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Background Plants can transmit somatic mutations and epimutations to offspring, which in turn can affect fitness. Knowledge of the rate at which these variations arise is necessary to understand how plant development contributes to local adaption in an ecoevolutionary context, particularly in long-lived perennials. Results Here, we generate a new high-quality reference genome from the oldest branch of a wild Populus trichocarpa tree with two dominant stems which have been evolving independently for 330 years. By sampling multiple, age-estimated branches of this tree, we use a multi-omics approach to quantify age-related somatic changes at the genetic, epigenetic, and transcriptional level. We show that the per-year somatic mutation and epimutation rates are lower than in annuals and that transcriptional variation is mainly independent of age divergence and cytosine methylation. Furthermore, a detailed analysis of the somatic epimutation spectrum indicates that transgenerationally heritable epimutations originate mainly from DNA methylation maintenance errors during mitotic rather than during meiotic cell divisions. Conclusion Taken together, our study provides unprecedented insights into the origin of nucleotide and functional variation in a long-lived perennial plant.

Stochastic changes in DNA methylation (i.e., spontaneous epimutations) contribute to methylome diversity in plants. Here, we describe AlphaBeta , a computational method for estimating the precise rate of such stochastic events using pedigree-based DNA methylation data as input. We demonstrate how AlphaBeta can be employed to study transgenerationally heritable epimutations in clonal or sexually derived mutation accumulation lines, as well as somatic epimutations in long-lived perennials. Application of our method to published and new data reveals that spontaneous epimutations accumulate neutrally at the genome-wide scale, originate mainly during somatic development and that they can be used as a molecular clock for age-dating trees.

Trees are long-lived plants characterized by the development of highly branched shoot systems. Along these structures, somatic mutations arise and may become fixed in reproductive tissues such as flowers and fruits. Because mature trees produce tens of thousands of terminal branches, limiting the accumulation of somatic mutations is critical to avoid mutational meltdown and inbreeding depression. Although recent evidence suggests that long-lived plants have evolved mechanisms that slow the buildup of somatic variants with age, the developmental basis for this remains unclear. Here, we derive a theoretical model linking crown development with cell lineage sampling to show that branching architecture strongly influences the accumulation of unique somatic mutations, often to the same extent as modulating the mutation rate itself. We find that tree forms that promote developmental path-sharing among branches restrict the spread of distinct cell lineages, lowering the crown-wide mutation burden by orders of magnitude even when mutation rates and branch numbers are held constant. This buffering effect suggests that branching strategies may evolve not only to optimize growth and resource allocation, but also to limit the genomic variation generated during ontogeny.

Nongenetic inheritance media—from methyl-accepting cytosines to culture—tend to mutate more frequently than DNA sequences. Whether this makes them inexhaustible suppliers for adaptive evolution will depend on the effect of nongenetic mutations (hereafter, epimutations) on fitness-related traits. Here we investigate how these effects might themselves evolve, specifically whether natural selection may set boundaries to the adaptive potential of nongenetic inheritance media because of their higher mutability. In our model, the genetic and epigenetic contributions to a nonneutral phenotype are controlled by an epistatic modifier locus, which evolves under the combined effects of drift and selection. We show that a pure genetic control evolves when the environment is stable—provided that the population is large—such that the phenotype becomes robust to frequent epimutations. When the environment fluctuates, however, selection on the modifier locus also fluctuates and can overall produce a large nongenetic contribution to the phenotype, especially when the epimutation rate matches the rate of environmental variation. We further show that selection on the modifier locus is generally insensitive to recombination, meaning it is mostly direct, that is, not relying on subsequent effects in future generations. These results suggest that unstable inheritance media might significantly contribute to fitness variation of traits subject to highly variable selective pressures but little to traits responding to scarcely variable aspects of the environment. More generally, our study demonstrates that the rate of mutation and the adaptive potential of any inheritance media should not be seen as independent properties.

To examine the effects of genetic variation, parental age and BMI on parental allele-specific methylation of imprinted genes in fetal cord blood samples. We have developed SNP genotyping and deep bisulphite sequencing assays for six imprinted genes to determine parental allele-specific methylation patterns in diploid somatic tissues. Multivariate linear regression analyses revealed a negative correlation of paternal age with paternal allele methylation in fetal cord blood. Methylation of the maternal allele showed a positive correlation with maternal age. Paternal BMI was positively correlated with paternal allele methylation. In addition to parental origin, allele-specific methylation of most imprinted genes was largely dependent on the underlying SNP haplotype. Our study supports the idea that parental factors can have an impact, although of small effect size, on the epigenome of the next generation, providing an additional layer of complexity to phenotypic diversity.

Population epigenetics explores the extent of epigenetic variation and its dynamics in natural populations encountering changing environmental conditions. In contrast to population genetics, the basic concepts of this field are still in their early stages, especially in animal populations. Epigenetic variation may play a crucial role in phenotypic plasticity and local adaptation as it can be affected by the environment, it is likely to have higher spontaneous mutation rate than nucleotide sequences do, and it may be inherited via non-mendelian processes. In this review, we aim to bring together natural animal population epigenetic studies to generate new insights into ecological epigenetics and its evolutionary implications. We first provide an overview of the extent of DNA methylation variation and its autonomy from genetic variation in wild animal population. Second, we discuss DNA methylation dynamics which create observed epigenetic population structures by including basic population genetics processes. Then, we highlight the relevance of DNA methylation variation as an evolutionary mechanism in the extended evolutionary synthesis. Finally, we suggest new research directions by highlighting gaps in the knowledge of the population epigenetics field. As for our results, DNA methylation diversity was found to reveal parameters that can be used to characterize natural animal populations. Some concepts of population genetics dynamics can be applied to explain the observed epigenetic structure in natural animal populations. The set of recent advancements in ecological epigenetics, especially in transgenerational epigenetic inheritance in wild animal population, might reshape the way ecologists generate predictive models of the capacity of organisms to adapt to changing environments.

Mutations in the genetic sequence of the DNA de novo methyltransferase DNMT3A (DNA methyltransferase 3A) are found in many patients with acute myeloid leukemia (AML). They lead to dysfunction of DNMT3A protein and represent a marker for poor prognosis. Effects of genetic mutations can be mimicked by epigenetic modifications in the DNA methylation (DNAm) pattern. Using DNAm profiles of the Cancer Genome Atlas Research Network (TCGA), we identified aberrant hypermethylation at an internal promoter region of DNMT3A , which occurred in about 40% of AML patients. Bisulfite pyrosequencing assays designed for this genomic region validated hypermethylation specifically in a subset of our AML samples. High DNAm levels at this site are particularly observed in samples without genetic mutations in DNMT3A . Epimutations and mutations of DNMT3A were associated with related gene expression changes such as upregulation of the homeobox genes in HOXA and HOXB clusters. Furthermore, epimutations in DNMT3A were enriched in patients with poor or intermediate cytogenetic risk, and in patients with shorter event-free survival and overall survival (OS). Taken together, aberrant DNA hypermethylation within the DNMT3A gene, in analogy to DNMT3A mutations, is frequently observed in AML and both modifications seem to be useful for risk stratification or choice of therapeutic regimen.