Accession-specific Parent-of-origin Dependent and Independent Genome Dosage Effects on Salt Tolerance in Arabidopsis Thaliana

Improving the salt stress tolerance of crops is an important goal in plant breeding. Changes in the number of chromosome pairs (i.e. ploidy level) cause genome dosage effects which can result in improved traits or emergence of novel traits. The genetic and epigenetic contribution of maternal or paternal chromosomes can differentially affect physiological and metabolic characteristics of F1 offspring. Hence genome dosage effects can be parent-of-origin independent or dependent. The model plant Arabidopsis thaliana displays both genome dosage and parent-of-origin effects on plant growth under normal, non-stress conditions. Using an insogenic ploidy series of diploid, triploid and tetraploid lines we investigate the extent of genome dosage effects and their parent-of-origin dependency on in vitro salt stress tolerance of seedlings across ten different A. thaliana accessions (genetic backgrounds). We demonstrate genome dosage effects on salt stress tolerance in five accessions, and using reciprocal triploid lines demonstrate parent-of-origin dependent genome dosage effects on salt stress tolerance in three accessions. Our results indicate that epigenetic genome dosage and genome dosage balance effects can have significant impacts on abiotic stress tolerance in plants.

Loss of imprinting of the Igf2-H19 ICR1 enhances placental endocrine capacity via sex-specific alterations in signalling pathways in the mouse

ABSTRACT Imprinting control region (ICR1) controls the expression of the Igf2 and H19 genes in a parent-of-origin specific manner. Appropriate expression of the Igf2-H19 locus is fundamental for normal fetal development, yet the importance of ICR1 in the placental production of hormones that promote maternal nutrient allocation to the fetus is unknown. To address this, we used a novel mouse model to selectively delete ICR1 in the endocrine junctional zone (Jz) of the mouse placenta (Jz-ΔICR1). The Jz-ΔICR1 mice exhibit increased Igf2 and decreased H19 expression specifically in the Jz. This was accompanied by an expansion of Jz endocrine cell types due to enhanced rates of proliferation and increased expression of pregnancy-specific glycoprotein 23 in the placenta of both fetal sexes. However, changes in the endocrine phenotype of the placenta were related to sexually-dimorphic alterations to the abundance of Igf2 receptors and downstream signalling pathways (Pi3k-Akt and Mapk). There was no effect of Jz-ΔICR1 on the expression of targets of the H19-embedded miR-675 or on fetal weight. Our results demonstrate that ICR1 controls placental endocrine capacity via sex-dependent changes in signalling.

Lipid-Associated Variants near ANGPTL3 and LPL Show Parent-of-Origin Specific Effects on Blood Lipid Levels and Obesity

Parent-of-origin effects (POE) and sex-specific parental effects have been reported for plasma lipid levels, and a strong relationship exists between dyslipidemia and obesity. We aim to explore whether genetic variants previously reported to have an association to lipid traits also show POE on blood lipid levels and obesity. Families from the Botnia cohort and the Hungarian Transdanubian Biobank (HTB) were genotyped for 12 SNPs, parental origin of alleles were inferred, and generalized estimating equations were modeled to assess parental-specific associations with lipid traits and obesity. POE were observed for the variants at the TMEM57, DOCK7/ANGPTL3, LPL, and APOA on lipid traits, the latter replicated in HTB. Sex-specific parental effects were also observed; variants at ANGPTL3/DOCK7 showed POE on lipid traits and obesity in daughters only, while those at LPL and TMEM57 showed POE on lipid traits in sons. Variants at LPL and DOCK7/ANGPTL3 showed POE on obesity-related traits in Botnia and HTB, and POE effects on obesity were seen to a higher degree in daughters. This highlights the need to include analysis of POEs in genetic studies of complex traits.

Parent of origin DNA methylation as a potential mechanism for genomic imprinting in bees.

Genomic imprinting is defined as parent-of-origin allele-specific expression. In order for genes to be expressed in this manner an `imprinting' mark must be present to distinguish the parental alleles within the genome. In mammals imprinted genes are primarily associated with DNA methylation. Genes exhibiting parent-of-origin expression have recently been identified in two species of Hymenoptera with functional DNA methylation systems; Apis mellifera and Bombus terrestris. We carried out whole genome bisulfite sequencing of parents and offspring from reciprocal crosses of two B. terrestris subspecies in order to identify parent-of-origin DNA methylation. We were unable to survey a large enough proportion of the genome to draw a conclusion on the presence of parent-of-origin DNA methylation however we were able to characterise the sex- and caste-specific methylomes of B. terrestris for the first time. We find males differ significantly to the two female castes, with differentially methylated genes involved in many histone modification related processes. We also analysed previously generated honeybee whole genome bisulfite data to see if genes previously identified as showing parent-of-origin DNA methylation in the honeybee show consistent allele-specific methylation in independent data sets. We have identified a core set of 12 genes in female castes which may be used for future experimental manipulation to explore the functional role of parent-of-origin DNA methylation in the honeybee. Finally, we have also identified allele-specific DNA methylation in honeybee male thorax tissue which suggests a role for DNA methylation in ploidy compensation in this species.

