Trans-Generational inheritance

How widespread is trans-generational inheritance of acquired phenotype characteristics?

Since this issue is central and requires careful attention to the details of the experimental evidence, I have included abstracts from the articles cited. This form of inheritance is now firmly established.

“Many maternal effects have subsequently been observed, and non-genomic transmission of disease risk has been firmly established (P. Gluckman & Hanson, 2004; P. D. Gluckman, Hanson, & Beedle, 2007). A study done in Scandinavia clearly shows the transgenerational effect of food availability to human grandparents influencing the longevity of grandchildren (Kaati, Bygren, Pembrey, & Sjostrom, 2007; Pembrey et al., 2006).”

Gluckman, P., & Hanson, M. (2004). The Fetal Matrix. Evolution, Development and Disease. Cambridge: Cambridge University Press.

Gluckman, P. D., Hanson, M. A., & Beedle, A. S. (2007). Non-genomic transgenerational inheritance of disease risk. Bioessays29, 145-154.

That there is a heritable or familial component of susceptibility to chronic non-communicable diseases such as type 2 diabetes, obesity and cardiovascular disease is well established, but there is increasing evidence that some elements of such heritability are transmitted non-genomically and that the processes whereby environmental influences act during early development to shape disease risk in later life can have effects beyond a single generation. Such heritability may operate through epigenetic mechanisms involving regulation of either imprinted or non-imprinted genes but also through broader mechanisms related to parental physiology or behaviour. We review evidence and potential mechanisms for non-genomic transgenerational inheritance of ‘lifestyle’ disease and propose that the ‘developmental origins of disease’ phenomenon is a maladaptive consequence of an ancestral mechanism of developmental plasticity that may have had adaptive value in the evolution of generalist species such as Homo sapiens.

Kaati, G., Bygren, L. O., Pembrey, M. E., & Sjostrom, M. (2007). Transgenerational response to nutrition, early life circumstances and longevity European Journal of Human Genetics15, 784-790.

Nutrition might induce, at some loci, epigenetic or other changes that could be transmitted to the next generation impacting on health. The slow growth period (SGP) before the prepubertal peak in growth velocity has emerged as a sensitive period where different food availability is followed by different transgenerational response (TGR). The aim of this study is to investigate to what extent the probands own childhood circumstances are in fact the determinants of the findings. In the analysis, data from three random samples, comprising 271 probands and their 1626 parents and grandparents, left after exclusions because of missing data, were utilized. The availability of food during any given year was classified based on regional statistics. The ancestors’ SGP was set at the ages of 8-12 years and the availability of food during these years classified as good, intermediate or poor. The probands’ childhood circumstances were defined by the father’s ownership of land, the number of siblings and order in the sibship, the death of parents and the parents’ level of literacy. An earlier finding of a sex-specific influence from the ancestors’ nutrition during the SGP, going from the paternal grandmother to the female proband and from the paternal grandfather to the male proband, was confirmed. In addition, a response from father to son emerged when childhood social circumstances of the son were accounted for. Early social circumstances influenced longevity for the male proband. TGRs to ancestors’ nutrition prevailed as the main influence on longevity.

Pembrey, M. E., Bygren, L. O., Kaati, G., Edvinsson, S., Northstone, K., Sjostrom, M., . . . ALSPAC_study_team. (2006). Sex-specific, male-line transgenerational responses in humans. European Journal of Human Genetics14, 159-166.

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.

Contrary to a widespread view that such effects always die out quickly, this form of inheritance can be just as strong as conventional genetic inheritance.

“Their article (Nelson et al, 2012) begins by noting that many environmental agents and genetic variants can induce heritable epigenetic changes that affect phenotypic variation and disease risk in many species. Moreover, these effects persist for many generations and are as strong as conventional genetic inheritance (Cuzin & Rassoulzadegan, 2010; Guerrero-Bosagna & Skinner, 2012; Jirtle & Skinner, 2007; Nelson & Nadeau, 2010; Richards, 2006; Youngson & Whitelaw, 2008).”

Cuzin, F., Grandjean, V., & Rassoulzadegan, M. (2008). Inherited variation at the epigenetic level: paramutation from the plant to the mouse. Curr  Opin Genet Dev18(2), 193-196.

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

Guerrero-Bosagna, C., & Skinner, M. K. (2012). Environmentally-induced epigenetic transgenerational inheritance of phenotype and disease Molecular and cellular endocrinology354, 3-8.

