The Logic of Transgenerational Inheritance: Timescales of Adaptation.

Myriad mechanisms have evolved to adapt to changing environments. Environmental stimuli alter organisms' physiology to create memories of previous environments. Whether these environmental memories can cross the generational barrier has interested scientists for centuries. The logic of passing on information from generation to generation is not well understood. When is it useful to remember ancestral conditions, and when might it be deleterious to continue to respond to a context that may no longer exist? The key might be found in understanding the environmental conditions that trigger long-lasting adaptive responses. We discuss the logic that biological systems may use to remember environmental conditions. Responses spanning different generational timescales employ different molecular machineries and may result from differences in the duration or intensity of the exposure. Understanding the molecular components of multigenerational inheritance and the logic underlying beneficial and maladaptive adaptations is fundamental to understanding how organisms acquire and transmit environmental memories across generations.

18S rRNA methyltransferases DIMT1 and BUD23 drive intergenerational hormesis.

Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are poorly understood. Here, we perform metabolic methyl-labeling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans (C. elegans). We find heritable methylation in DNA, RNA, proteins, and lipids. We find that parental starvation elicits reduced fertility, increased heat stress resistance, and extended longevity in fed, naïve progeny. This intergenerational hormesis is accompanied by a heritable increase in N6'-dimethyl adenosine (m6,2A) on the 18S ribosomal RNA at adenosines 1735 and 1736. We identified DIMT-1/DIMT1 as the m6,2A and BUD-23/BUD23 as the m7G methyltransferases in C. elegans that are both required for intergenerational hormesis, while other rRNA methyltransferases are dispensable. This study labels and tracks heritable non-genetic material across generations and demonstrates the importance of rRNA methylation for regulating epigenetic inheritance.

Inheritance of H3K9 methylation regulates genome architecture in Drosophila early embryos.

Constitutive heterochromatin is essential for transcriptional silencing and genome integrity. The establishment of constitutive heterochromatin in early embryos and its role in early fruitfly development are unknown. Lysine 9 trimethylation of histone H3 (H3K9me3) and recruitment of its epigenetic reader, heterochromatin protein 1a (HP1a), are hallmarks of constitutive heterochromatin. Here, we show that H3K9me3 is transmitted from the maternal germline to the next generation. Maternally inherited H3K9me3, and the histone methyltransferases (HMT) depositing it, are required for the organization of constitutive heterochromatin: early embryos lacking H3K9 methylation display de-condensation of pericentromeric regions, centromere-centromere de-clustering, mitotic defects, and nuclear shape irregularities, resulting in embryo lethality. Unexpectedly, quantitative CUT&Tag and 4D microscopy measurements of HP1a coupled with biophysical modeling revealed that H3K9me2/3 is largely dispensable for HP1a recruitment. Instead, the main function of H3K9me2/3 at this developmental stage is to drive HP1a clustering and subsequent heterochromatin compaction. Our results show that HP1a binding to constitutive heterochromatin in the absence of H3K9me2/3 is not sufficient to promote proper embryo development and heterochromatin formation. The loss of H3K9 HMTs and H3K9 methylation alters genome organization and hinders embryonic development.

ATF7-Dependent Epigenetic Changes Are Required for the Intergenerational Effect of a Paternal Low-Protein Diet.

Paternal dietary conditions may contribute to metabolic disorders in offspring. We have analyzed the role of the stress-dependent epigenetic regulator cyclic AMP-dependent transcription factor 7 (ATF7) in paternal low-protein diet (pLPD)-induced gene expression changes in mouse liver. Atf7+/- mutations cause an offspring phenotype similar to that caused by pLPD, and the effect of pLPD almost vanished when paternal Atf7+/- mice were used. ATF7 binds to the promoter regions of ∼2,300 genes, including cholesterol biosynthesis-related and tRNA genes in testicular germ cells (TGCs). LPD induces ATF7 phosphorylation by p38 via reactive oxygen species (ROS) in TGCs. This leads to the release of ATF7 and a decrease in histone H3K9 dimethylation (H3K9me2) on its target genes. These epigenetic changes are maintained and induce expression of some tRNA fragments in spermatozoa. These results indicate that LPD-induced and ATF7-dependent epigenetic changes in TGCs play an important role in paternal diet-induced metabolic reprograming in offspring.

