Hybridization alters maternal and paternal genome contributions to early plant embryogenesis.

After fertilization, zygotic genome activation results in a transcriptionally competent embryo. Hybrid transcriptome experiments in Arabidopsis have concluded that the maternal and paternal genomes make equal contributions to zygotes and embryos, yet embryo defective (emb) mutants in the Columbia (Col) ecotype display early maternal effects. Here, we show that hybridization of Col with Landsberg erecta (Ler) or Cape Verde Islands (Cvi) ecotypes decreases the maternal effects of emb mutants. Reanalysis of Col/Ler and Col/Cvi transcriptomes confirmed equal parental contributions in Col/Cvi early embryos. By contrast, thousands of genes in Col/Ler zygotes and one-cell embryos were biallelic in one cross and monoallelic in the reciprocal cross, with analysis of intron reads pointing to active transcription as responsible for this parent-of-origin bias. Our analysis shows that, contrary to previous conclusions, the maternal and paternal genomes in Col/Ler zygotes are activated in an asymmetric manner. The decrease in maternal effects in hybrid embryos compared with those in isogenic Col along with differences in genome activation between Col/Cvi and Col/Ler suggest that neither of these hybrids accurately reflects the general trends of parent-of-origin regulation in Arabidopsis embryogenesis.

A multivariate gametic model for the analysis of purebred and crossbred data. An example between two populations of Iberian pigs.

Crossbreeding plays a pivotal role within pig breeding programmes, aiming to maximize heterosis and improve reproductive traits in crossbred maternal lines. Nevertheless, there is evidence indicating that the performance of reciprocal crosses between two genetic lines might exhibit variability. These variations in performance can be attributed to differences in the correlations between gametic effects, acting as either sire or dam, within purebred and crossbred populations. To address this issue, we propose a multivariate gametic model that incorporates up to four correlated gametic effects for each parental population. The model is employed on a data set comprising litter size data (total number of piglets born-TNB- and number of piglets born alive-NBA-) derived from a reciprocal cross involving two Iberian pig populations: Entrepelado and Retinto. The data set comprises 6933 records from 1564 purebred Entrepelado (EE) sows, 4995 records from 1015 Entrepelado × Retinto (ER) crosses, 2977 records from 756 Retinto × Entrepelado (RE) crosses and 7497 records from 1577 purebred Retinto (RR) sows. The data set is further supplemented by a pedigree encompassing 6007 individual-sire-dam entries. The statistical model also included the order of parity (with six levels), the breed of the service sire (five levels) and the herd-year-season effects (141 levels). Additionally, the model integrates random dominant and permanent environmental sow effects. The analysis employed a Bayesian approach, and the results revealed all the posterior estimates of the gametic correlations to be positive. The range of the posterior mean estimates of the correlations varied across different gametic effects and traits, with a range between 0.04 (gametic correlation between the paternal effects for purebred and the maternal for crossbred in Retinto) and 0.53 (gametic correlation between the paternal effects for purebred and the paternal for crossbred in Entrepelado). Furthermore, the posterior mean variance estimates of the maternal gametic effects were consistently surpassed those for paternal effects within all four populations. The results suggest the possible influence of imprinting effects on the genetic control of litter size, and underscore the importance of incorporating crossbred data into the breeding value predictions for purebred individuals.

Efficient inference of parent-of-origin effect using case-control mother-child genotype data.

Parent-of-origin effect plays an important role in mammal development and disorder. Case-control mother-child pair genotype data can be used to detect parent-of-origin effect and is often convenient to collect in practice. Most existing methods for assessing parent-of-origin effect do not incorporate any covariates, which may be required to control for confounding factors. We propose to model the parent-of-origin effect through a logistic regression model, with predictors including maternal and child genotypes, parental origins, and covariates. The parental origins may not be fully inferred from genotypes of a target genetic marker, so we propose to use genotypes of markers tightly linked to the target marker to increase inference efficiency. A robust statistical inference procedure is developed based on a modified profile log-likelihood in a retrospective way. A computationally feasible expectation-maximization algorithm is devised to estimate all unknown parameters involved in the modified profile log-likelihood. This algorithm differs from the conventional expectation-maximization algorithm in the sense that it is based on a modified instead of the original profile log-likelihood function. The convergence of the algorithm is established under some mild regularity conditions. This expectation-maximization algorithm also allows convenient handling of missing child genotypes. Large sample properties, including weak consistency, asymptotic normality, and asymptotic efficiency, are established for the proposed estimator under some mild regularity conditions. Finite sample properties are evaluated through extensive simulation studies and the application to a real dataset.