Environmental epigenetics has an important role in regulating phenotype formation or disease etiology. The ability of environmental factors and exposures early in life to alter somatic cell epigenomes and subsequent development is a critical factor in how environment affects biology. Environmental epigenetics provides a molecular mechanism to explain long term effects of environment on the development of altered phenotypes and “emergent” properties, which the “genetic determinism” paradigm cannot. When environmental factors permanently alter the germ line epigenome, then epigenetic transgenerational inheritance of these environmentally altered phenotypes and diseases can occur. This environmental epigenetic transgenerational inheritance of phenotype and disease is reviewed with a systems biology perspective.

Jirtle, R. L., & Skinner, M. K. (2007). Environmental epigenomics and disease susceptibility Nature Reviews Genetics8, 253-262.

Epidemiological evidence increasingly suggests that environmental exposures early in development have a role in susceptibility to disease in later life. In addition, some of these environmental effects seem to be passed on through subsequent generations. Epigenetic modifications provide a plausible link between the environment and alterations in gene expression that might lead to disease phenotypes. An increasing body of evidence from animal studies supports the role of environmental epigenetics in disease susceptibility. Furthermore, recent studies have demonstrated for the first time that heritable environmentally induced epigenetic modifications underlie reversible transgenerational alterations in phenotype. Methods are now becoming available to investigate the relevance of these phenomena to human disease

Nelson VR, Heaney JD, Tesar PJ, Davidson NO & Nadeau JH (2012). Transgenerational epigenetic effects ofApobec1 deficiency on testicular germ cell tumor susceptibility and embryonic viability. Proc Natl Acad Sci U S A 109, E2766–E2773

Environmental agents and genetic variants can induce heritable epigenetic changes that affect phenotypic variation and disease risk in many species. These transgenerational effects challenge conventional understanding about the modes and mechanisms of inheritance, but their molecular basis is poorly understood. The Deadend1 (Dnd1) gene enhances susceptibility to testicular germ cell tumors (TGCTs) in mice, in part by interacting epigenetically with other TGCT modifier genes in previous generations. Sequence homology to A1cf, the RNA-binding subunit of the ApoB editing complex, raises the possibility that the function of Dnd1 is related to Apobec1 activity as a cytidine deaminase. We conducted a series of experiments with a genetically engineered deficiency of Apobec1 on the TGCT-susceptible 129/Sv inbred background to determine whether dosage of Apobec1 modifies susceptibility, either alone or in combination with Dnd1, and either in a conventional or a transgenerational manner. In the paternal germ-lineage, Apobec1 deficiency significantly increased susceptibility among heterozygous but not wild-type male offspring, without subsequent transgenerational effects, showing that increased TGCT risk resulting from partial loss of Apobec1 function is inherited in a conventional manner. By contrast, partial deficiency in the maternal germ-lineage led to suppression of TGCTs in both partially and fully deficient males and significantly reduced TGCT risk in a transgenerational manner among wild-type offspring. These heritable epigenetic changes persisted for multiple generations and were fully reversed after consecutive crosses through the alternative germ-lineage. These results suggest that Apobec1 plays a central role in controlling TGCT susceptibility in both a conventional and a transgenerational manner.

Nelson, V. R., & Nadeau, J. H. (2010). Transgenerational genetic effects. Epigenomics2, 797-806.

Since Mendel, studies of phenotypic variation and disease risk have emphasized associations between genotype and phenotype among affected individuals in families and populations. Although this paradigm has led to important insights into the molecular basis for many traits and diseases, most of the genetic variants that control the inheritance of these conditions continue to elude detection. Recent studies suggest an alternative mode of inheritance where genetic variants that are present in one generation affect phenotypes in subsequent generations, thereby decoupling the conventional relations between genotype and phenotype, and perhaps, contributing to ‘missing heritability’. Under some conditions, these transgenerational genetic effects can be as frequent and strong as conventional inheritance, and can persist for multiple generations. Growing evidence suggests that RNA mediates these heritable epigenetic changes. The primary challenge now is to identify the molecular basis for these effects, characterize mechanisms and determine whether transgenerational genetic effects occur in humans.

Richards, E. J. (2006). Inherited epigenetic variation – revisiting soft inheritance Nature Reviews Genetics7, 395-401.

Phenotypic variation is traditionally parsed into components that are directed by genetic and environmental variation. The line between these two components is blurred by inherited epigenetic variation, which is potentially sensitive to environmental inputs. Chromatin and DNA methylation-based mechanisms mediate a semi-independent epigenetic inheritance system at the interface between genetic control and the environment. Should the existence of inherited epigenetic variation alter our thinking about evolutionary change?

