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In flowering plants, F1 hybrid seed lethality is a common outcome of crosses between closely related diploid species, but the genetic basis of this early-acting and potentially widespread form of postzygotic reproductive isolation is largely unknown. We intercrossed two closely related species of monkeyflower, Mimulus guttatus and Mimulus tilingii, to characterize the mechanisms and strength of postzygotic reproductive isolation. Then, using a reciprocal backcross design, we performed high-resolution genetic mapping to determine the genetic architecture of hybrid seed lethality and directly test for loci with parent-of-origin effects. We found that F1 hybrid seed lethality is an exceptionally strong isolating barrier between Mimulus species, with reciprocal crosses producing < 1% viable seeds. This form of postzygotic reproductive isolation appears to be highly polygenic, indicating that multiple incompatibility loci have accumulated rapidly between these closely related Mimulus species. It is also primarily caused by genetic loci with parent-of-origin effects, suggesting a possible role for imprinted genes in the evolution of Mimulus hybrid seed lethality. Our findings suggest that divergence in loci with parent-of-origin effects, which is probably driven by genomic coevolution within lineages, might be an important source of hybrid incompatibilities between flowering plant species.

The heritability and parent-of-origin effect hypotheses for chronic diseases can be evaluated by estimating and conducting inference about the parameters that measure the within-family dependences in disease onset times. We model the within-family associations in these times using a Gaussian copula whose correlation matrix accommodates the different pairwise family relationships. We derive score-type statistics to test the heritability and parent-of-origin effect hypotheses when the families selection protocol induces a sampling bias. We illustrate the use of the developed methods through an application to a motivating family study in Psoriatic arthritis and provide strong evidence of excessive paternal transmission of risk.

Allele-specific expression (ASE) analyses from RNA-Seq data provide quantitative insights into genomic imprinting and the genetic variants that affect transcription. Robust ASE analysis requires the integration of multiple computational steps, including read alignment, read counting, data visualization, and statistical testing—this complexity creates challenges for reproducibility, scalability, and ease of use. Here, we present ASE Toolkit (ASET), an end-to-end pipeline that streamlines SNP-level ASE data generation, visualization, and testing for parent-of-origin (PofO) effect. ASET includes a modular pipeline built with Nextflow for ASE quantification from short-read transcriptome sequencing reads, an R library for data visualization, and a Julia script for PofO testing. ASET performs comprehensive read quality control, SNP-tolerant alignment to reference genomes, read counting with allele and strand resolution, annotation with genes and exons, and estimation of contamination. In sum, ASET provides a complete and easy-to-use solution for molecular and biomedical scientists to identify and interpret patterns of ASE from RNA-Seq data.

Gene regulatory networks (GRNs) that direct animal embryogenesis must respond to varying environmental and physiological conditions to ensure robust construction of organ systems. While GRNs are evolutionarily modified by natural genomic variation, the roles of epigenetic processes in shaping plasticity of GRN architecture are not well understood. The endoderm GRN in Caenorhabditis elegans is initiated by the maternally supplied SKN-1/Nrf2 bZIP transcription factor; however, the requirement for SKN-1 in endoderm specification varies widely among distinct C. elegans wild isotypes, owing to rapid developmental system drift driven by accumulation of cryptic genetic variants. We report here that heritable epigenetic factors that are stimulated by transient developmental diapause also underlie cryptic variation in the requirement for SKN-1 in endoderm development. This epigenetic memory is inherited from the maternal germline, apparently through a nuclear, rather than cytoplasmic, signal, resulting in a parent-of-origin effect (POE), in which the phenotype of the progeny resembles that of the maternal founder. The occurrence and persistence of POE varies between different parental pairs, perduring for at least 10 generations in one pair. This long-perduring POE requires piwi-interacting RNA (piRNA) function and the germline nuclear RNA interference (RNAi) pathway, as well as MET-2 and SET-32, which direct histone H3K9 trimethylation and drive heritable epigenetic modification. Such nongenetic cryptic variation may provide a resource of additional phenotypic diversity through which adaptation may facilitate evolutionary changes and shape developmental regulatory systems.

Parent-of-origin effects, whereby specific phenotypes are differentially inherited paternally or maternally, provide useful clues to better understand transgenerational effect transmission. Ancestral diet influences offspring phenotypes, including body composition and fitness. However, the specific role that mothers and fathers play in the transmission of altered phenotypes to male and female offspring remains unclear. We investigated the influence of the parent-of-origin's diet on adult progeny phenotypes and reproductive output for three generations in fruit flies ( Drosophila melanogaster ). Males and females reared on a control diet were exposed to the control diet or one of two altered (no- or high-) sugar treatment diets for a single generation. Flies from one of the two altered diet treatments were then mated to control flies in a full-factorial design to produce F 1 offspring and kept on control media for each following generation. We found parent-of-origin (triglyceride) and non-parent-of-origin (sugar) body composition effects, which were transgenerational and sex-specific. Additionally, we observed a negative correlation between intergenerational maternal reproductive output and triglyceride levels, suggesting that ancestral diet may affect fitness. This work demonstrates that ancestral diet can transmit altered phenotypes in a parent-of-origin and sex-specific manner and highlights that mechanisms regulating such transmission have been greatly overlooked. This article is part of the theme issue ‘The role of plasticity in phenotypic adaptation to rapid environmental change’.

