[Multigenerational epigenetic inheritance in human: the past, present and perspectives]. / L'héritage épigénétique multigénérationnel chez l'Homme : le passé, le présent et les perspectives.

Nowadays, a growing body of evidence suggests that the developmental programs of each individual could be modified. The acquired new phenotypic changes could be persistent throughout the individual's life and even transmitted to the next generation. While the exact mechanism for that preservation is not well understood yet, there are many evidences showing that epigenetic alterations, which are robust and dynamic in response to the influence of the environmental factors, could be responsible for that inheritance. A growing number of external factors such as social stress, environmental pollution and climate changes make adaptation to these environmental changes rather challenging. According to the Developmental Origin of Human Disease theory, formulated by David Barker, environmental conditions experienced during the first phases of development can have long term effects on later phases of life. This phenomenon is linked to the biological plasticity of development, which allows reprogramming of physiological functions in response to different stimuli. Consequently, in utero exposure to environmental pollutants can increase predisposition to different pathologies that can occur both in early and later phases of life not only in the living generation but also in subsequent ones. Here, we have summarised some findings in human epigenetic research studies performed for the past few years which address the question whether transgenerational effects observed in model organisms could also occur in humans.

Title: L'héritage épigénétique multigénérationnel chez l'Homme : le passé, le présent et les perspectives. Abstract: De nos jours, de nombreuses études suggèrent que les programmes de développement de chaque individu seraient susceptibles d'être modifiés. Les changements phénotypiques acquis pourraient persister tout au long de la vie de l'individu et même être transmis à la génération suivante. Bien que le mécanisme exact de cette préservation ne soit pas encore bien compris, de nombreuses observations suggèrent que les altérations épigénétiques en réponse à l'influence des facteurs environnementaux seraient responsables de cette hérédité. Le nombre croissant de facteurs externes tels que le stress social, la pollution environnementale et les changements climatiques rend difficile l'adaptation à ce nouvel environnement. Selon la théorie de l'origine développementale des maladies humaines, formulée par David Barker, les conditions environnementales rencontrées au cours des premières phases du développement peuvent avoir des effets à long terme sur les phases ultérieures de la vie. Ce phénomène est lié à la plasticité biologique du développement, qui permet une reprogrammation des fonctions physiologiques en réponse à différents stimuli. L'exposition in utero à des polluants environnementaux accroîtrait la prédisposition à des pathologies survenant dans les phases précoces et tardives de la vie, non seulement pour les générations présentes mais aussi les suivantes. Nous avons résumé ici des résultats d'études épidémiologiques et épigénétiques menées ces dernières années sur des données humaines afin de savoir si les effets transgénérationnels observés dans des organismes modèles peuvent également exister chez l'homme.

Inheritance of Partial Resistance to Isolate VdLs17 of Verticillium dahliae Within Lactuca spp.

Lettuce (Lactuca sativa L.) production is greatly threatened by Verticillium wilt, which is caused by three pathogenic races (races 1, 2, and 3) of the soilborne fungus Verticillium dahliae. Race 1 is predominant, and resistant varieties that provide full protection against it are commercially available. However, heavily relying on race 1-resistant cultivars could shift the population towards resistance-breaking isolates and impact the durability of plant resistance. This study determined the inheritance of partial resistance to isolate VdLs17 of V. dahliae within Lactuca spp. using 258 F2:3 progeny generated from a cross between two partially resistant accessions, 11G99 (L. serriola) and PI 171674 (L. sativa). Eight experiments were performed under greenhouse and growth room conditions across 3 years using a randomized complete block design, and segregation analysis was conducted to determine the inheritance pattern. The results indicate that partial resistance to isolate VdLs17 of V. dahliae is conditioned by a two-major-gene genetic model with additive-dominance-epistatic effects. Transgressive segregants were infrequent but observed in both directions, indicating that favorable and adverse alleles are dispersed in both parents. Combining favorable alleles of these two partially resistant parents appears to be challenging because of epistatic effects and a significant role of environment in disease severity. The probability of capturing favorable additive genes could be maximized by generating and evaluating a large population and making selections at late generations. This study provides valuable insights into the inheritance pattern of partial resistance to isolate VdLs17 of V. dahliae that will be helpful in designing efficient breeding strategies in lettuce.[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Phenotypic cross-species conservation and cross-generation directionality switching in epigenetic inheritance.