Absolute income mobility obscures marginalized children's disadvantages.

Intergenerational mobility captures the distance between the socioeconomic positions of parents versus their adult children. Researchers measure this distance in absolute and relative units, such as absolute dollars and relative ranks. Absolute and relative mobility often diverge. For example, absolute mobility can rise while relative mobility declines. How should scholars and policymakers understand this divergence? We conclude that they should understand it as follows: absolute mobility is less reflective than relative mobility of marginalized children's socioeconomic disadvantages. We base this conclusion on analyses of survey, administrative, and simulated data on income mobility in the contemporary United States. We analyze multiple points of difference in mobility, which facilitates the recognition of several asymmetries. First, high-income children's experiences weigh more heavily in absolute-mobility trends than low-income children's experiences, particularly when economic growth is positive. Second, this asymmetry is more characteristic of absolute- than relative-mobility trends. Third, absolute-mobility differences across demographic groups are more prone than relative-mobility differences to obscure marginalized groups' socioeconomic disadvantages. These asymmetries have policy implications: We caution that focusing on absolute mobility as a policy target can divert attention away from society's most disadvantaged children.

Social mobility in the Tang Dynasty as the Imperial Examination rose and aristocratic family pedigree declined, 618-907 CE.

Data from the distant past are fertile ground for testing social science theories of education and social mobility. In this study, we construct a dataset from 3,640 tomb epitaphs of males in China's Tang Dynasty (618-907 CE), which contain granular and extensive information about the ancestral origins, family background, and career histories of the deceased elites. Our statistical analysis of the complete profiles yields evidence of the transition away from an aristocratic society in three key trends: 1) family pedigree (i.e., aristocracy) mattered less for career achievement over time, 2) passing the Imperial Examination (Keju) became an increasingly important predictor of one's career achievement, and 3) father's position always mattered throughout the Tang, especially for men who did not pass the Keju. The twilight of medieval Chinese aristocracy, according to the data, began in as early as the mid-seventh century CE.

An organismal understanding of C. elegans innate immune responses, from pathogen recognition to multigenerational resistance.

The nematode Caenorhabditis elegans has been a model for studying infection since the early 2000s and many major discoveries have been made regarding its innate immune responses. C. elegans has been found to utilize some key conserved aspects of immune responses and signaling, but new interesting features of innate immunity have also been discovered in the organism that might have broader implications in higher eukaryotes such as mammals. Some of the distinctive features of C. elegans innate immunity involve the mechanisms this bacterivore uses to detect infection and mount specific immune responses to different pathogens, despite lacking putative orthologs of many important innate immune components, including cellular immunity, the inflammasome, complement, or melanization. Even when orthologs of known immune factors exist, there appears to be an absence of canonical functions, most notably the lack of pattern recognition by its sole Toll-like receptor. Instead, recent research suggests that C. elegans senses infection by specific pathogens through contextual information, including unique products produced by the pathogen or infection-induced disruption of host physiology, similar to the proposed detection of patterns of pathogenesis in mammalian systems. Interestingly, C. elegans can also transfer information of past infection to their progeny, providing robust protection for their offspring in face of persisting pathogens, in part through the RNAi pathway as well as potential new mechanisms that remain to be elucidated. Altogether, some of these strategies employed by C. elegans share key conceptual features with vertebrate adaptive immunity, as the animal can differentiate specific microbial features, as well as propagate a form of immune memory to their offspring.

Passing down maternal dietary memories through lncRNAs.

Parental diet is known to influence the offspring in an intergenerational manner, and this has been implicated in species adaptation and general health. Recent studies highlight the role of maternal long noncoding RNAs (lncRNAs) in serving as one of the 'memories' of maternal diet in regulating offspring development and predisposition to metabolic disease.

Protecting axons in grandchildren.

Prenatal exposure to environmental agents can influence the fitness of not only the fetus, but also subsequent generations. In a recent study, Wang et al. demonstrated that feeding ursolic acid (UA), a plant-derived compound, to Caenorhabditis elegans mothers during their reproductive period prevented neurodegeneration in not only their offspring, but also the F2 progeny.

Multigenerational adversity impacts on human gut microbiome composition and socioemotional functioning in early childhood.

