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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.

Unhealthful dietary habits are leading risk factors for life-altering diseases and mortality. Large-scale biobanks now enable genetic analysis of traits with modest heritability, such as diet. We perform a genomewide association on 85 single food intake and 85 principal component-derived dietary patterns from food frequency questionnaires in UK Biobank. We identify 814 associated loci, including olfactory receptor associations with fruit and tea intake; 136 associations are only identified using dietary patterns. Mendelian randomization suggests our top healthful dietary pattern driven by wholemeal vs. white bread consumption is causally influenced by factors correlated with education but is not strongly causal for coronary artery disease or type 2 diabetes. Overall, we demonstrate the value in complementary phenotyping approaches to complex dietary datasets, and the utility of genomic analysis to understand the relationships between diet and human health. The choice of food intake is at least partially influenced by genetics, even though the effect sizes appear rather modest. Here, Cole et al. perform GWAS for food intake (85 individual food items and 85 derived dietary patterns) and test potential causal relationships with cardiometabolic traits using Mendelian randomization.

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.

Many genes of large double-stranded DNA viruses have a cellular origin, suggesting that host-to-virus horizontal transfer (HT) of DNA is recurrent. Yet, the frequency of these transfers has never been assessed in viral populations. Here we used ultra-deep DNA sequencing of 21 baculovirus populations extracted from two moth species to show that a large diversity of moth DNA sequences (n = 86) can integrate into viral genomes during the course of a viral infection. The majority of the 86 different moth DNA sequences are transposable elements (TEs, n = 69) belonging to 10 superfamilies of DNA transposons and three superfamilies of retrotransposons. The remaining 17 sequences are moth sequences of unknown nature. In addition to bona fide DNA transposition, we uncover microhomology-mediated recombination as a mechanism explaining integration of moth sequences into viral genomes. Many sequences integrated multiple times at multiple positions along the viral genome. We detected a total of 27,504 insertions of moth sequences in the 21 viral populations and we calculate that on average, 4.8% of viruses harbor at least one moth sequence in these populations. Despite this substantial proportion, no insertion of moth DNA was maintained in any viral population after 10 successive infection cycles. Hence, there is a constant turnover of host DNA inserted into viral genomes each time the virus infects a moth. Finally, we found that at least 21 of the moth TEs integrated into viral genomes underwent repeated horizontal transfers between various insect species, including some lepidopterans susceptible to baculoviruses. Our results identify host DNA influx as a potent source of genetic diversity in viral populations. They also support a role for baculoviruses as vectors of DNA HT between insects, and call for an evaluation of possible gene or TE spread when using viruses as biopesticides or gene delivery vectors.

Single-cell RNA sequencing has revealed extensive transcriptional cell state diversity in cancer, often observed independently of genetic heterogeneity, raising the central question of how malignant cell states are encoded epigenetically. To address this, here we performed multiomics single-cell profiling—integrating DNA methylation, transcriptome and genotype within the same cells—of diffuse gliomas, tumors characterized by defined transcriptional cell state diversity. Direct comparison of the epigenetic profiles of distinct cell states revealed key switches for state transitions recapitulating neurodevelopmental trajectories and highlighted dysregulated epigenetic mechanisms underlying gliomagenesis. We further developed a quantitative framework to directly measure cell state heritability and transition dynamics based on high-resolution lineage trees in human samples. We demonstrated heritability of malignant cell states, with key differences in hierarchal and plastic cell state architectures in IDH-mutant glioma versus IDH-wild-type glioblastoma, respectively. This work provides a framework anchoring transcriptional cancer cell states in their epigenetic encoding, inheritance and transition dynamics. Multimodal DNA methylation and transcriptome profiling of single glioma cells links tumor cell transcriptional states to epigenetics via interaction with PRC2 and shows that these states are heritable and important for tumor plasticity.