Youngson, N. A., & Whitelaw, E. (2008). Transgenerational epigenetic effects Annual Review of Genomics and Human Genetics9, 233-257.

Transgenerational epigenetic effects include all processes that have evolved to achieve the nongenetic determination of phenotype. There has been a long-standing interest in this area from evolutionary biologists, who refer to it as non-Mendelian inheritance. Transgenerational epigenetic effects include both the physiological and behavioral (intellectual) transfer of information across generations. Although in most cases the underlying molecular mechanisms are not understood, modifications of the chromosomes that pass to the next generation through gametes are sometimes involved, which is called transgenerational epigenetic inheritance. There is a trend for those outside the field of molecular biology to assume that most cases of transgenerational epigenetic effects are the result of transgenerational epigenetic inheritance, in part because of a misunderstanding of the terms. Unfortunately, this is likely to be far from the truth.

RNA transmitted changes independent of DNA have been followed in planarians for 100 generations:

Rechavi O, Minevish G & Hobert O (2011). Transgenerational inheritance of an acquired small RNA-based antiviral response in C. elegans. Cell 147, 1248–1256.

Induced expression of the Flock House virus in the soma of C. elegans results in the RNAi-dependent production of virus-derived, small-interfering RNAs (viRNAs), which in turn silence the viral genome. We show here that the viRNA-mediated viral silencing effect is transmitted in a non-Mendelian manner to many ensuing generations. We show that the viral silencing agents, viRNAs, are transgenerationally transmitted in a template-independent manner and work in trans to silence viral genomes present in animals that are deficient in producing their own viRNAs. These results provide evidence for the transgenerational inheritance of an acquired trait, induced by the exposure of animals to a specific, biologically relevant physiological challenge. The ability to inherit such extragenic information may provide adaptive benefits to an animal.

Transgenerational epigenetic effects in the brain are reviewed in

Bohacek J, Gapp K, Saab BJ & Mansuy IM. (2013). Transgenerational Epigenetic Effects on Brain Functions. Biological Psychiatry 73, 313-320.

Psychiatric diseases are multifaceted disorders with complex etiology, recognized to have strong heritable components. Despite intense research efforts, genetic loci that substantially account for disease heritability have not yet been identified. Over the last several years, epigenetic processes have emerged as important factors for many brain diseases, and the discovery of epigenetic processes in germ cells has raised the possibility that they may contribute to disease heritability and disease risk. This review examines epigenetic mechanisms in complex diseases and summarizes the most illustrative examples of transgenerational epigenetic inheritance in mammals and their relevance for brain function. Environmental factors that can affect molecular processes and behavior in exposed individuals and their offspring, and their potential epigenetic underpinnings, are described. Possible routes and mechanisms of transgenerational transmission are proposed, and the major questions and challenges raised by this emerging field of research are considered.

Transgenerational epigenetic effects underly the inheritance of sensitivity to odors in mice:

Dias BG & Ressler KJ. (2013). Parental olfactory experience influences behavior and neural structure in subsequent generations. Nature Neurosciencedoi:10.1038/nn.3594

Using olfactory molecular specificity, we examined the inheritance of parental traumatic exposure, a phenomenon that has been frequently observed, but not understood. We subjected F0 mice to odor fear conditioning before conception and found that subsequently conceived F1 and F2 generations had an increased behavioral sensitivity to the F0-conditioned odor, but not to other odors. When an odor (acetophenone) that activates a known odorant receptor (Olfr151) was used to condition F0 mice, the behavioral sensitivity of the F1 and F2 generations to acetophenone was complemented by an enhanced neuroanatomical representation of the Olfr151 pathway. Bisulfite sequencing of sperm DNA from conditioned F0 males and F1 naive offspring revealed CpG hypomethylation in the Olfr151 gene. In addition, in vitro fertilization, F2 inheritance and cross-fostering revealed that these transgenerational effects are inherited via parental gametes. Our findings provide a framework for addressing how environmental information may be inherited transgenerationally at behavioral, neuroanatomical and epigenetic levels.

For examples of epigenetic inheritance in plants see

Pennisi, E (2013) Evolution Heresy? Epigenetics Underlies Heritable Plant Traits Science 341 6 September

“For some evolutionary biologists, just hearing the term epigenetics raises hackles. They balk at suggestions that something other than changes in DNA sequences—such as the chemical addition of methyl groups to DNA or other so-called epigenetic modifications— has a role in evolution. All of which guarantees that a provocative study presented at an evolutionary biology meeting …. last month will get close scrutiny. It found that heritable changes in plant flowering time and other traits were the result of epigenetics alone, unaided by any sequence changes.”