Evidence supporting non-DNA sequence-based inheritance in animals has increasingly been described in recent years, often under intergenerational inheritance or transgenerational epigenetic inheritance (TEI). Existence of the latter, a stronger indicator of germline transmission, has been demonstrated in invertebrates and mammals alike. The mechanisms and physiological implications of TEI, however, remain unclear. Here, in an unbiased approach, we compared existing transcriptomic data associated with so far available Drosophila models of inter- and trans-, and rodent models of inter-generational inheritance; observed phenotypic cross-species conservation and cross-generation directionality shift therein; and confirmed these observations experimentally in flies. Specifically, previous models of cold and diet-induced inheritance in both flies and mice were commonly associated with altered regulation of proteolysis genes. Besides, fly TEI models were in general characterized by opposite phenotypic regulation in transgenerational offsprings, compared to the ancestors. As insulin-producing cell (IPC) ablation was also associated with proteolysis gene dysregulation in one of the mouse models, we opted to use genetic ablation of IPCs in flies for the experimental validation. Remarkably, the ablation led to transcriptomic alterations across multiple generations, with dysregulated genes showing proteolysis enrichment. Similarly, phenotypic directionality changed in the opposite direction in transgenerational offsprings, in comparison of the ancestors. These results support evolutionary conservation, and both physiologically adaptive and maladaptive consequences of germline mediated epigenetic inheritance.

When and why are mitochondria paternally inherited?

In contrast with nuclear genes that are passed on through both parents, mitochondrial genes are maternally inherited in most species, most of the time. The genetic conflict stemming from this transmission asymmetry is well-documented, and there is an abundance of population-genetic theory associated with it. While occasional or aberrant paternal inheritance occurs, there are only a few cases where exclusive paternal inheritance of mitochondrial genomes is the evolved state. Why this is remains poorly understood. By examining commonalities between species with exclusive paternal inheritance, we discuss what they may tell us about the evolutionary forces influencing mitochondrial inheritance patterns. We end by discussing recent technological advances that make exploring the causes and consequences of paternal inheritance feasible.

Epigenetic control of heredity.

Epigenetics is the field of science that deals with the study of changes in gene function that do not involve changes in DNA sequence and are heritable while epigenetics inheritance is the process of transmission of epigenetic modifications to the next generation. It can be transient, intergenerational, or transgenerational. There are various epigenetic modifications involving mechanisms such as DNA methylation, histone modification, and noncoding RNA expression, all of which are inheritable. In this chapter, we summarize the information on epigenetic inheritance, its mechanism, inheritance studies on various organisms, factors affecting epigenetic modifications and their inheritance, and the role of epigenetic inheritance in the heritability of diseases.

Inheritance and molecular mapping of solitary/cluster fruit-bearing habit in Luffa.