Adversity exposures in the prenatal and postnatal period are associated with an increased risk for psychopathology, which can be perpetuated across generations. Nonhuman animal research highlights the gut microbiome as a putative biological mechanism underlying such generational risks. In a sample of 450 mother-child dyads living in Singapore, we examined associations between three distinct adversity exposures experienced across two generations-maternal childhood maltreatment, maternal prenatal anxiety, and second-generation children's exposure to stressful life events-and the gut microbiome composition of second-generation children at 2 y of age. We found distinct differences in gut microbiome profiles linked to each adversity exposure, as well as some nonaffected microbiome features (e.g., beta diversity). Remarkably, some of the microbial taxa associated with concurrent and prospective child socioemotional functioning shared overlapping putative functions with those affected by adversity, suggesting that the intergenerational transmission of adversity may have a lasting impact on children's mental health via alterations to gut microbiome functions. Our findings open up a new avenue of research into the underlying mechanisms of intergenerational transmission of mental health risks and the potential of the gut microbiome as a target for intervention.

Using parent-offspring pairs and trios to estimate indirect genetic effects in education.

We investigated indirect genetic effects (IGEs), also known as genetic nurture, in education with a novel approach that uses phased data to include parent-offspring pairs in the transmitted/nontransmitted study design. This method increases the power to detect IGEs, enhances the generalizability of the findings, and allows for the study of effects by parent-of-origin. We validated and applied this method in a family-based subsample of adolescents and adults from the Lifelines Cohort Study in the Netherlands (N = 6147), using the latest genome-wide association study data on educational attainment to construct polygenic scores (PGS). Our results indicated that IGEs play a role in education outcomes in the Netherlands: we found significant associations of the nontransmitted PGS with secondary school level in youth between 13 and 24 years old as well as with education attainment and years of education in adults over 25 years old (ß = 0.14, 0.17 and 0.26, respectively), with tentative evidence for larger maternal IGEs. In conclusion, we replicated previous findings and showed that including parent-offspring pairs in addition to trios in the transmitted/nontransmitted design can benefit future studies of parental IGEs in a wide range of outcomes.

Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala.

We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the regulation of anxiety and fear responses. C57BL/6 mice consumed drinking water containing 0.015% or 0.03% aspartame, a dose equivalent of 8 to 15% of the FDA recommended maximum human daily intake, or plain drinking water. Robust anxiety-like behavior (evaluated using open field test and elevated zero maze) was observed in male and female mice consuming the aspartame-containing water. Diazepam, an allosteric modulator of the GABA-A receptor, alleviated the anxiety-like behavior. RNA sequencing of the amygdala followed by KEGG biological pathway analysis of differentially expressed genes showed glutamatergic and GABAergic synapse pathways as significantly enriched. Quantitative PCR showed upregulation of mRNA for the glutamate NMDA receptor subunit 2D (Grin2d) and metabotropic receptor 4 (Grm4) and downregulation of the GABA-A receptor associated protein (Gabarap) mRNA. Thus, taken together, our diazepam and gene expression data show that aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation. Even more strikingly, the anxiety-like behavior, its response to diazepam, and changes in amygdala gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males. Extrapolation of the findings to humans suggests that aspartame consumption at doses below the FDA recommended maximum daily intake may produce neurobehavioral changes in aspartame-consuming individuals and their descendants. Thus, human population at risk of aspartame's potential mental health effects may be larger than current expectations, which only include aspartame-consuming individuals.

The intergenerational sources of the U-turn in gender segregation.

In the early 1970s, the balkanization of the US labor market into "men's occupations" and "women's occupations" began to unravel, as women entered the professions and other male-typed sectors in record numbers. This decline in gender segregation continued on for several decades but then suddenly stalled at the turn of the century and shows no signs of resuming. Although the stall is itself undisputed, its sources remain unclear. Using nearly a half-century of data from the General Social Survey, we show that a resurgence in segregation-inducing forms of intergenerational transmission stands behind the recent stall. Far from serving as impartial conduits, fathers are now disproportionately conveying male-typed occupations to their sons, whereas mothers are effectively gender-neutral in their transmission outcomes. This segregative turn among fathers accounts for 47% of the stall in the gender segregation trend (between 2000 and 2018), while the earlier integrative turn among fathers accounts for 34% of the initial downturn in segregation (between 1972 and 1999). It follows that a U-turn in intergenerational processes lies behind the U-turn in gender segregation.

