric and pregnancy complications. Although the effects of these risk factors may be genetically confounded to a degree, evidence from controlled studies suggests that a substantial part is environmental. Recent evidence from a range of animal studies has indicated that non-genetic inheritance of the influence of traumatic stress may co-determine variability in functional abilities of the brain and in behavioural profiles of offspring. While this concept has great potential for psychiatry as well as the broader fields of medicine and society, actual studying non-genetic inheritance in humans is very challenging and filled with potential pitfalls. The presentation will cover the complex aetiologies of mental disorders and provide a critical overview of first human studies on transgenerational inheritance, with a focus on the relation between trauma and health.

Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance

SummaryGenerally repressed by epigenetic mechanisms, retrotransposons represent around 40% of the murine genome. At the Agouti viable yellow (Avy) locus, an endogenous retrovirus (ERV) of the intracisternal A particle (IAP) class retrotransposed upstream of the agouti coat-color locus, providing an alternative promoter that is variably DNA methylated in genetically identical individuals. This results in variable expressivity of coat color that is inherited transgenerationally. Here, a systematic genome-wide screen identifies multiple C57BL/6J murine IAPs with Avy epigenetic properties. Each exhibits a stable methylation state within an individual but varies between individuals. Only in rare instances do they act as promoters controlling adjacent gene expression. Their methylation state is locus-specific within an individual, and their flanking regions are enriched for CTCF. Variably methylated IAPs are reprogrammed after fertilization and re-established as variable loci in the next generation, indicating reconstruction of metastable epigenetic states and challenging the generalizability of non-genetic inheritance at these regions.

Diplogastrellus nematodes are sexually transmitted mutualists that alter the bacterial and fungal communities of their beetle host

A recent accumulation of studies has demonstrated that nongenetic, maternally transmitted factors are often critical to the health and development of offspring and can therefore play a role in ecological and evolutionary processes. In particular, microorganisms such as bacteria have been championed as heritable, symbiotic partners capable of conferring fitness benefits to their hosts. At the same time, parents may also pass various nonmicrobial organisms to their offspring, yet the roles of such organisms in shaping the developmental environment of their hosts remain largely unexplored. Here, we show that the nematode Diplogastrellus monhysteroides is transgenerationally inherited and sexually transmitted by the dung beetle Onthophagus taurus By manipulating artificial chambers in which beetle offspring develop, we demonstrate that the presence of D. monhysteroides nematodes enhances the growth of beetle offspring, empirically challenging the paradigm that nematodes are merely commensal or even detrimental to their insect hosts. Finally, our research presents a compelling mechanism whereby the nematodes influence the health of beetle larvae: D. monhysteroides nematodes engineer the bacterial and fungal communities that also inhabit the beetle developmental chambers, including specific taxa known to be involved in biomass degradation, possibly allowing larval beetles better access to their otherwise recalcitrant, plant-based diet. Thus, our findings illustrate that nongenetic inheritance can include intermediately sized organisms that live and proliferate in close association with, and in certain cases enhance, the development of their hosts' offspring.

Lineage space and the propensity of bacterial cells to undergo growth transitions.

The molecular makeup of the offspring of a dividing cell gradually becomes phenotypically decorrelated from the parent cell by noise and regulatory mechanisms that amplify phenotypic heterogeneity. Such regulatory mechanisms form networks that contain thresholds between phenotypes. Populations of cells can be poised near the threshold so that a subset of the population probabilistically undergoes the phenotypic transition. We sought to characterize the diversity of bacterial populations around a growth-modulating threshold via analysis of the effect of non-genetic inheritance, similar to conditions that create antibiotic-tolerant persister cells and other examples of bet hedging. Using simulations and experimental lineage data in Escherichia coli, we present evidence that regulation of growth amplifies the dependence of growth arrest on cellular lineage, causing clusters of related cells undergo growth arrest in certain conditions. Our simulations predict that lineage correlations and the sensitivity of growth to changes in toxin levels coincide in a critical regime. Below the critical regime, the sizes of related growth arrested clusters are distributed exponentially, while in the critical regime clusters sizes are more likely to become large. Furthermore, phenotypic diversity can be nearly as high as possible near the critical regime, but for most parameter values it falls far below the theoretical limit. We conclude that lineage information is indispensable for understanding regulation of cellular growth.

Cocaine alters the mouse testicular epigenome with direct impact on histone acetylation and DNA methylation marks.