Fruiting behaviour and sex form are important goals for Luffa breeders and this study aimed to shed light upon inheritance patterns for both these traits. The hermaphrodite form of Luffa acutangula (known as Satputia) is an underutilized vegetable with a unique clustered fruiting habit. Its desirable traits, such as plant architecture, earliness, as well as contrasting traits like unique clustered fruiting, bisexual flower, and crossability with Luffa acutangula (monoecious ridge gourd with solitary fruits), make it a potential source for trait improvement and mapping of desirable traits in Luffa. In the present study, we have elucidated the inheritance pattern of fruiting behaviour in Luffa using F2 mapping population generated from a cross between Pusa Nutan (Luffa acutangula, monoecious, solitary fruiting) × DSat-116 (Luffa acutangula, hermaphrodite, cluster fruiting). In F2 generation, the observed distribution of plant phenotypes fitted in the expected ratio of 3:1 (solitary vs cluster) for fruit-bearing habit. This is the first report of monogenic recessive control for cluster fruit-bearing habit in Luffa. Herein, we designate for the first time the gene symbol cl for cluster fruit bearing in Luffa. Linkage analysis revealed that SRAP marker ME10 EM4-280 was linked to the fruiting trait at the distance of 4.6 cM from the Cl locus. In addition, the inheritance pattern of hermaphrodite sex form in Luffa was also studied in the F2 population of Pusa Nutan × DSat-116 that segregated into 9:3:3:1 ratio (monoecious:andromonoecious:gynoecious:hermaphrodite), suggesting a digenic recessive control of hermaphrodite sex form in Luffa, which was further confirmed by the test cross. The inheritance and identification of molecular marker for cluster fruiting trait provides a basis for breeding in Luffa species.

The third barrier to transgenerational inheritance in animals: somatic epigenetic resetting.

After early controversy, it is now increasingly clear that acquired responses to environmental factors may perpetuate across multiple generations-a phenomenon termed transgenerational epigenetic inheritance (TEI). Experiments with Caenorhabditis elegans, which exhibits robust heritable epigenetic effects, demonstrated small RNAs as key factors of TEI. Here, we discuss three major barriers to TEI in animals, two of which, the "Weismann barrier" and germline epigenetic reprogramming, have been known for decades. These are thought to effectively prevent TEI in mammals but not to the same extent in C. elegans. We argue that a third barrier-that we termed "somatic epigenetic resetting"-may further inhibit TEI and, unlike the other two, restricts TEI in C. elegans as well. While epigenetic information can overcome the Weismann barrier and transmit from the soma to the germline, it usually cannot "travel back" directly from the germline to the soma in subsequent generations. Nevertheless, heritable germline memory may still influence the animal's physiology by indirectly modifying gene expression in somatic tissues.

Mechanisms of transgenerational epigenetic inheritance: lessons from animal model organisms.

Epigenetic inheritance is a phenomenon whereby stochastic or signal-induced changes to parental germline epigenome modulate phenotypic output in one or more subsequent generations, independently of mutations in the genomic DNA. While the number of reported epigenetic inheritance phenomena across phyla is exponentially growing, much remains to be elucidated about their mechanistic underpinnings, and their significance for organismal homeostasis and adaptation. Here, we review the most recent epigenetic inheritance examples in animal models, outlining molecular details behind environmental sensing by the germline, and the functional relationships connecting epigenetic mechanisms and phenotypic traits after fertilization. We touch upon the experimental challenges associated with studying the scope of environmental input on phenotypic outcomes between generations. Finally, we discuss the implications of mechanistic findings from model organisms for the emergent examples of parental effects in human populations.

Transgenerational inheritance and its modulation by environmental cues.

The epigenome plays an important role in shaping phenotypes. However, whether the environment can alter an organism's phenotype across several generations through epigenetic remodeling in the germline is still a highly debated topic. In this chapter, we briefly review the mechanisms of epigenetic inheritance and their connection with germline development before highlighting specific developmental windows of susceptibility to environmental cues. We further discuss the evidence of transgenerational inheritance to a range of different environmental cues, both epidemiological in humans and experimental in rodent models. Doing so, we pinpoint the current challenges in demonstrating transgenerational inheritance to environmental cues and offer insight in how recent technological advances may help deciphering the epigenetic mechanisms at play. Together, we draw a detailed picture of how our environment can influence our epigenomes, ultimately reshaping our phenotypes, in an extended theory of inheritance.

Structural variants identified using non-Mendelian inheritance patterns advance the mechanistic understanding of autism spectrum disorder.