Tissue- and ethnicity-independent hypervariable DNA methylation states show evidence of establishment in the early human embryo

We analysed DNA methylation data from 30 datasets comprising 3,474 individuals, 19 tissues and 8 ethnicities at CpGs covered by the Illumina450K array. We identified 4,143 hypervariable CpGs ('hvCpGs') with methylation in the top 5% most variable sites across multiple tissues and ethnicities. hvCpG methylation was influenced but not determined by genetic variation, and was not linked to probe reliability, epigenetic drift, age, sex or cell heterogeneity effects. hvCpG methylation tended to covary across tissues derived from different germ-layers and hvCpGs were enriched for associations with periconceptional environment, proximity to ERV1 and ERVK retrovirus elements and parent-of-origin-specific methylation. They also showed distinctive methylation signatures in monozygotic twins. Together, these properties position hvCpGs as strong candidates for studying how stochastic and/or environmentally influenced DNA methylation states which are established in the early embryo and maintained stably thereafter can influence life-long health and disease.

Parent-of-origin effects in the UK Biobank

Identical genetic variations can have different phenotypic effects depending on their parent of origin (PofO). Yet, studies focussing on PofO effects have been largely limited in terms of sample size due to the need of parental genomes or known genealogies. Here, we used a novel probabilistic approach to infer PofO of individual alleles in the UK Biobank that does not require parental genomes nor prior knowledge of genealogy. Our model uses Identity-By-Descent (IBD) sharing with second- and third-degree relatives to assign alleles to parental groups and leverages chromosome X data in males to distinguish maternal from paternal groups. When combined with robust haplotype inference and haploid imputation, this allowed us to infer the PofO at 5.4 million variants genome-wide for 26,393 UK Biobank individuals. We used this large dataset to systematically screen 59 biomarkers and 38 anthropomorphic phenotypes for PofO effects and discovered 101 significant associations, demonstrating that this type of effects is widespread. Notably, we retrieved well known PofO effects, such as the MEG3/DLK1 locus on platelet count, and we discovered many new ones often at loci outside currently known imprinted regions and previously thought to harbour additive associations, implying that the underlying molecular mechanisms may be more complex than expected.

Genomic evidence of paternal genome elimination in globular springtails

Paternal genome elimination (PGE) - a type of reproduction in which males inherit but fail to pass on the genome of their father - evolved independently in six to eight arthropod clades. Thousands of species, including several important for agriculture, reproduce via this mode of reproduction. While some of the clades are well established PGE systems, the evidence in globular springtails (Symphypleona) remains elusive, even though they represent the oldest and most species rich clade putatively reproducing via PGE. We sequenced genomic DNA from whole bodies of Allacma fusca males with sufficiently high fractions (31 - 38%) of sperm to conclusively confirm that all the sperm carry one parental haplotype only. Although it is suggestive that the single haplotype present in sperm is maternally inherited, definitive genetic proof of the parent of origin is still needed. The genomic approach we developed allows for detection of genotypic differences between germline and soma in all species with sufficiently high fraction of germline in their bodies. This opens new opportunities for scans for reproductive modes in small animals.

The parent-of-origin lncRNA MISSEN regulates rice endosperm development

The cereal endosperm is a major factor determining seed size and shape. However, the molecular mechanisms of endosperm development are not fully understood. Long noncoding RNAs (lncRNAs) function in various biological processes. Here we show a lncRNA, MISSEN, that plays an essential role in early endosperm development in rice (Oryza sativa). MISSEN is a parent-of-origin lncRNA expressed in endosperm, and negatively regulates endosperm development, leading to a prominent dent and bulge in the seed. Mechanistically, MISSEN functions through hijacking a helicase family protein (HeFP) to regulate tubulin function during endosperm nucleus division and endosperm cellularization, resulting in abnormal cytoskeletal polymerization. Finally, we revealed that the expression of MISSEN is inhibited by histone H3 lysine 27 trimethylation (H3K27me3) modification after pollination. Therefore, MISSEN is the first lncRNA identified as a regulator in endosperm development, highlighting the potential applications in rice breeding.

Parent-of-origin effects in the UK Biobank

Identical genetic variations can have different phenotypic effects depending on their parent of origin (PofO). Yet, studies focussing on PofO effects have been largely limited in terms of sample size due to the need of parental genomes or known genealogies. Here, we used a novel probabilistic approach to infer PofO of individual alleles in the UK Biobank that does not require parental genomes nor prior knowledge of genealogy. Our model uses Identity-By-Descent (IBD) sharing with second- and third-degree relatives to assign alleles to parental groups and leverages chromosome X data in males to distinguish maternal from paternal groups. When combined with robust haplotype inference and haploid imputation, this allowed us to infer the PofO at 5.4 million variants genome-wide for 26,393 UK Biobank individuals. We used this large dataset to systematically screen 59 biomarkers and 38 anthropomorphic phenotypes for PofO effects and discovered 101 significant associations, demonstrating that this type of effects contributes to the genetics of complex traits. Notably, we retrieved well known PofO effects, such as the MEG3/DLK1 locus on platelet count, and we discovered many new ones at loci often unsuspected of being imprinted and, in some cases, previously thought to harbour additive associations.