Colomé-Tatché M, Cortijo S, Wardenaar R, Morgado L, Lahouze B, Sarazin A, Etcheverry M, Martin A, Feng S, Duvernois-Berthet E, Labadie K, Wincker P, Jacobsen SE, Jansen RC, Colot V, Johannes F (2012). Features of the Arabidopsis recombination landscape resulting from the combined loss of sequence variation and DNA methylation. Proc. Natl. Acad. Sci. USA doi:10.1073/pnas.1212955109. Research reported by Frank Johannes (Groningen)

Schmitz, R.J. et al (2011) Transgenerational Epigenetic Instability is a source of Novel Methylation Variants. Science334, 369-373. “We examined spontaneously occurring variation in DNA methylation in Arabidopsis thaliana plants propagated by single-seed descent for 30 generations…… transgenerational epigenetic variation in DNA methylation may generate new allelic states that alter transcription, providing a mechanism for phenotypic diversity in the absence of genetic mutation.” “Regardless of their origin, the majority of epialleles identified in this study are meiotically stable and heritable across many generations in this population.”

 Schmitz, R.J. et al (2013) Epigenome-wide inheritance of cytosine methylation variants in a recombinant inbred population. Genome Research23, 1663-1674. “a comprehensive study of the patterns and heritability of methylation variants in a complex genetic population over multiple generations, paving the way for understanding how methylation variants contribute to phenotypic variation.”

The big question now is how large a role these forms of inheritance have played in the evolutionary process. But that is a question that applies to all the proposed mechanisms of evolutionary change and also to the ways in which they must have interacted. Articles relevant to that question include:

Hua, Z. (2013) Epigenomic programming contributes to the genomic drift evolution of the F-Box protein superfamily in ArabidopsisPNAS110, 16927–16932. “Comparisons within expanding sequence databases have revealed a dynamic interplay among genomic and epigenomic forces in driving plant evolution. Such forces are especially obvious within the F-Box (FBX) superfamily, one of the largest and most polymorphic gene families in land plants, where its frequent lineage-specific expansions and contractions provide an excellent model to assess how genetic variation impacted gene function before and after speciation.” “…reversible epigenomic modifications helped shape FBX gene evolution by transcriptionally suppressing the adverse effects of gene dosage imbalance and harmful FBX alleles that arise during genomic drift, while simultaneously allowing innovations to emerge through epigenomic reprogramming.”

Takuno, S & Gaut B.S. (2013) Gene body methylation is conserved between plant orthologs and is of evolutionary consequence. PNAS110, 1797-1802. “Gene body methylation was strongly conserved between orthologs of the two species and affected a biased subset of long, slowly evolving genes. Because gene body methylation is conserved over evolutionary time, it shapes important features of plant genome evolution, such as the bimodality of G+C content among grass genes.”

The following article is a useful critique of the inheritability of stress-induced chromatin changes in plants, and lays out some criteria to be used in further work.

Pecinka, A. & Scheid, O.M. (2012)  Stress-Induced Chromatin Changes: A Critical View on Their Heritability. Plant Cell Physiol 53, 801-808. “We propose a set of criteria that should be applied to substantiate the data for stress-induced, chromatin-encoded new traits. Well-controlled stress treatments, thorough phenotyping and application of refined genome-wide epigenetic analysis tools should be helpful in moving from interesting observations towards robust evidence.” “plants are good candidates for a further, unprepossessed search. Constant refinement of chromatin analysis tools and growing genetic information, also for non-model species, together with the criteria listed here, will help answer whether it is time for a renaissance of Lamarck’s ideas.”

This is also a valuable review:

O’Malley R.C. & Ecker, J.R. (2012) Epiallelic Variation in Arabidopsis thalianaCold Spring Harbour Symp Quant Biol77, 135-145. “Genotype is the primary determinate of phenotype. During the past two decades, however, there has been an emergent recognition of the epigenotype, a separate layer of heredity distinct from the primary DNA sequence that can have profound effects on phenotype.” “We discuss examples of epialleles that have been created in the laboratory and others that have been identified in natural populations, because these two models provide complementary information regarding the genetic pathways, mechanisms of transmission, and biological and evolutionary context for the role of the epigenotype in phenotypic variation.”