Analysis of parent-of-origin effects for secondary phenotypes using case-control mother-child pair data.

The detection of parent-of-origin effects (POEs) has become a research focus in genetic association studies since POEs play an important role in explaining the heritability of many complex human disorders. Genetic association studies are commonly conducted based on case-control designs. Case-control genetic association studies often collect additional information on secondary phenotypes other than the case-control status. Various statistical methods have been proposed to analyze the secondary phenotypes, but no methods are specifically tailored for identifying POEs of offspring genes on the secondary phenotypes. The parental origin information may not be determined unambiguously using the genotypes of the test locus for some families, and ignoring such families would lose considerable information. In this article, we focus on case-control mother-child pair design that has been widely used for studying human early life growth and development, and propose a robust and efficient retrospective likelihood method to detect POEs for the secondary phenotypes using multilocus genotypes. The proposed method fully utilizes the information from multilocus genotypes, Hardy-Weinberg equilibrium (HWE), Mendelian inheritance law, and conditional independence between child genotype and maternal covariate given maternal genotype. Large sample properties, including consistency and asymptotic normality, are established for our proposed statistical method. The finite sample performance of our method are demonstrated through extensive simulation studies and application to the Danish National Birth Cohort data.

Estimation of genetic heritabilities of human traits in case-control studies.

It is of great interest to detect missing heritability for human complex traits. Additive genetic effects (ADD), maternal genetic effects (MGE), and parent-of-origin effects (POE) play important roles in genetic mechanisms. Methods have been developed in the literature to analyze heritabilities due to ADD, POE, and MGE separately but not simultaneously. In this paper, a new model termed APM is proposed based on mother-child duos genetic data, which orthogonally decomposes heritabilities due to ADD, POE, and MGE. This orthogonal decomposition is biologically interpretable since it ideally characterizes independent contributions due to the three effects. We focus on case-control data that are widely adopted in genetics studies and develop a novel method R-PCGC by adjusting estimation biases due to sampling bias in case-control studies and imposing nonnegative constraints on the heritability estimates. Large sample properties such as consistency and asymptotic normality are established for R-PCGC. The desired properties of R-PCGC (i.e., asymptotic unbiasedness and nonnegativity) are confirmed through simulations. Finally, R-PCGC regression is applied to a case-control study of preterm births from the Danish National Birth Cohort (DNBC).

Somatic embryo initiation by rice BABY BOOM1 involves activation of zygote-expressed auxin biosynthesis genes.

Plant embryogenesis results from the fusion of male and female gametes but can also be induced in somatic cells. The molecular pathways for embryo initiation are poorly understood, especially in monocots. In rice, the male gamete expressed BABY BOOM1 (OsBBM1) transcription factor functions as an embryogenic trigger in the zygote and can also promote somatic embryogenesis when ectopically expressed in somatic tissues. We used gene editing, transcriptome profiling, and chromatin immunoprecipitation to determine the molecular players involved in embryo initiation downstream of OsBBM1. We identify OsYUCCA (OsYUC) auxin biosynthesis genes as direct targets of OsBBM1. Unexpectedly, these OsYUC targets in zygotes are expressed only from the maternal genome, whereas the paternal genome exclusively provides functional OsBBM1 to initiate embryogenesis. Induction of somatic embryogenesis by exogenous auxin requires OsBBM genes and downstream OsYUC targets. Ectopic OsBBM1 initiates somatic embryogenesis without exogenous auxins but requires functional OsYUC genes. Thus, an OsBBM-OsYUC module is a key player for both somatic and zygotic embryogenesis in rice. Zygotic embryo initiation involves a partnership of male and female genomes, through which paternal OsBBM1 activates maternal OsYUC genes. In somatic embryogenesis, exogenous auxin triggers OsBBM1 expression, which then activates endogenous auxin biosynthesis OsYUC genes.