The heritability of autism spectrum disorder (ASD), based on 680,000 families and five countries, is estimated to be nearly 80%, yet heritability reported from SNP-based studies are consistently lower, and few significant loci have been identified with genome-wide association studies. This gap in genomic information may reside in rare variants, interaction among variants (epistasis), or cryptic structural variation (SV) and may provide mechanisms that underlie ASD. Here we use a method to identify potential SVs based on non-Mendelian inheritance patterns in pedigrees using parent-child genotypes from ASD families and demonstrate that they are enriched in ASD-risk genes. Most are in non-coding genic space and are over-represented in expression quantitative trait loci, suggesting that they affect gene regulation, which we confirm with their overlap of differentially expressed genes in postmortem brain tissue of ASD individuals. We then identify an SV in the GRIK2 gene that alters RNA splicing and a regulatory region of the ACMSD gene in the kynurenine pathway as significantly associated with a non-verbal ASD phenotype, supporting our hypothesis that these currently excluded loci can provide a clearer mechanistic understanding of ASD. Finally, we use an explainable artificial intelligence approach to define subgroups demonstrating their use in the context of precision medicine.

A CRISPR endonuclease gene drive reveals distinct mechanisms of inheritance bias.

CRISPR/Cas gene drives can bias transgene inheritance through different mechanisms. Homing drives are designed to replace a wild-type allele with a copy of a drive element on the homologous chromosome. In Aedes aegypti, the sex-determining locus is closely linked to the white gene, which was previously used as a target for a homing drive element (wGDe). Here, through an analysis using this linkage we show that in males inheritance bias of wGDe did not occur by homing, rather through increased propagation of the donor drive element. We test the same wGDe drive element with transgenes expressing Cas9 with germline regulatory elements sds3, bgcn, and nup50. We only find inheritance bias through homing, even with the identical nup50-Cas9 transgene. We propose that DNA repair outcomes may be more context dependent than anticipated and that other previously reported homing drives may, in fact, bias their inheritance through other mechanisms.

Inheritance of androgenesis response in pepper.

BACKGROUND: Anther culture has become an important part of pepper breeding. Response to haploidy via androgenesis is highly genotype-specific. However, studies on the inheritance of response to anther culture are lacking. Therefore, the study aimed to determine the inheritance of androgenesis. METHODS AND RESULTS: The plant material included crosses involving Capsicum annuum L. (253 A, and Inan3363) X C. chinense PI 159,236 populations. To estimate the heritability of the trait, two pepper lines with very high androgenesis responses were crossed with PI 159,236, a non-responsive accession. The androgenesis response was phenotyped using the parents, F1, F2, BC1P1, and BC1P2/P3 created through reciprocal crosses. Using variance components, the number of genes controlling the trait, broad (H2 = 0.97), and narrow sense heritabilities (h2 = 0.20), genetic variance (VG=113.8), the additive (VA=23.9), and the dominance gene variances (VD = 89.9), as well as the environmental variance (VE = 3.6) were calculated. Additive and dominant gene effects were 21% and 79%, respectively. Results derived from two different populations showed that the number of genes controlling the trait was between 1.96 and 2.46, and H2 = 0.96-0.97, h2 = 0.20-0.65, VG=91.8-113.8, VA, = 23.9-62.7, VD = 29.1-89.9, and VE=3.5-3.6 were calculated. The X2 analysis indicated that the most suitable one is the 9: 3: 4 epistatic genetic model (X2 = 2.13, P = 0.343, N = 155). CONCLUSIONS: Results obtained from two different populations indicate the existence of a few major genes for response to androgenesis in pepper. Elucidating the inheritance of androgenesis is expected to pave the way for tagging the gene(s) in the pepper genome.

Mechanisms of chromatin-based epigenetic inheritance.