Recent evidence suggests that cocaine administration in animal models can trigger non-genetic inheritance of addiction traits from father to offspring, affecting development and behaviour. Is chronic cocaine intake involved in alterations of epigenetic homeostasis in the testis? Epigenetic marks and mediators in testis and isolated germ cells of adult mice treated with cocaine (10mg/kg) or vehicle (sterile saline solution) were evaluated in an intermittent binge protocol: three intraperitoneal injections, 1h apart, one day on/off for 13 days, collecting tissue 24h after the last binge administration (day 14). It was shown that chronic cocaine intake in mice disrupts testicular epigenetic homeostasis, increasing global methylated cytosine levels in DNA from germ cells and sperm. Cocaine also increased testicular and germ cell acetylated histone 3 and 4 and decreased expression of histone deacetylases HDAC1/2. Immunolocalization studies showed that HDAC1/2 and acetylated histone 3 and 4 proteins localize to meiotic germ cells. Analysis of mRNA expression in isolated germ cells shows decreased levels of Hdac1/2/8, Dnmt3b and Tet1 and increased levels of Dnmt3a gene expression after cocaine treatment. Cocaine intake is associated with testicular toxicity and significant reproductive function impairment. The results presented here broaden the basic knowledge of the impact of addictive stimulants on testicular pathophysiology, fertility and male reproductive health and imply that altered epigenetic homeostasis by cocaine may have potential consequences on future generations.

Paternal line effects of early experiences persist across three generations in rhesus macaques.

The effects of early stress may not be limited to the exposed generation, but are sometimes passed on to subsequent generations. Such non-genetic transgenerational inheritance is a potentially important developmental and evolutionary force. We compared the transgenerational effects of maternal and paternal line early stress on anxiety- and health-related traits in three non-exposed generations (F1, F2 and F3) of semi-naturalistically raised rhesus macaques. As infants, F0 macaques were exposed to nursery rearing (NR) or semi-naturalistic social conditions (CONTROL). Three hundred forty non-exposed F1-F3 descendants were CONTROL reared and physiological and behavioral measures were collected during standardized assessment at 3-4months of age. Paternal line NR was significantly associated with greater nervousness in F1-F3 and lower immune cell counts in F1-F2. Maternal-line NR effects were not observed. This study suggests that acquired stress-related traits may be "inherited" across generations in primates, through complex social or germ-line mechanisms.

Evolution without standing genetic variation: change in transgenerational plastic response under persistent predation pressure.

Transgenerational phenotypic plasticity is a fast non-genetic response to environmental modifications that can buffer the effects of environmental stresses on populations. However, little is known about the evolution of plasticity in the absence of standing genetic variation although several non-genetic inheritance mechanisms have now been identified. Here we monitored the pea aphid transgenerational phenotypic response to ladybird predators (production of winged offspring) during 27 generations of experimental evolution in the absence of initial genetic variation (clonal multiplication starting from a single individual). We found that the frequency of winged aphids first increased rapidly in response to predators and then remained stable over 25 generations, implying a stable phenotypic reconstruction at each generation. We also found that the high frequency of winged aphids persisted for one generation after removing predators. Winged aphid frequency then entered a refractory phase during which it dropped below the level of control lines for at least two generations before returning to it. Interestingly, the persistence of the winged phenotype decreased and the refractory phase lasted longer with the increasing number of generations of exposure to predators. Finally, we found that aphids continuously exposed to predators for 22 generations evolved a significantly weaker plastic response than aphids never exposed to predators, which, in turn, increased their fitness in presence of predators. Our findings therefore showcased an example of experimental evolution of plasticity in the absence of initial genetic variation and highlight the importance of integrating several components of non-genetic inheritance to detect evolutionary responses to environmental changes.

Beyond epigenetics Extended Heredity: A New Understanding of Inheritance and Evolution Russell Bonduriansky and Troy Day Princeton University Press, 2018. 302 pp.

A pair of evolutionary biologists takes a closer look at nongenetic inheritance

Parental phenotype not predator cues influence egg warning coloration and defence levels

In species that advertise their toxicity to predators through visual signals, there is considerable variation among individuals in both signal appearance and levels of defence. Parental effects, a type of nongenetic inheritance, may play a key role in creating and maintaining this within-species diversity in aposematic signals; however, a comprehensive test of this notion is lacking. Using the ladybird Adalia bipunctata, we assessed how egg coloration and defence level (concentration of the toxic alkaloid (-)-adaline) is influenced both by simulated predation risk in the egg-laying environment and by parental phenotype (coloration and toxin level). We found that egg toxin level and colour were predicted by parental phenotype but were not altered in response to cues of egg predators. Egg luminance (lightness) was positively correlated with paternal elytral luminance, while maternal toxin level positively predicted egg toxin level. In response to egg predator cues, ladybird mothers altered the timing of laying and total egg number, but not egg toxin level or colour. It appears therefore that in A. bipunctata variation between individuals of the same morph in the colour and toxin level of the eggs they lay, that is, egg aposematic phenotype, is more strongly influenced by individual variation in parental aposematic traits than by environmental cues of egg predation risk. Furthermore, these results provide the first indication that, in a warningly coloured species, male coloration may play a dual role as predator deterrent and indicator of paternal quality, influencing maternal investment in offspring.

Dairy cows - an opportunity in the research field of non-genetic inheritance?

More than 1 billion cattle are raised annually for meat and milk production. Dairy cows are repeatedly impregnated and separated from their calves, usually within the first 24 h after birth. Here, I suggest that dairy cows undergo a procedure comparable to the ‘Maternal separation combined with unpredictable maternal stress’ paradigm (MSUS), which is used to study the non-genetic inheritance (NGI) of phenotypes in rodents. I discuss what research on dairy cows may bring to the research field of NGI. The resulting research findings are likely to have benefits to our understanding of MSUS, NGI and consumer safety.