The uncertainty of copy number variants: pregnancy decisions and clinical follow-up.

BACKGROUND: Next-generation sequencing for copy number variants is often used as a follow-up investigation of unusual fetal ultrasound results and is capable of detecting copy number variations with a resolution of ∼0.1 Mb. In a prenatal setting, observation and subsequent management of pregnancies with a fetal variant of uncertain significance remains problematic for counseling. OBJECTIVE: This study aimed to follow the decision-making processes in pregnancies with a fetal variant of uncertain significance and prospectively assess copy number variation interpretations and implications under the newer 2020 American College of Medical Genetics and Genomics guidelines. STUDY DESIGN: In a single prenatal unit, prospective chromosome testing using copy number variation sequencing for 8030 fetuses with unexpected noninvasive findings identified 139 pregnancies with a copy number variation classified as a variant of uncertain significance according to the 2015 American College of Medical Genetics and Genomics guidelines current at the time. Parent-of-origin testing was subsequently performed to determine if the copy number variation was inherited or de novo. All couples were offered specialized genetic counseling to assist in pregnancy management decisions. For the continued pregnancies that reached term, newborns were clinically assessed for evidence of any disease at 0 to 10 months and/or at 2 to 4 years of age. RESULTS: Of the 139 variants of uncertain significance found, most (78%) were inherited with no evidence of disease in the carrier parent. On the basis of primary ultrasound findings combined with results from noninvasive prenatal screening tests, most inherited variant of uncertain significance pregnancies were continued, whereas most pregnancies involving de novo variants of uncertain significance were terminated. From clinical follow-up of the 113 live births, only 5 showed any evidence of a phenotype that was not apparently related to the original variant of uncertain significance. Prospective reanalysis of the 139 variants of uncertain significance using recent 2020 American College of Medical Genetics and Genomics guidelines changed the status of 24 variants of uncertain significance, with 15 reclassified as benign and 9 as pathogenic. However, the 5 children born with an inherited variant of uncertain significance reclassified as pathogenic showed no evidence of a disease phenotype on clinical follow-up. CONCLUSION: The severity of fetal ultrasound findings combined with results from parent-of-origin testing were the key drivers in pregnancy management decisions for patients. According to birth outcomes from continued pregnancies, most variants of uncertain significance proved to be apparently benign in nature and potentially of low risk of adverse disease outcome. There was a discordance rate of 17% for variant of uncertain significance scoring between the 2015 and 2020 American College of Medical Genetics and Genomics guidelines for defining a variant of uncertain significance, suggesting that difficulties remain for predicting true pathogenicity. Nonetheless, with increasing knowledge of population copy number variation polymorphisms, and a more complete assessment for alternative genetic causes, patients having prenatal assessments should feel less anxious when a fetal variant of uncertain significance is identified.

Natural cryptic variation in epigenetic modulation of an embryonic gene regulatory network.

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.

Clinical features and magnesium levels: Novel insights in 15q11.2 BP1-BP2 copy number variants.