Key Points Recent evidence increasingly supports the idea that certain ancestral life experiences acquired in the environment can be inherited by offspring; paternally acquired characteristics can be encoded in the sperm in the form of epigenetic information in addition to DNA sequences. Sperm RNAs, in particular sperm microRNAs (miRNAs) and tRNA-derived small RNAs (tsRNAs), can mediate intergenerational transmission of paternally acquired phenotypes such as diet-induced metabolic disorders and mental stress phenotypes. The mechanisms by which sperm RNAs respond to environmental changes and encode the acquired traits remain unclear but may involve environmental–somatic–germline interactions that may be mediated by extracellular vesicles (EVs) and mobile RNAs, and involve a breach of the somatic–germline barrier. Sperm RNAs may initiate a transcriptional cascade of effects throughout embryonic development to induce a paternally acquired phenotype in offspring; how the initial effects caused by sperm RNAs are converted to a stable form of information to allow transgenerational inheritance remains a major puzzle but possibly involves interplay among transposable elements, DNA methylation and chromatin structure. Emerging evidence suggests that RNA modifications in sperm RNAs have an essential role in modulating epigenetic memory. Novel methods are required to map the locations of multiple RNA modifications in each RNA species, especially for tsRNAs and miRNAs that can induce offspring phenotypes. It remains unknown how many types of acquired traits can be transmitted to offspring through the germ line and under what circumstances this is likely to occur. Studies have demonstrated that paternal traits acquired in response to environmental conditions can be inherited by the offspring, sometimes persisting for multiple generations. In this Review, the authors discuss the accumulating evidence of a major role for sperm RNAs and RNA modifications in the inheritance of acquired traits and the mechanisms that may underlie this. Once deemed heretical, emerging evidence now supports the notion that the inheritance of acquired characteristics can occur through ancestral exposures or experiences and that certain paternally acquired traits can be 'memorized' in the sperm as epigenetic information. The search for epigenetic factors in mammalian sperm that transmit acquired phenotypes has recently focused on RNAs and, more recently, RNA modifications. Here, we review insights that have been gained from studying sperm RNAs and RNA modifications, and their roles in influencing offspring phenotypes. We discuss the possible mechanisms by which sperm become acquisitive following environmental–somatic–germline interactions, and how they transmit paternally acquired phenotypes by shaping early embryonic development.

Key messageThe integration of new technologies into public plant breeding programs can make a powerful step change in agricultural productivity when aligned with principles of quantitative and Mendelian genetics.The breeder’s equation is the foundational application of quantitative genetics to crop improvement. Guided by the variables that describe response to selection, emerging breeding technologies can make a powerful step change in the effectiveness of public breeding programs. The most promising innovations for increasing the rate of genetic gain without greatly increasing program size appear to be related to reducing breeding cycle time, which is likely to require the implementation of parent selection on non-inbred progeny, rapid generation advance, and genomic selection. These are complex processes and will require breeding organizations to adopt a culture of continuous optimization and improvement. To enable this, research managers will need to consider and proactively manage the, accountability, strategy, and resource allocations of breeding teams. This must be combined with thoughtful management of elite genetic variation and a clear separation between the parental selection process and product development and advancement process. With an abundance of new technologies available, breeding teams need to evaluate carefully the impact of any new technology on selection intensity, selection accuracy, and breeding cycle length relative to its cost of deployment. Finally breeding data management systems need to be well designed to support selection decisions and novel approaches to accelerate breeding cycles need to be routinely evaluated and deployed.

Animals transmit not only DNA but also other molecules, such as RNA, proteins and metabolites, to their progeny via gametes. It is currently unclear to what extent these molecules convey information between generations and whether this information changes according to their physiological state and environment. Here, we review recent work on the molecular mechanisms by which ‘epigenetic’ information is transmitted between generations over different timescales, and the importance of this information for development and physiology. Perez and Lehner summarize recent discoveries regarding epigenetic inheritance across generations and review the molecular mechanisms underlying non-DNA sequence-based transmissions.

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.

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index–increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P  = 4.4 × 10 − 36 ). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow. Genetic analyses identify widespread sex-differential participation bias in population-based studies and show how this bias can lead to incorrect inferences. These findings highlight new challenges for association studies as sample sizes continue to grow.