Transgenerational epigenetic inheritance

In sexually reproducing organisms, much of the epigenetic modification within cells is reset during meiosis (e.g. marks at the FLC locus controlling plant vernalization[11]), though some epigenetic responses have been shown to be conserved (e.g. transposon methylation in plants[11]). Differential inheritance of epigenetic marks due to underlying maternal or paternal biases in removal or retention mechanisms may lead to the assignment of epigenetic causation to some parent of origin effects in animals[12] and plants.[13]

In mammals, epigenetic marks are erased during two phases of the life cycle. Firstly just after fertilization and secondly, in the developing primordial germ cells, the precursors to future gametes.[2] During fertilization the male and female gametes join in different cell cycle states and with different configuration of the genome. The epigenetic marks of the male are rapidly diluted. First, the protamines associated with male DNA are replaced with histones from the female's cytoplasm, most of which are acetylated due to either higher abundance of acetylated histones in the female's cytoplasm or through preferential binding of the male DNA to acetylated histones.[14][15] Second, male DNA is systematically demethylated in many organisms,[16][17] possibly through 5-hydroxymethylcytosine. However, some epigenetic marks, particularly maternal DNA methylation, can escape this reprogramming; leading to parental imprinting.

In the primordial germ cells (PGC) there is a more extensive erasure of epigenetic information. However, some rare sites can also evade erasure of DNA methylation.[18] If epigenetic marks evade erasure during both zygotic and PGC reprogramming events, this could enable transgenerational epigenetic inheritance.

Recognition of the importance of epigenetic programming to the establishment and fixation of cell line identity during early embryogenesis has recently stimulated interest in artificial removal of epigenetic programming.[19] Epigenetic manipulations may allow for restoration of totipotency in stem cells or cells more generally, thus generalizing regenerative medicine.

Cellular mechanisms may allow for co-transmission of some epigenetic marks. During replication, DNA polymerases working on the leading and lagging strands are coupled by the DNA processivity factor proliferating cell nuclear antigen (PCNA), which has also been implicated in patterning and strand crosstalk that allows for copy fidelity of epigenetic marks.[20][21] Work on histone modification copy fidelity has remained in the model phase, but early efforts suggest that modifications of new histones are patterned on those of the old histones and that new and old histones randomly assort between the two daughter DNA strands.[22] With respect to transfer to the next generation, many marks are removed as described above. Emerging studies are finding patterns of epigenetic conservation across generations. For instance, centromeric satellites resist demethylation.[23] The mechanism responsible for this conservation is not known, though some evidence suggests that methylation of histones may contribute.[23][24] Dysregulation of the promoter methylation timing associated with gene expression dysregulation in the embryo was also identified.[25]

Whereas the mutation rate in a given 100-base gene may be 10⁻⁷ per generation, epigenes may "mutate" several times per generation or may be fixed for many generations.[26] This raises the question: do changes in epigene frequencies constitute evolution? Rapidly decaying epigenetic effects on phenotypes (i.e. lasting less than three generations) may explain some of the residual variation in phenotypes after genotype and environment are accounted for. However, distinguishing these short-term effects from the effects of the maternal environment on early ontogeny remains a challenge.