BACKGROUND: Investigating copy number variations (CNVs) such as microdeletions or microduplications can significantly contribute to discover the aetiology of neurodevelopmental disorders. 15q11.2 genomic region, including NIPA1 and NIPA2 genes, contains a recurrent but rare CNV, flanked by the break points BP1 and BP2. Both BP1-BP2 microdeletion and microduplication have been associated with intellectual disability (ID), neuropsychiatric/behavioural disturbances and mild clinical features, even if with incomplete penetrance and variable expressivity. The pathogenic role of this CNV is quite unclear though. Unknown variants in other DNA regions and parent-of-origin effect (POE) are some of the mechanisms that have been proposed as an explanation of the wide phenotypic variability. As NIPA1 and NIPA2 encode for proteins that mediate magnesium (Mg2+ ) metabolism, it has been suggested that urinary Mg2+ levels could potentially represent informative and affordable biomarkers for a rapid screening of 15q11.2 duplications or deletions. Furthermore, magnesium supplementation has been proposed as possible therapeutic strategy. METHODS: Thirty one children with ID and/or other neurodevelopmental disorders carrying either a duplication or a deletion in 15q11.2 BP1-BP2 region have been recruited. When available, blood samples from parents have been analysed to identify the CNV origin. All participants underwent family and medical data collection, physical examination and neuropsychiatric assessment. Electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) scan were performed in 15 children. In addition, 11 families agreed to participate to the assessment of blood and urinary Mg2+ levels. RESULTS: We observed a highly variable phenotypic spectrum of developmental issues encompassing ID in most subjects as well as a variety of behavioural disorders such as autism and attention-deficit disorder/attention-deficit hyperactivity disorder. Dysmorphic traits and malformations were detected only in a minority of the participants, and no clear association with growth anomalies was found. Abnormal brain MRI and/or EEG were reported respectively in 64% and 92% of the subjects. Inheritance assessment highlighted an excess of duplication of maternal origin, while cardiac alterations were detected only in children with 15q11.2 CNV inherited from the father. We found great variability in Mg2+ urinary values, without correlation with 15q11.2 copy numbers. However, the variance of urinary Mg2+ levels largely increases in individuals with 15q11.2 deletion/duplication. CONCLUSIONS: This study provides further evidence that 15q11.2 BP1-BP2 CNV is associated with a broad spectrum of neurodevelopmental disorders and POE might be an explanation for clinical variability. However, some issues may question the real impact of 15q11.2 CNV on the phenotype in the carriers: DNA sequencing could be useful to exclude other pathogenic gene mutations. Our results do not support the possibility that urinary Mg2+ levels can be used as biomarkers to screen children with neurodevelopmental disorders for 15q11.2 duplication/deletion. However, there are evidences of correlations between 15q11.2 BP1-BP2 CNV and Mg2+ metabolism and future studies may pave the way to new therapeutic options.

Quantitative analysis of parent-of-origin effect in reproductive and morphological selection criteria in the Pura Raza Española horse.

It is generally assumed that parents make a genetically equal contribution to their offspring, but this assumption might not always hold. This is because the expression of a gene can be blocked by methylation during gametogenesis, and the degree of methylation can depend on the origin of the parental gene (imprinting) or by preferential management associated with genetic merit. The first consequences of this for quantitative genetics is that the mean phenotypes of reciprocal heterozygotes need no longer be the same, as would be expected according to Mendelian heritage. We analysed three mare reproductive traits (reproductive efficiency, age at first foaling and foaling number) and three morphological traits (height at withers, thoracic circumference, and scapula-ischial length) in the Pura Raza Española (PRE) horse population, which possesses a deep and reliable pedigree, making it a perfect breed for analysing the quantitative effect of parent-of-origin. The number of animals analysed ranged from 44,038 to 144,191, all of them with both parents known. The model comparison between a model without parent-of-origin effects and three different models with parent-of-origin effects revealed that both maternal and paternal gametic effects influence all the analysed traits. The maternal gametic effect had a higher influence on most traits, accounting for between 3% and 11% of the total phenotypic variance, while the paternal gametic effect accounted for a higher proportion of variance in one trait, age at first foaling (4%). As expected, the Pearson's correlations between additive breeding values of models that consider parent-of-origin and that do not consider parent-of-origin were very high; however, the percentage of coincident animals slightly decreases when comparing animals with the highest estimated breeding values. Ultimately, this work demonstrates that parent-of-origin effects exist in horse gene transmission from a quantitative point of view. Additionally, including an estimate of the parent-of-origin effect within the PRE horse breeding program could be a great tool for a better parent's selection and that could be of interest for breeders, as this value will determine whether the animals acquire genetic categories and are much more highly valued.

[The search for the origins of the person entrusted to the adoption]. / La quête des origines chez la personne confiée à l'adoption.

