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Development of tau-based therapies for Alzheimer’s disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer’s disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments. Site-specific hyperphosphorylations of tau in the cerebrospinal fluid change with disease course, and correlate with pathology and cognitive decline in dominantly inherited Alzheimer’s disease.

Increasing evidence indicates that non-DNA sequence-based epigenetic information can be inherited across several generations in organisms ranging from yeast to plants to humans. This raises the possibility of heritable ‘epimutations’ contributing to heritable phenotypic variation and thus to evolution. Recent work has shed light on both the signals that underpin these epimutations, including DNA methylation, histone modifications and non-coding RNAs, and the mechanisms by which they are transmitted across generations at the molecular level. These mechanisms can vary greatly among species and have a more limited effect in mammals than in plants and other animal species. Nevertheless, common principles are emerging, with transmission occurring either via direct replicative mechanisms or indirect reconstruction of the signal in subsequent generations. As these processes become clearer we continue to improve our understanding of the distinctive features and relative contribution of DNA sequence and epigenetic variation to heritable differences in phenotype.In this Review, Fitz-James and Cavalli discuss the diverse and often multilayered mechanisms by which transgenerational epigenetic inheritance can occur in different species.

DNA methylation can cause heritable phenotypic modifications in the absence of changes in DNA sequence. Environmental stresses can trigger methylation changes and this may have evolutionary consequences, even in the absence of sequence variation. However, it remains largely unknown to what extent environmentally induced methylation changes are transmitted to offspring, and whether observed methylation variation is truly independent or a downstream consequence of genetic variation between individuals. Genetically identical apomictic dandelion (Taraxacum officinale) plants were exposed to different ecological stresses, and apomictic offspring were raised in a common unstressed environment. We used methylation-sensitive amplified fragment length polymorphism markers to screen genome-wide methylation alterations triggered by stress treatments and to assess the heritability of induced changes. Various stresses, most notably chemical induction of herbivore and pathogen defenses, triggered considerable methylation variation throughout the genome. Many modifications were faithfully transmitted to offspring. Stresses caused some epigenetic divergence between treatment and controls, but also increased epigenetic variation among plants within treatments. These results show the following. First, stress-induced methylation changes are common and are mostly heritable. Second, sequence-independent, autonomous methylation variation is readily generated. This highlights the potential of epigenetic inheritance to play an independent role in evolutionary processes, which is superimposed on the system of genetic inheritance.

De novo DNA methylation (DNAme) during mouse oogenesis occurs within transcribed regions enriched for H3K36me3. As many oocyte transcripts originate in long terminal repeats (LTRs), which are heterogeneous even between closely related mammals, we examined whether species-specific LTR-initiated transcription units (LITs) shape the oocyte methylome. Here we identify thousands of syntenic regions in mouse, rat, and human that show divergent DNAme associated with private LITs, many of which initiate in lineage-specific LTR retrotransposons. Furthermore, CpG island (CGI) promoters methylated in mouse and/or rat, but not human oocytes, are embedded within rodent-specific LITs and vice versa. Notably, at a subset of such CGI promoters, DNAme persists on the maternal genome in fertilized and parthenogenetic mouse blastocysts or in human placenta, indicative of species-specific epigenetic inheritance. Polymorphic LITs are also responsible for disparate DNAme at promoter CGIs in distantly related mouse strains, revealing that LITs also promote intra-species divergence in CGI DNAme. De novo DNA methylation during mouse oogenesis occurs within transcribed regions. Here the authors investigate the role of species-specific long terminal repeats (LTRs)-initiated transcription units in regulating the oocyte methylome, identifying syntenic regions in mouse, rat and human with divergent DNA methylation associated with private LITs.

Ancestral environmental exposures to a variety of factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. One of the most widely used agricultural pesticides worldwide is the herbicide glyphosate (N-(phosphonomethyl)glycine), commonly known as Roundup. There are an increasing number of conflicting reports regarding the direct exposure toxicity (risk) of glyphosate, but no rigorous investigations on the generational actions. The current study using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed. The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities. Epigenetic analysis of the F1, F2 and F3 generation sperm identified differential DNA methylation regions (DMRs). A number of DMR associated genes were identified and previously shown to be involved in pathologies. Therefore, we propose glyphosate can induce the transgenerational inheritance of disease and germline (e.g. sperm) epimutations. Observations suggest the generational toxicology of glyphosate needs to be considered in the disease etiology of future generations.