Studies concerning transgenerational epigenetic inheritance in plants have been reported as early as the 1950s.[33] One of the earliest and best characterized examples of this is b1 paramutation in maize.[33][34][35][36][37][38][39][40] The b1 gene encodes a basic helix-loop-helix transcription factor that is involved in the anthocyanin production pathway. When the b1 gene is expressed, the plant accumulates anthocyanin within its tissues, leading to a purple coloration of those tissues. The B-I allele (for B-Intense) has high expression of b1 resulting in the dark pigmentation of the sheath and husk tissues while the B' (pronounced B-prime) allele has low expression of b1 resulting in low pigmentation in those tissues.[41] When homozygous B-I parents are crossed to homozygous B', the resultant F1 offspring all display low pigmentation which is due to gene silencing of b1.[33][41] Unexpectedly, when F1 plants are self-crossed, the resultant F2 generation all display low pigmentation and have low levels of b1 expression. Furthermore, when any F2 plant (including those that are genetically homozygous for B-I) are crossed to homozygous B-I, the offspring will all display low pigmentation and expression of b1.[33][41] The lack of darkly pigmented individuals in the F2 progeny is an example of non-Mendelian inheritance and further research has suggested that the B-I allele is converted to B' via epigenetic mechanisms.[35][36] The B' and B-I alleles are considered to be epialleles because they are identical at the DNA sequence level but differ in the level of DNA methylation, siRNA production, and chromosomal interactions within the nucleus.[39][42][38][37] Additionally, plants defective in components of the RNA-directed DNA-methylation pathway show an increased expression of b1 in B' individuals similar to that of B-I, however, once these components are restored, the plant reverts to the low expression state.[40][43][44][45] Although spontaneous conversion from B-I to B' has been observed, a reversion from B' to B-I (green to purple) has never been observed over 50 years and thousands of plants in both greenhouse and field experiments.[46] s

Examples of environmentally induced transgenerational epigenetic inheritance in plants has also been reported.[47][48][49] In one case, rice plants that were exposed to drought-simulation treatments displayed increased tolerance to drought after 11 generations of exposure and propagation by single-seed descent as compared to non-drought treated plants.[47] Differences in drought tolerance was linked to directional changes in DNA-methylation levels throughout the genome, suggesting that stress-induced heritable changes in DNA-methylation patterns may be important in adaptation to recurring stresses.[47] In another study, plants that were exposed to moderate caterpillar herbivory over multiple generations displayed increased resistance to herbivory in subsequent generations (as measured by caterpillar dry mass) compared to plants lacking herbivore pressure.[48] This increase in herbivore resistance persisted after a generation of growth without any herbivore exposure suggesting that the response was transmitted across generations.[48] The report concluded that components of the RNA-directed DNA-methylation pathway are involved in the increased resistance across generations.[48] Transgenerational epigenetic inheritance has also been observed in polyploid plants. Genetically identical reciprocal F1 hybrid triploids have been shown to display transgenerational epigenetic effects on viable F2 seed development.[50]

Although genetic inheritance is important when describing phenotypic outcomes, it cannot entirely explain why offspring resemble their parents. Aside from genes, offspring come to inherit similar environmental conditions established by previous generations.[9]

One environment that human offspring commonly share for nine months is the womb. Considering the duration of the fetal stages of development, the environment of the mother’s womb can have long lasting effects on the health of offspring.[9]

An example of how the environment within the womb can affect the health of an offspring is the Dutch hunger winter and its causal effect on induced transgenerational epigenetic inherited diseases.[9]

A number of studies suggest the existence of transgenerational epigenetic inheritance in humans,[2] which includes the Dutch famine of 1944–45.

During the Dutch hunger winter, the offspring born during the famine were smaller than those born the year before the famine. The effects of this famine on development lasted up to two generations.

Moreover, the offspring born during the famine were found to have an increased risk of glucose intolerance in adulthood.[51]

Differential DNA methylation has been found in adult female offspring who had been exposed to famine in utero, but it is unknown whether these differences in DNA methylation were passed on to their germline.[51]

It is hypothesized that inhibiting the PIM3 gene may have caused slower metabolism in later generations, but causation has not been proven, only correlation.[52] The phenomenon is sometimes referred to as Dutch Hunger Winter Syndrome.

Furthermore, the increased rates of metabolic diseases, cardiovascular diseases, and other increased risk factors to the health of F1 and F2 generations during the Dutch hunger winter is a known phenomenon called “fetal programming,” which is caused by exposure to harmful environmental factors in utero.[9]

Another study hypothesized that epigenetic changes on the Y chromosome could explain differences in lifespan among the male descendants of prisoners of war in the American Civil War.

The Överkalix study noted sex-specific effects; a greater body mass index (BMI) at 9 years in sons, but not daughters, of fathers who began smoking early.

The paternal grandfather's food supply was only linked to the mortality RR of grandsons and not granddaughters. The paternal grandmother's food supply was only associated with the granddaughters' mortality risk ratio. When the grandmother had a good food supply was associated with a twofold higher mortality (RR).