The importance of elders: Extending Hamilton's force of selection to include intergenerational transfers.

In classical evolutionary models, the force of natural selection diminishes with age toward zero by last reproduction. However, intergenerational resource transfers and other late-life contributions in social species may select for postreproductive longevity. We present a formal framework for estimating indirect fitness contributions via production transfers in a skills-intensive foraging niche, reflecting kinship and cooperation among group members. Among contemporary human hunter-gatherers and horticulturalists, indirect fitness contributions from transfers exceed direct reproductive contributions from before menopause until ages when surpluses end, around the modal age of adult death (∼70 y). Under reasonable assumptions, these benefits are the equivalent to having up to several more offspring after age 50. Despite early independence, minimal production surplus, and a shorter lifespan, chimpanzees could theoretically make indirect contributions if they adopted reliable food-sharing practices. Our results for chimpanzees hypothetically adopting hunter-gatherer subsistence suggest that a skills-intensive foraging ecology with late independence and late peak production could select for human-like life histories via positive feedback between longevity and late-life transfers. In contrast, life history changes preceding subsistence shifts would not favor further life extension or subsistence shifts. Our results formalize the theory that longevity can be favored under socioecological conditions characterized by parental and alloparental care funded through transfers of mid- to late-life production surpluses. We also extend our analysis beyond food transfers to illustrate the potential for indirect fitness contributions from pedagogy, or information transfers. While we focus mostly on humans, our approach is adaptable to any context or species where transfers can affect fitness.

Multigenerational epigenetic inheritance: Transmitting information across generations.

Inherited epigenetic information has been observed to regulate a variety of complex organismal phenotypes across diverse taxa of life. This continually expanding body of literature suggests that epigenetic inheritance plays a significant, and potentially fundamental, role in inheritance. Despite the important role these types of effects play in biology, the molecular mediators of this non-genetic transmission of information are just now beginning to be deciphered. Here we provide an intellectual framework for interpreting these findings and how they can interact with each other. We also define the different types of mechanisms that have been found to mediate epigenetic inheritance and to regulate whether epigenetic information persists for one or many generations. The field of epigenetic inheritance is entering an exciting phase, in which we are beginning to understand the mechanisms by which non-genetic information is transmitted to, and deciphered by, subsequent generations to maintain essential environmental information without permanently altering the genetic code. A more complete understanding of how and when epigenetic inheritance occurs will advance our understanding of numerous different aspects of biology ranging from how organisms cope with changing environments to human pathologies influenced by a parent's environment.

The global value of freshwater lakes.

Lakes face threats from human activities like unsustainable development, population growth and industrial technologies. These challenges impact the ecosystem services of lakes. Research has assessed the monetary value of services from freshwater biomes annually. This article reviews these values, estimating lakes' global ecosystem services to be within the region of USD 1.3-5.1 trillion annually. Their natural asset value is estimated at USD 87-340 trillion, comparable to the monetary value of global real estate, assuming a relatively high social discount rate to account for future increased standards of living. Considering environmental degradation, future generations may experience a lower living standard. Using a 0.1% discount rate, recognizing potential harm and aligning with indigenous values raises the lakes' value to USD 1300-5100 trillion, which is at least equal to the global monetary value of wealth created. This valuation is shared by all as a collective asset, unlike the skewed distribution of created wealth.

Grandmaternal pre-pregnancy body mass index and infant birthweight: a mediation analysis of maternal pre-pregnancy body mass index.

The objectives of this study were to examine the total effect of grandmaternal [G0] pre-pregnancy body mass index (BMI) on infant [G2] birthweight z-score and to quantify the mediation role of maternal [G1] pre-pregnancy BMI. Data were extracted from the Nova Scotia 3G Multigenerational Cohort. The association between G0 pre-pregnancy BMI and G2 birthweight z-score and the mediated effect by G1 pre-pregnancy BMI were estimated using g-computation with adjustment for confounders identified using a directed acyclic graph and accounting for intermediate confounding. 20822 G1-G2 dyads from 18450 G0 were included. Relative to G0 normal weight, G0 underweight decreased mean G2 birthweight z-score (-0.11, 95% confidence interval (CI) -0.20, -0.030), while G0 overweight and obesity increased mean G2 birthweight z-score (0.091 [95% CI 0.034, 0.15] and 0.22 [95% CI 0.11, 0.33]). G1 pre-pregnancy BMI partly mediated the association, with the largest effect size observed for G0 obesity (0.11, 95% CI 0.080, 0.14). Estimates of the direct effect were close to the null. In conclusion, grandmaternal pre-pregnancy BMI was associated with infant birthweight z-score. Maternal pre-pregnancy BMI partly mediated the association, suggesting that factors related to BMI may play an important role in the transmission of weight across the maternal line.