This text offers the testimony of a reality sometimes very complex to conceive, that of a person entrusted to adoption who goes in search of his origins. The process seems simple, but it covers many intertwined aspects, which make the quest perilous. The adopted person, his adoptive parents as well as the original ones, will all find themselves embarked on a new page of their history, full of emotions. They will have to tame the result and continue their journey with this new personal baggage.

Phasing of de novo mutations using a scaled-up multiple amplicon long-read sequencing approach.

De novo mutations (DNMs) play an important role in severe genetic disorders that reduce fitness. To better understand their role in disease, it is important to determine the parent-of-origin and timing of mutational events that give rise to these mutations, especially in sex-specific developmental disorders such as male infertility. However, currently available short-read sequencing approaches are not ideally suited for phasing, as this requires long continuous DNA strands that span both the DNM and one or more informative single-nucleotide polymorphisms. To overcome these challenges, we optimized and implemented a multiplexed long-read sequencing approach using Oxford Nanopore technologies MinION platform. We focused on improving target amplification, integrating long-read sequenced data with high-quality short-read sequence data, and developing an anchored phasing computational method. This approach handled the inherent phasing challenges of long-range target amplification and the normal accumulation of sequencing error associated with long-read sequencing. In total, 77 of 109 DNMs (71%) were successfully phased and parent-of-origin identified. The majority of phased DNMs were prezygotic (90%), the accuracy of which is highlighted by an average mutant allele frequency of 49.6% and standard error of 0.84%. This study demonstrates the benefits of employing an integrated short-read and long-read sequencing approach for large-scale DNM phasing.

Covariate adjusted inference of parent-of-origin effects using case-control mother-child paired multilocus genotype data.

It is of great interest to identify parent-of-origin effects (POEs) since POEs play an important role in many human heritable disorders and human early life growth and development. POE is sometimes referred to as imprinting effect in the literature. Compared with the standard logistic regression analyses, retrospective likelihood-based statistical methods are more powerful in identifying POEs when data are collected from related individuals retrospectively. However, none of existing retrospective-based methods can appropriately incorporate covariates that should be adjusted for if they are confounding factors. In this paper, a novel semiparametric statistical method, M-HAP, is developed to detect POEs by fully exploring available information from multilocus genotypes of case-control mother-child pairs and covariates. Some large sample properties are established for M-HAP. Finite sample properties of M-HAP are illustrated by extensive simulation studies and real data applications to the Jerusalem Perinatal Study and the Danish National Birth Cohort study, which confirm the desired superiority of M-HAP over some existing methods. M-HAP has been implemented in the updated R package CCMO.

DNA Methylation Analysis of Imprinted Genes in the Cortex and Hippocampus of Cross-Fostered Mice Selectively Bred for Increased Voluntary Wheel-Running.

We have previously shown that high runner (HR) mice (from a line genetically selected for increased wheel-running behavior) have distinct, genetically based, neurobiological phenotypes as compared with non-selected control (C) mice. However, developmental programming effects during early life, including maternal care and parent-of-origin-dependent expression of imprinted genes, can also contribute to variation in physical activity. Here, we used cross-fostering to address two questions. First, do HR mice have altered DNA methylation profiles of imprinted genes in the brain compared to C mice? Second, does maternal upbringing further modify the DNA methylation status of these imprinted genes? To address these questions, we cross-fostered all offspring at birth to create four experimental groups: C pups to other C dams, HR pups to other HR dams, C pups to HR dams, and HR pups to C dams. Bisulfite sequencing of 16 imprinted genes in the cortex and hippocampus revealed that the HR line had altered DNA methylation patterns of the paternally imprinted genes, Rasgrf1 and Zdbf2, as compared with the C line. Both fostering between the HR and C lines and sex modified the DNA methylation profiles for the paternally expressed genes Mest, Peg3, Igf2, Snrpn, and Impact. Ig-DMR, a gene with multiple paternal and maternal imprinted clusters, was also affected by maternal upbringing and sex. Our results suggest that differential methylation patterns of imprinted genes in the brain could contribute to evolutionary increases in wheel-running behavior and are also dependent on maternal upbringing and sex.