This transgenerational inheritance was observed with exposure during the slow growth period (SGP). The SGP is the time before the start of puberty, when environmental factors have a larger impact on the body. The ancestors' SGP in this study was set between the ages of 9-12 for boys and 8–10 years for girls. This occurred in the SGP of both grandparents, or during the gestation period/infant life of the grandmothers, but not during either grandparent's puberty.

The father's poor food supply and the mother's good food supply were associated with a lower risk of cardiovascular death.[51][52]

The loss of genetic expression which results in Prader–Willi syndrome or Angelman syndrome has in some cases been found to be caused by epigenetic changes (or "epimutations") on both the alleles, rather than involving any genetic mutation. In all 19 informative cases, the epimutations that, together with physiological imprinting and therefore silencing of the other allele, were causing these syndromes were localized on a chromosome with a specific parental and grandparental origin.

Specifically, the paternally derived chromosome carried an abnormal maternal mark at the SNURF-SNRPN, and this abnormal mark was inherited from the paternal grandmother.[51]

Similarly, epimutations on the MLH1 gene has been found in two individuals with a phenotype of hereditary nonpolyposis colorectal cancer, and without any frank MLH1 mutation which otherwise causes the disease. The same epimutations were also found on the spermatozoa of one of the individuals, indicating the potential to be transmitted to offspring.[51]

In addition to epimutations to the MLH1 gene, it has been determined that certain cancers, such as breast cancer, can originate during the fetal stages within the uterus.[53]

Furthermore, evidence collected in various studies utilizing model systems (i.e. animals) have found that exposure during parental generations can result in multigenerational and transgenerational inheritance of breast cancer.[53]

More recently, studies have discovered a connection between the adaptation of male germinal cells via pre-conception paternal diets and the regulation of breast cancer in developing offspring.[53] More specifically, studies have begun to uncover new data that underscores a relationship between transgenerational epigenetic inheritance of breast cancer and ancestral alimentary components or associated markers, such as birth weight.[53]

By utilizing model systems, such as mice, studies have shown that stimulated paternal obesity at the time of conception can epigenetically alter the paternal germ-line. The paternal germ-line is responsible for regulating their daughters’ weight at birth and the potential for their daughter to develop breast cancer.[54]

Furthermore, it was found that modifications to the miRNA expression profile of the male germline is coupled with elevated body weight.[54] Additionally, paternal obesity resulted in an increase in the percentage of female offspring developing carcinogen-induced mammary tumors, which is caused by changes to mammary miRNA expression.[54]

Aside from cancer related afflictions associated with the effects of transgenerational epigenetic inheritance, transgenerational epigenetic inheritance has recently been implicated in the progression of pulmonary arterial hypertension (PAH).[55]

Recent studies have found that transgenerational epigenetic inheritance is likely to be involved in the progression of PAH because current therapies for PAH do not repair the irregular phenotypes associated with this disease.[55] Current treatments for PAH have attempted to correct symptoms of PAH with vasodilators and antithrombotic protectors, but neither has effectively alleviated the complications related to the impaired phenotypes associated with PAH.[55] The inability of vasodilators and antithrombotic protectants to correct PAH suggests that the progression of PAH is dependent upon multiple variables, which is likely to be consequent of transgenerational epigenetic inheritance.[55]

Specifically, it is thought that transgenerational epigenetics is linked to the phenotypic changes associated with vascular remodeling.[55] For example, hypoxia during gestation may induce transgenerational epigenetic alterations that could prove to be detrimental during the early phases of fetal development and increase the possibility of developing PAH as an adult.[55]

Taking the potential effects of transgenerational epigenetics during fetal development into consideration is derived from the fetal origins of adult disease (FOAD) hypothesis, which is related to the concept of fetal programming.[55]

Though hypoxic states could induce the transgenerational epigenetic variance associated with PAH, there is strong evidence to support that a variety of maternal risk factors are linked to the eventual progression of PAH.[55] Such maternal risk factors linked to late-onset PAH includes placental dysfunction, hypertension, obesity, and preeclampsia.[55] These maternal risk factors and environmental stressors coupled with transgenerational epigenetic changes can result in prolonged insult to the signaling pathways associated with the vascular development during fetal stages, thus increasing the likelihood of having PAH.[55]