Impact of Parental Exposure on Offspring Health in Humans.

The possibility that parental life experiences and environmental exposures influence mental and physical health across generations is an important concept in biology and medicine. Evidence from animal models has established the existence of a non-genetic mode of inheritance. This form of heredity involves transmission of the effects of parental exposure to the offspring through epigenetic changes in the germline. Studying the mechanisms of epigenetic inheritance in humans is challenging because it is difficult to obtain multigeneration cohorts, to collect reproductive cells in exposed parents, and to exclude psychosocial and cultural confounders. Nonetheless, epidemiological studies in humans exposed to famine, stress/trauma, or toxicants have provided evidence that parental exposure can impact the health of descendants, in some cases, across several generations. A few studies have also started to reveal epigenetic changes in the periphery and sperm after certain exposures. This article reviews these studies and evaluates the current evidence for the potential contribution of epigenetic factors to heredity in humans. The challenges and limitations of this fundamental biological process, its implications, and its societal relevance are also discussed.

Robust genetic nurture effects on education: A systematic review and meta-analysis based on 38,654 families across 8 cohorts.

Similarities between parents and offspring arise from nature and nurture. Beyond this simple dichotomy, recent genomic studies have uncovered "genetic nurture" effects, whereby parental genotypes influence offspring outcomes via environmental pathways rather than genetic transmission. Such genetic nurture effects also need to be accounted for to accurately estimate "direct" genetic effects (i.e., genetic effects on a trait originating in the offspring). Empirical studies have indicated that genetic nurture effects are particularly relevant to the intergenerational transmission of risk for child educational outcomes, which are, in turn, associated with major psychological and health milestones throughout the life course. These findings have yet to be systematically appraised across contexts. We conducted a systematic review and meta-analysis to quantify genetic nurture effects on educational outcomes. A total of 12 studies comprising 38,654 distinct parent(s)-offspring pairs or trios from 8 cohorts reported 22 estimates of genetic nurture effects. Genetic nurture effects on offspring's educational outcomes (ßgenetic nurture = 0.08, 95% CI [0.07, 0.09]) were smaller than direct genetic effects (ßdirect genetic = 0.17, 95% CI [0.13, 0.20]). Findings were largely consistent across studies. Genetic nurture effects originating from mothers and fathers were of similar magnitude, highlighting the need for a greater inclusion of fathers in educational research. Genetic nurture effects were largely explained by observed parental education and socioeconomic status, pointing to their role in environmental pathways shaping child educational outcomes. Findings provide consistent evidence that environmentally mediated parental genetic influences contribute to the intergenerational transmission of educational outcomes, in addition to effects due to genetic transmission.

Paternal MTHFR deficiency leads to hypomethylation of young retrotransposons and reproductive decline across two successive generations.

5,10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in the folate metabolic pathway with a key role in generating methyl groups. As MTHFR deficiency impacts male fertility and sperm DNA methylation, there is the potential for epimutations to be passed to the next generation. Here, we assessed whether the impact of MTHFR deficiency on testis morphology and sperm DNA methylation is exacerbated across generations in mouse. Although MTHFR deficiency in F1 fathers has only minor effects on sperm counts and testis weights and histology, F2 generation sons show further deterioration in reproductive parameters. Extensive loss of DNA methylation is observed in both F1 and F2 sperm, with >80% of sites shared between generations, suggestive of regions consistently susceptible to MTHFR deficiency. These regions are generally methylated during late embryonic germ cell development and are enriched in young retrotransposons. As retrotransposons are resistant to reprogramming of DNA methylation in embryonic germ cells, their hypomethylated state in the sperm of F1 males could contribute to the worsening reproductive phenotype observed in F2 MTHFR-deficient males, compatible with the intergenerational passage of epimutations.