A family-based study of genetic and epigenetic effects across multiple neurocognitive, motor, social-cognitive and social-behavioral functions.

Many psychiatric and neurodevelopmental disorders are known to be heritable, but studies trying to elucidate the genetic architecture of such traits often lag behind studies of somatic traits and diseases. The reasons as to why relatively few genome-wide significant associations have been reported for such traits have to do with the sample sizes needed for the detection of small effects, the difficulty in defining and characterizing the phenotypes, partially due to overlaps in affected underlying domains (which is especially true for cognitive phenotypes), and the complex genetic architectures of the phenotypes, which are not wholly captured in traditional case-control GWAS designs. We aimed to tackle the last two issues by performing GWASs of eight quantitative neurocognitive, motor, social-cognitive and social-behavioral traits, which may be considered endophenotypes for a variety of psychiatric and neurodevelopmental conditions, and for which we employed models capturing both general genetic association and parent-of-origin effects, in a family-based sample comprising 402 children and their parents (mostly family trios). We identified 48 genome-wide significant associations across several traits, of which 3 also survived our strict study-wide quality criteria. We additionally performed a functional annotation of implicated genes, as most of the 48 associations were with variants within protein-coding genes. In total, our study highlighted associations with five genes (TGM3, CACNB4, ANKS1B, CSMD1 and SYNE1) associated with measures of working memory, processing speed and social behavior. Our results thus identify novel associations, including previously unreported parent-of-origin associations with relevant genes, and our top results illustrate new potential gene → endophenotype → disorder pathways.

Genome-Wide Scan for Parent-of-Origin Effects in a sub-Saharan African Cohort With Nonsyndromic Cleft Lip and/or Cleft Palate (CL/P).

OBJECTIVE: Nonsyndromic cleft lip and/or cleft palate (NSCL/P) have multifactorial etiology where genetic factors, gene-environment interactions, stochastic factors, gene-gene interactions, and parent-of-origin effects (POEs) play cardinal roles. POEs arise when the parental origin of alleles differentially impacts the phenotype of the offspring. The aim of this study was to identify POEs that can increase risk for NSCL/P in humans using a genome-wide dataset. METHODS: The samples (174 case-parent trios from Ghana, Ethiopia, and Nigeria) included in this study were from the African only genome wide association studies (GWAS) that was published in 2019. Genotyping of individual DNA using over 2 million multiethnic and African ancestry-specific single-nucleotide polymorphisms from the Illumina Multi-Ethnic Genotyping Array v2 15070954 A2 (genome build GRCh37/hg19) was done at the Center for Inherited Diseases Research. After quality control checks, PLINK was employed to carry out POE analysis employing the pooled subphenotypes of NSCL/P. RESULTS: We observed possible hints of POEs at a cluster of genes at a 1 mega base pair window at the major histocompatibility complex class 1 locus on chromosome 6, as well as at other loci encompassing candidate genes such as ASB18, ANKEF1, AGAP1, GABRD, HHAT, CCT7, DNMT3A, EPHA7, FOXO3, lncRNAs, microRNA, antisense RNAs, ZNRD1, ZFAT, and ZBTB16. CONCLUSION: Findings from our study suggest that some loci may increase the risk for NSCL/P through POEs. Additional studies are required to confirm these suggestive loci in NSCL/P etiology.