Superior stimulation of female fecundity by subordinate males provides a mechanism for telegony.

When females mate promiscuously, rival males compete to fertilise the ova. In theory, a male can increase his success at siring offspring by inducing the female to lay more eggs, as well as by producing more competitive sperm. Here we report that the evolutionary consequences of fecundity stimulation extend beyond rival males, by experimentally uncovering effects on offspring. With experiments on the burying beetle Nicrophorus vespilloides, we show that smaller subordinate males are better able to stimulate female fecundity than larger, dominant males. Furthermore dominant males also benefit from the greater fecundity induced by smaller males, and so gain from the female's earlier promiscuity ‐ just as predicted by theory. By inducing females to produce more offspring on a limited resource, smaller males cause each larva to be smaller, even those they do not sire themselves. Fecundity stimulation thus promotes the non‐genetic inheritance of offspring body size, and provides a mechanism for telegony.

Bugs in the program: can pregnancy drugs and smoking disturb molecular reprogramming of the fetal germline, increasing heritable risk for autism and neurodevelopmental disorders?

In a seeming paradox, the prevalence of autism spectrum disorder (ASD) has surged, while at the same time research has pointed to the strong heritability of this neurodevelopmental pathology. Here an autism research philanthropist suggests a biological phenomenon of exogenously induced ‘gamete disruption’ that could reconcile these seemingly contradictory observations. Mining information from her own family history and that of her fellow autism parents, while also engaging with the scientific community, she proposes that a subset of the autisms may be rooted in a variety of molecular glitches in parental gametes induced by certain acute exposures during the parents’ own fetal or neonatal development. These exposures include but are not limited to synthetic hormone drugs, tobacco, and general anesthesia. Consistent with this hypothesis, animal models have demonstrated adverse neurobehavioral outcomes in grandoffspring of gestating dams exposed to hormone-disrupting compounds, tobacco components, and general anesthesia. A recent epidemiological study showed a link between grandmaternal smoking and risk for ASD in grandoffspring through the maternal line. Given the urgency of the autism crisis, combined with the biological plausibility of this mostly unexplored paradigm, the writer contends that questions of nongenetic inheritance should be a priority in autism research.

POHaD: why we should study future fathers.

The growing field of ‘Developmental Origin of Health and Disease’ (DOHaD) generally reflects environmental influences from mother to child. The importance of maternal lifestyle, diet and other environmental exposures before and during gestation period is well recognized. However, few epidemiological designs explore potential influences from the paternal environment on offspring health. This is surprising given that numerous animal models have provided evidence that the paternal environment plays a role in a non-genetic inheritance of pre-conceptional exposures through the male germ line. Recent findings in humans suggest that the epigenome of sperm cells can indeed be affected by paternal exposures. Defects in epigenetic sperm mechanisms may result in persistent modifications, affecting male fertility or offspring health status. We addressed this issue at the LATSIS Symposium ‘Transgenerational Epigenetic Inheritance: Impact for Biology and Society’, in Zürich, 28–30 August 2017, and here provide important arguments why environmental and lifestyle-related exposures in young men should be studied. The Paternal Origins of Health and Disease (POHaD) paradigm was introduced to stress the need for more research on the role of the father in the transmission of acquired environmental messages from his environment to his offspring. A better understanding of pre-conceptional origins of disease through the paternal exposome will be informative to the field of transgenerational epigenetics and will ultimately help instruct and guide public health policies in the future.

Does cross-generational epigenetic inheritance contribute to cultural continuity?

Human studies of cross-generational epigenetic inheritance have to consider confounding by social patterning down the generations, often referred to as ‘cultural inheritance’. This raises the question to what extent is ‘cultural inheritance’ itself epigenetically mediated rather than just learnt. Human studies of non-genetic inheritance have demonstrated that, beyond foetal life, experiences occurring in mid-childhood before puberty are the most likely to be associated with cross-generational responses in the next generation(s). It is proposed that cultural continuity is played out along the axis, or ‘payoff’, between responsiveness and stability. During the formative years of childhood a stable family and/or home permits small children to explore and thereby learn. To counter disruptions to this family home ideal, cultural institutions such as local schools, religious centres and market places emerged to provide ongoing stability, holding the received wisdom of the past in an accessible state. This cultural support allows the growing child to freely indulge their responsiveness. Some of these prepubertal experiences induce epigenetic responses that also transfer molecular signals to the gametes through which they contribute to the conception of future offspring. In parallel co-evolution with growing cultural support for increasing responsiveness, ‘runaway’ responsiveness is countered by the positive selection of genetic variants that dampen responsiveness. Testing these ideas within longitudinal multigenerational cohorts will need information on ancestors/parents’ own communities and experiences (Exposome scans) linked to ongoing Phenome scans on grandchildren; coupled with epigenome analysis, metastable epialleles and DNA methylation age. Interactions with genetic variants affecting responsiveness should help inform the broad hypothesis.