Multi-cellular organisms such as humans contain hundreds of cell types that share the same genetic information (DNA sequences), and yet have different cellular traits and functions. While how genetic information is passed through generations has been extensively characterized, it remains largely obscure how epigenetic information encoded by chromatin regulates the passage of certain traits, gene expression states and cell identity during mitotic cell divisions, and even through meiosis. In this review, we will summarize the recent advances on molecular mechanisms of epigenetic inheritance, discuss the potential impacts of epigenetic inheritance during normal development and in some disease conditions, and outline future research directions for this challenging, but exciting field.

Three legs of the missing heritability problem.

The so-called 'missing heritability problem' is often characterized by behavior geneticists as a numerical discrepancy between alternative kinds of heritability. For example, while 'traditional heritability' derived from twin and family studies indicates that approximately ∼50% of variation in intelligence is attributable to genetics, 'SNP heritability' derived from genome-wide association studies indicates that only ∼10% of variation in intelligence is attributable to genetics. This 40% gap in variance accounted for by alternative kinds of heritability is frequently referred to as what's "missing." Philosophers have picked up on this reading, suggesting that "dissolving" the missing heritability problem is merely a matter of closing the numerical gap between traditional and molecular kinds of heritability. We argue that this framing of the problem undervalues the severity of the many challenges to scientific understanding of the "heritability" of human behavior. On our view, resolving the numerical discrepancies between alternative kinds of heritability will do little to advance scientific explanation and understanding of behavior genetics. Thus, we propose a new conceptual framework of the missing heritability problem that comprises three independent methodological and explanatory challenges: the numerical gap, the prediction gap, and the mechanism gap.

Epigenetic Inheritance: Intergenerational Effects of Pesticides and Other Endocrine Disruptors on Cancer Development.

Parental environmental experiences affect disease susceptibility in the progeny through epigenetic inheritance. Pesticides are substances or mixtures of chemicals-some of which are persistent environmental pollutants-that are used to control pests. This review explores the evidence linking parental exposure to pesticides and endocrine disruptors to intergenerational and transgenerational susceptibility of cancer in population studies and animal models. We also discuss the impact of pesticides and other endocrine disruptors on the germline epigenome as well as the emerging evidence for how epigenetic information is transmitted between generations. Finally, we discuss the importance of this mode of inheritance in the context of cancer prevention and the challenges ahead.

Machine learning approaches to explore digenic inheritance.

Some rare genetic disorders, such as retinitis pigmentosa or Alport syndrome, are caused by the co-inheritance of DNA variants at two different genetic loci (digenic inheritance). To capture the effects of these disease-causing variants and their possible interactive effects, various statistical methods have been developed in human genetics. Analogous developments have taken place in the field of machine learning, particularly for the field that is now called Big Data. In the past, these two areas have grown independently and have started to converge only in recent years. We discuss an overview of each of the two fields, paying special attention to machine learning methods for uncovering the combined effects of pairs of variants on human disease.

Environmental induced transgenerational inheritance impacts systems epigenetics in disease etiology.

Environmental toxicants have been shown to promote the epigenetic transgenerational inheritance of disease through exposure specific epigenetic alterations in the germline. The current study examines the actions of hydrocarbon jet fuel, dioxin, pesticides (permethrin and methoxychlor), plastics, and herbicides (glyphosate and atrazine) in the promotion of transgenerational disease in the great grand-offspring rats that correlates with specific disease associated differential DNA methylation regions (DMRs). The transgenerational disease observed was similar for all exposures and includes pathologies of the kidney, prostate, and testis, pubertal abnormalities, and obesity. The disease specific DMRs in sperm were exposure specific for each pathology with negligible overlap. Therefore, for each disease the DMRs and associated genes were distinct for each exposure generational lineage. Observations suggest a large number of DMRs and associated genes are involved in a specific pathology, and various environmental exposures influence unique subsets of DMRs and genes to promote the transgenerational developmental origins of disease susceptibility later in life. A novel multiscale systems biology basis of disease etiology is proposed involving an integration of environmental epigenetics, genetics and generational toxicology.