Recent advances in microscopy have enabled studying chromosome organization at the single-molecule level, yet little is known about inherited chromosome organization. Here we adapt single-molecule chromosome tracing to distinguish two C. elegans strains (N2 and HI) and find that while their organization is similar, the N2 chromosome influences the folding parameters of the HI chromosome, in particular the step size, across generations. Furthermore, homologous chromosomes overlap frequently, but alignment between homologous regions is rare, suggesting that transvection is unlikely. We present a powerful tool to investigate chromosome architecture and to track the parent of origin.

Triploid breeding is a promising avenue for generating seedless varieties with enhanced vigor, yet the underlying molecular mechanisms, particularly the relative contributions of hybridity, ploidy level, and parent-of-origin effects (POE), remain largely elusive in perennial fruit crops. This study focuses on loquat ( Eriobotrya japonica ), a highly heterozygous woody perennial, to explore the molecular mechanism of triploid seedling vigor heterosis. RNA-seq across a series of reciprocal diploid (2x), triploid (3x) and tetraploid (4x) hybrids with clear genetic background revealed POE as the predominant driver of triploid heterosis at the transcriptomic level. Specifically, 784 POE-responsive differentially expressed genes (DEGs) were identified between paternal-excess [3x(p)] and maternal-excess [3x(m)] triploids, exceeding the effects of ploidy (218–652 DEGs) and hybridity (8–90 DEGs). For an in-depth investigation, reciprocal crosses between L2 and L4 were further selected for an integrated transcriptome, allele-specific expression (ASE), and allele-specific methylation (ASM) analysis. Our findings demonstrate that POE orchestrates multilayered regulation, including (i) coordinated upregulation of vigor-related pathways (i.e., photosynthesis, starch metabolism, plant circadian rhythm) in 3x(p); (ii) a dual ASE pattern with maternal bias in gene quantity but paternal enhancement in levels, including five paternally expressed imprinted genes (PEGs); (iii) non-classical epigenetic regulation where paternal gene body hypermethylation (mCG) paradoxically enhances transcription, especially in circadian clock genes. Finally, qRT-PCR-based diurnal expression across all crosses validated that POE-dependent reprogramming of key circadian oscillator genes ( EjCCA1 , EjLHY , EjGI , EjTOC1 ), suggesting optimized metabolic efficiency through circadian clock modulation might contribute to enhanced vigor in 3x(p) hybrids. This study provides fundamental insights into the dosage-sensitive gene networks and epigenetic regulation underlying POE-driven heterosis in woody perennials, advancing polyploid heterosis theory and offering novel targets for genetic improvement.

Low-penetrance pathogenic copy number variations (CNVs), variation of uncertain significance (VUS) CNVs and likely pathogenic CNVs present a challenge for prenatal diagnosis. Previous studies have clarified the influence of a parent-of-origin test on the prenatal VUS CNVs. However, the influence of parent-of-origin tests on prenatal likely pathogenic (LP) or low-penetrance pathogenic CNVs (pCNVs) have not been evaluated. Here, among 2273 pregnant women undergoing prenatal diagnosis, 236 CNVs were reported by chromosomal microarray analysis (CMA) including 69 full-penetrance pCNVs, 44 low-penetrance pCNVs, 113 VUS CNVs and 10 LP CNVs. Based on the subsequent parent-of-origin tests, CNVs were classified as de novo , inherited and unknown group. Firstly, a total of 112 couple (62 VUS CNVs, two LP CNVs and 48 pCNVs) chose parent-of-origin tests and 88 inherited CNVs (51 VUS CNVs, two LP CNVs and 35 pCNVs ) were identified. Then, the effect of parent-of-origin tests was focused on 44 low-penetrance pCNVs, 113 VUS CNVs and 10 LP CNVs in this study ( n  = 167). For 44 low-penetrance pCNVs, termination of pregnancy (TOP) rates in de novo , inherited and unknown group were 100% (5/5), 23.5% (4/17) and 40.9% (9/22), respectively. TOP decisions in low-penetrance pCNVs were mainly affected by de novo and abnormal ultrasound findings. For 113 VUS CNVs, inherited VUS CNVs dramatically reduced anxiety reflected by TOP rates in de novo (18.2%, 2/11), inherited (0/51) and unknown group (2.0%, 1/51). Notably, prenatal minor structural defects often disappeared after birth. These results suggested the majority VUS CNVs have no appreciable pathogenicity. For 10 LP CNVs, TOP rates in inherited and unknown group were 0% (0/2) and 87.5% (7/8), which suggested that it is imperative that parent-of-origin tests be offered for LP CNVs to bring the classification to pathogenic or VUS.

In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed three datasets covering two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin-specific methylation and germline differentially methylated regions, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 embryonic stem cells and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental ‘hotspots’ providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease.

Parent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological traits. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F 16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these parent-of-origin effects phenomena. We propose that non-imprinted genes can generate complex parent-of-origin effects on metabolic traits through interactions with imprinted genes. Here, we employ data from mouse populations at different levels of intercrossing (F 0 , F 1 , F 2 , F 16 ) of the LG/J and SM/J inbred mouse lines to test this hypothesis. Using multiple populations and incorporating genetic, genomic, and physiological data, we leverage orthogonal evidence to identify networks of genes through which parent-of-origin effects propagate. We identify a network comprised of three imprinted and six non-imprinted genes that show parent-of-origin effects. This epistatic network forms a nutritional responsive pathway and the genes comprising it jointly serve cellular functions associated with growth. We focus on two genes, Nnat and F2r , whose interaction associates with serum glucose levels across generations in high-fat-fed females. Single-cell RNAseq reveals that Nnat expression increases and F2r expression decreases in pre-adipocytes along an adipogenic trajectory, a result that is consistent with our observations in bulk white adipose tissue.