One study has shown childhood abuse, which is defined as "sexual contact, severe physical abuse and/or severe neglect," leads to epigenetic modifications of glucocorticoid receptor expression.[56][57]

Glucocorticoid receptor expression plays a vital role in hypothalamic-pituitary-adrenal (HPA) activity. Additionally, animal experiments have shown that epigenetic changes can depend on mother-infant interactions after birth.[58]

Furthermore, a recent study investigating the correlations between maternal stress in pregnancy and methylation in teenagers/their mothers has found that children of women who were abused during pregnancy were more likely to have methylated glucocorticoid-receptor genes.[59] Thus, children with methylated glucocorticoid-receptor genes experience an altered response to stress, ultimately leading to a higher susceptibility of experiencing anxiety.[59]

Additional studies examining the effects of diethylstilbestrol (DES), which is an endocrine disruptor, have found that the grandchildren (third-generation) of women exposed to DES significantly increased the probability of their grandchildren developing attention-deficit/hyperactivity disorder (ADHD).[60] This is because women exposed to endocrine disruptors, such as DES, during gestation may be linked to multigenerational neurodevelopmental deficits.[60]

Furthermore, animal studies indicate that endocrine disruptors have a profound impact on germline cells and neurodevelopment.[60] The cause of DES's multigenerational impact is postulated to be the result of biological processes associated with epigenetic reprogramming of the germline, though this has yet to be determined.[60]

Inherited epigenetic marks may be important for regulating important components of fitness. In plants, for instance, the Lcyc gene in Linaria vulgaris controls the symmetry of the flower. Linnaeus first described radially symmetric mutants, which arise when Lcyc is heavily methylated.[62] Given the importance of floral shape to pollinators,[63] methylation of Lcyc homologues (e.g. CYCLOIDEA) may have deleterious effects on plant fitness. In animals, numerous studies have shown that inherited epigenetic marks can increase susceptibility to disease. Transgenerational epigenetic influences are also suggested to contribute to disease, especially cancer, in humans. Tumor methylation patterns in gene promoters have been shown to correlate positively with familial history of cancer.[64] Furthermore, methylation of the MSH2 gene is correlated with early-onset colorectal and endometrial cancers.[65]

Experimentally demethylated seeds of the model organism Arabidopsis thaliana have significantly higher mortality, stunted growth, delayed flowering, and lower fruit set,[66] indicating that epigenes may increase fitness. Furthermore, environmentally induced epigenetic responses to stress have been shown to be inherited and positively correlated with fitness.[67] In animals, communal nesting changes mouse behavior increasing parental care regimes[68] and social abilities[69] that are hypothesized to increase offspring survival and access to resources (such as food and mates), respectively.

In 2021, it was shown for the first time how immunity is inherited – via epigenetic changes – in mammals (mice).[70]

Blending inheritance leads to the averaging out of every characteristic, which as the engineer Fleeming Jenkin pointed out, makes evolution by natural selection impossible.

Addressing these related questions, scientists during the time of the Enlightenment largely argued for the blending hypothesis, in which parental traits were homogenized in the offspring much like buckets of different colored paint being mixed together.[73] Critics of Charles Darwin's On the Origin of Species, pointed out that under this scheme of inheritance, variation would quickly be swamped by the majority phenotype.[74] In the paint bucket analogy, this would be seen by mixing two colors together and then mixing the resulting color with only one of the parent colors 20 times; the rare variant color would quickly fade.

Unknown to most of the European scientific community, the monk Gregor Mendel had resolved the question of how traits are conserved between generations through breeding experiments with pea plants.[75] Charles Darwin thus did not know of Mendel's proposed "particulate inheritance" in which traits were not blended but passed to offspring in discrete units that we now call genes. Darwin came to reject the blending hypothesis even though his ideas and Mendel's were not unified until the 1930s, a period referred to as the modern synthesis.