Key Points An emerging idea in evolutionary biology is that inheritance implies more than the sole transmission of the DNA sequence across generations. Non-genetic inheritance of information across generations results from various processes that contribute to parent–offspring resemblance, a property that is called heritability. The concept of heritability has been generalized into that of inclusive heritability, which is the heredity of differences, including all forms of inheritance. It unifies genetic and non-genetic heritability into a single framework encompassing the multiple dimensions of inheritance. We briefly provide evidence for the four identified processes of non-genetic inheritance. Epigenetic changes in DNA expression result in epigenetic inheritance when they are transmitted across generations, thus contributing to the transgenerational transmission of phenotypic variation. Epigenetic changes are usually mediated by changes in environmental conditions. Examples include the inheritance of maternal behaviour in rodents or the inheritance of flower symmetry. Parental non-genetic effects can result in the inheritance of non-genetic information across generations, thus contributing to the non-genetic component of inclusive heritability. Examples include the inheritance of immunocompetence against given parasites in birds or flexible adaptation to the maternal light environment in plants. Ecological inheritance occurs when offspring inherit the habitat of their parents. This indicates that any modification of the environment that results from ancestral activity and that affects fitness will change subsequent selective pressures. Examples include the webs, nests, dams and burrows that numerous animal species create, but also the changes in atmospheric gases and soil nutrients brought about by bacteria and plant species. Culture is the part of phenotypic variance that is transmitted through social learning. Recent evidence suggests that cultural transmission is widespread among animals. Examples concern mate choice and species recognition. Cultural selection constitutes another engine of evolution when it interacts with natural selection in both animals and humans. Non-genetic inheritance can easily be confounded with genetic inheritance. It is the intricate network of genetic and non-genetic inheritance systems that produce parent–offspring resemblance, which constitutes the whole evolutionary potential of a trait quantified by inclusive heritability. We formally partition inclusive heritability and propose methods to disentangle its components in order to better integrate them into a comprehensive view of inheritance. We propose specific designs coupling field or experimental longitudinal data with animal model types of statistical tools. Such methods should help to unravel fascinating enigmas in evolution and medicine, such as major evolutionary transitions or the 'missing heritability' in the human genome. The time is ripe to broaden concepts of inheritance and heritability in order to fully grasp the richness of evolutionary processes, and we call for a multidimensional modern synthesis that would merge the current modern synthesis with an inclusive view of inheritance. Increasing evidence indicates that non-genetic information, as well as DNA sequence, is transmitted across generations to influence evolution. The authors review the evidence for different modes of non-genetic inheritance and discuss how they can be accounted for in evolutionary studies. Many biologists are calling for an 'extended evolutionary synthesis' that would 'modernize the modern synthesis' of evolution. Biological information is typically considered as being transmitted across generations by the DNA sequence alone, but accumulating evidence indicates that both genetic and non-genetic inheritance, and the interactions between them, have important effects on evolutionary outcomes. We review the evidence for such effects of epigenetic, ecological and cultural inheritance and parental effects, and outline methods that quantify the relative contributions of genetic and non-genetic heritability to the transmission of phenotypic variation across generations. These issues have implications for diverse areas, from the question of missing heritability in human complex-trait genetics to the basis of major evolutionary transitions.

Neural stem/progenitor cells (NSPCs) generate new neurons throughout adulthood. However, the underlying regulatory processes are still not fully understood. Lipid metabolism plays an important role in regulating NSPC activity: build-up of lipids is crucial for NSPC proliferation, whereas break-down of lipids has been shown to regulate NSPC quiescence. Despite their central role for cellular lipid metabolism, the role of lipid droplets (LDs), the lipid storing organelles, in NSPCs remains underexplored. Here we show that LDs are highly abundant in adult mouse NSPCs, and that LD accumulation is significantly altered upon fate changes such as quiescence and differentiation. NSPC proliferation is influenced by the number of LDs, inhibition of LD build-up, breakdown or usage, and the asymmetric inheritance of LDs during mitosis. Furthermore, high LD-containing NSPCs have increased metabolic activity and capacity, but do not suffer from increased oxidative damage. Together, these data indicate an instructive role for LDs in driving NSPC behaviour. Lipid droplets (LDs) are central to lipid metabolism, which is known to regulate neural stem cell behavior. Here, the authors show that LDs influence neural stem cell proliferation and metabolic activity and change upon differentiation or quiescence.

Ancestral environmental exposures have previously been shown to promote epigenetic transgenerational inheritance and influence all aspects of an individual's life history. In addition, proximate life events such as chronic stress have documented effects on the development of physiological, neural, and behavioral phenotypes in adulthood. We used a systems biology approach to investigate in male rats the interaction of the ancestral modifications carried transgenerationally in the germ line and the proximate modifications involving chronic restraint stress during adolescence. We find that a single exposure to a common-use fungicide (vinclozolin) three generations removed alters the physiology, behavior, metabolic activity, and transcriptome in discrete brain nuclei in descendant males, causing them to respond differently to chronic restraint stress. This alteration of baseline brain development promotes a change in neural genomic activity that correlates with changes in physiology and behavior, revealing the interaction of genetics, environment, and epigenetic transgenerational inheritance in the shaping of the adult phenotype. This is an important demonstration in an animal that ancestral exposure to an environmental compound modifies how descendants of these progenitor individuals perceive and respond to a stress challenge experienced during their own life history.

Indirect genetic effects from relatives may result in misleading quantifications of heritability, but can also be of interest in their own right. In this paper we propose Trio-GCTA, a model for separating direct and indirect genetic effects when genome-wide single nucleotide polymorphism data have been collected from parent-offspring trios. The model is applicable to phenotypes obtained from any of the family members. We discuss appropriate parameter interpretations and apply the method to three exemplar phenotypes: offspring birth weight, maternal relationship satisfaction, and paternal body-mass index, using real data from the Norwegian Mother, Father and Child Cohort Study (MoBa).

Albinism is the most common color variation described in fish and is characterized by a white or yellow phenotype according to the species. In rainbow trout Oncorhynchus mykiss, aside from yellow-albino phenotypes, cobalt blue variants with autosomal, recessive inheritance have also been reported. In this study, we investigated the inheritance pattern and chromatophores distribution/abundance of cobalt blue trouts obtained from a local fish farm. Based on crosses with wild-type and dominant yellow-albino lines, we could infer that cobalt blue are dominant over wild-type and co-dominant in relation to yellow-albino phenotype, resulting in a fourth phenotype: the white-albino. Analysis of chromatophores revealed that cobalt blue trouts present melanophores, as the wild-type, and a reduced number of xanthophores. As regards to the white-albino phenotype, they were not only devoid of melanophores but also presented a reduced number of xanthophores. Cobalt blue and white-albino trouts also presented reduced body weight and a smaller pituitary gland compared to wild-type and yellow-albino phenotypes. The transcription levels of tshb and trh were up regulated in cobalt blue compared to wild type, suggesting the involvement of thyroid hormone in the expression of blue color. These phenotypes represent useful models for research on body pigmentation in salmonids and on the mechanisms behind endocrine control of color patterning.