Sex differences in parent-offspring recurrence of attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder sharing genetic risk factors with other common psychiatric disorders. However, intergenerational recurrence patterns of ADHD from parents to sons and daughters are not known. We aimed to examine the risk of ADHD in offspring of parents with ADHD and parents with other psychiatric disorders by parental and offspring sex, using parents without the specific disorders as comparison. METHODS: In a generation study linking data from several population-based registries, all Norwegians born 1967-2011 (n = 2,486,088; Medical Birth Registry of Norway) and their parents were followed to 2015. To estimate intergenerational recurrence risk, we calculated prevalence differences (PD) and the relative risk (RR) of ADHD in offspring by parental ADHD, bipolar disorder (BD), schizophrenia spectrum disorder (SCZ), major depression (MDD), all by parental and offspring sex. RESULTS: The absolute prevalence of ADHD in offspring of parents with ADHD was very high, especially in sons of two affected parents (41.5% and 25.1% in sons and daughters, respectively), and far higher than in offspring of parents with BD, SCZ or MDD. Intergenerational recurrence risks were higher for maternal than paternal ADHD (RRmaternal 8.4, 95% confidence interval (CI) 8.2-8.6 vs. RRpaternal 6.2, 6.0-6.4) and this was also true on the absolute scale (PDmaternal 21.1% (20.5-21.7) vs. PDpaternal 14.8% (14.3-15.4)). RRs were higher in daughters, while PDs higher in sons. Parental SCZ, BD and MDD were associated with an approximately doubled risk of offspring ADHD compared to parents without the respective disorders, and estimates did not differ significantly between daughters and sons. CONCLUSIONS: The intergenerational recurrence risks of ADHD were high and higher from mothers with ADHD than fathers with ADHD. Other parental psychiatric disorders also conferred increased risk of offspring ADHD, but far lower, indicating a sex- and diagnosis-specific intergenerational recurrence risk in parents with ADHD.

Fruit quality and DNA methylation are affected by parental order in reciprocal crosses of tomato.

KEY MESSAGE: Reciprocal effects were found for tomato fruit quality and DNA methylation. The epigenetic identity of reciprocal hybrids indicates that DNA methylation might be one of the mechanisms involved in POEs. Crosses between different genotypes and even between different species are commonly used in plant breeding programs. Reciprocal hybrids are obtained by changing the cross direction (or the sexual role) of parental genotypes in a cross. Phenotypic differences between these hybrids constitute reciprocal effects (REs). The aim of this study was to evaluate phenotypic differences in tomato fruit traits and DNA methylation profiles in three inter- and intraspecific reciprocal crosses. REs were detected for 13 of the 16 fruit traits analyzed. The number of traits with REs was the lowest in the interspecific cross, whereas the highest was found in the cross between recombinant inbred lines (RILs) derived from the same interspecific cross. An extension of gene action analysis was proposed to incorporate parent-of-origin effects (POEs). Maternal and paternal dominance were found in four fruit traits. REs and paternal inheritance were found for epiloci located at coding and non-coding regions. The epigenetic identity displayed by the reciprocal hybrids accounts for the phenotypic differences among them, indicating that DNA methylation might be one of the mechanisms involved in POEs.

Genomic Imprinting As a Window into Human Language Evolution.

Humans spend large portions of their time and energy talking to one another, yet it remains unclear whether this activity is primarily selfish or altruistic. Here, it is shown how parent-of-origin specific gene expression-or "genomic imprinting"-may provide an answer to this question. First, it is shown why, regarding language, only altruistic or selfish scenarios are expected. Second, it is pointed out that an individual's maternal-origin and paternal-origin genes may have different evolutionary interests regarding investment into language, and that this intragenomic conflict may drive genomic imprinting which-as the direction of imprint depends upon whether investment into language is relatively selfish or altruistic-may be used to discriminate between these two possibilities. Third, predictions concerning the impact of various mutations and epimutations at imprinted loci on language pathologies are derived. In doing so, a framework is developed that highlights avenues for using intragenomic conflicts to investigate the evolutionary drivers of language.

Imprinted Genes and Multiple Sclerosis: What Do We Know?

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disease of the central nervous system that arises from interplay between non-genetic and genetic risk factors. The epigenetics functions as a link between these factors, affecting gene expression in response to external influence, and therefore should be extensively studied to improve the knowledge of MS molecular mechanisms. Among others, the epigenetic mechanisms underlie the establishment of parent-of-origin effects that appear as phenotypic differences depending on whether the allele was inherited from the mother or father. The most well described manifestation of parent-of-origin effects is genomic imprinting that causes monoallelic gene expression. It becomes more obvious that disturbances in imprinted genes at the least affecting their expression do occur in MS and may be involved in its pathogenesis. In this review we will focus on the potential role of imprinted genes in MS pathogenesis.