In his 1809 book, Philosophie Zoologique,[76] Jean-Baptiste Lamarck recognized that each species experiences a unique set of challenges due to its form and environment. Thus, he proposed that the characters used most often would accumulate a "nervous fluid." Such acquired accumulations would then be transmitted to the individual's offspring. In modern terms, a nervous fluid transmitted to offspring would be a form of epigenetic inheritance.

Lamarckism, as this body of thought became known, was the standard explanation for change in species over time when Charles Darwin and Alfred Russel Wallace co-proposed a theory of evolution by natural selection in 1859. Responding to Darwin and Wallace's theory, a revised neo-Lamarckism attracted a small following of biologists,[77] though the Lamarckian zeal was quenched in large part due to Weismann's[78] famous experiment in which he cut off the tails of mice over several successive generations without having any effect on tail length. Thus the emergent consensus that acquired characteristics could not be inherited became canon.[2]

Non-genetic variation and inheritance, however, proved to be quite common. Concurrent with the 20th-century development of the modern evolutionary synthesis (unifying Mendelian genetics and natural selection), C. H. Waddington (1905-1975) was working to unify developmental biology and genetics. In so doing, he adopted the word "epigenetic"[79] to represent the ordered differentiation of embryonic cells into functionally distinct cell types despite having identical primary structure of their DNA.[80] Researchers discussed Waddington's epigenetics sporadically - it became more of a catch-all for puzzling non-genetic heritable characters rather than a concept advancing the body of inquiry.[81][82] Consequently, the definition of Waddington's word has itself evolved, broadening beyond the subset of developmentally signaled, inherited cell specialization.

Some scientists have questioned whether epigenetic inheritance compromises the foundation of the modern synthesis. Outlining the central dogma of molecular biology, Francis Crick[83] succinctly stated, "DNA is held in a configuration by histone[s] so that it can act as a passive template for the simultaneous synthesis of RNA and protein[s]. None of the detailed 'information' is in the histone." However, he closes the article stating, "this scheme explains the majority of the present experimental results!" Indeed, the emergence of epigenetic inheritance (in addition to advances in the study of evolutionary-development, phenotypic plasticity, evolvability, and systems biology) has strained the current framework of the modern evolutionary synthesis, and prompted the re-examination of previously dismissed evolutionary mechanisms.[84]

Furthermore, patterns in epigenetic inheritance and the evolutionary implications of the epigenetic codes in living organisms are connected to both Lamarck's and Darwin's theories of evolution.[85] For example, Lamarck postulated that environmental factors were responsible for modifying phenotypes hereditarily, which supports the constructs that exposure to environmental factors during critical stages of development can result in epimutations in germlines, thus augmenting phenotypic variance.[85] In contrast, Darwin’s theory claimed that natural selection strengthened a populations ability to survive and remain reproductively fit by favoring populations that are able to readily adapt.[85] This theory is consistent with intergenerational plasticity and phenotypic variance resulting from heritable adaptivity.[85]

In addition, some epigenetic variability may provide beneficial plasticity, so that certain organisms can adapt to fluctuating environmental conditions. However, the exchange of epigenetic information between generations can result in epigenetic aberrations, which are epigenetic traits that deviate from the norm. Therefore, the offspring of the parental generations may be predisposed to specific diseases and reduced plasticity due to epigenetic aberrations. Though the ability to readily adapt when faced with a new environment may be beneficial to certain populations of species that can quickly reproduce, species with long generational gaps may not benefit from such an ability. If a species with a longer generational gap does not appropriately adapt to the anticipated environment, then the reproductive fitness of the offspring of that species will be diminished.

There has been critical discussion of mainstream evolutionary theory by Edward J Steele, Robyn A Lindley and colleagues,[86][87][88][89][90] Fred Hoyle and N. Chandra Wickramasinghe,[91][92][93] Yongsheng Liu[94][95] Denis Noble,[96][97] John Mattick[98] and others that the logical inconsistencies as well as Lamarckian Inheritance effects involving direct DNA modifications, as well as the just described indirect, viz. epigenetic, transmiss'ions, challenge conventional thinking in evolutionary biology and adjacent fields.