Pervasive polymorphic imprinted methylation in the human placenta.

The maternal and paternal copies of the genome are both required for mammalian development, and this is primarily due to imprinted genes, those that are monoallelically expressed based on parent-of-origin. Typically, this pattern of expression is regulated by differentially methylated regions (DMRs) that are established in the germline and maintained after fertilization. There are a large number of germline DMRs that have not yet been associated with imprinting, and their function in development is unknown. In this study, we developed a genome-wide approach to identify novel imprinted DMRs in the human placenta and investigated the dynamics of these imprinted DMRs during development in somatic and extraembryonic tissues. DNA methylation was evaluated using the Illumina HumanMethylation450 array in 134 human tissue samples, publicly available reduced representation bisulfite sequencing in the human embryo and germ cells, and targeted bisulfite sequencing in term placentas. Forty-three known and 101 novel imprinted DMRs were identified in the human placenta by comparing methylation between diandric and digynic triploid conceptions in addition to female and male gametes. Seventy-two novel DMRs showed a pattern consistent with placental-specific imprinting, and this monoallelic methylation was entirely maternal in origin. Strikingly, these DMRs exhibited polymorphic imprinted methylation between placental samples. These data suggest that imprinting in human development is far more extensive and dynamic than previously reported and that the placenta preferentially maintains maternal germline-derived DNA methylation

Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivation

X-chromosome inactivation (XCI) results in the differential marking of the active and inactive X with epigenetic modifications including DNA methylation. Consistent with the previous studies showing that CpG island-containing promoters of genes subject to XCI are approximately 50% methylated in females and unmethylated in males while genes which escape XCI are unmethylated in both sexes; our chromosome-wide (Methylated DNA ImmunoPrecipitation) and promoter-targeted methylation analyses (Illumina Infinium HumanMethylation27 array) showed the largest methylation difference (D = 0.12, p < 2.2 E−16) between male and female blood at X-linked CpG islands promoters. We used the methylation differences between males and females to predict XCI statuses in blood and found that 81% had the same XCI status as previously determined using expression data. Most genes (83%) showed the same XCI status across tissues (blood, fetal: muscle, kidney and nerual); however, the methylation of a subset of genes predicted different XCI statuses in different tissues. Using previously published expression data the effect of transcription on gene-body methylation was investigated and while X-linked introns of highly expressed genes were more methylated than the introns of lowly expressed genes, exonic methylation did not differ based on expression level. We conclude that the XCI status predicted using methylation of X-linked promoters with CpG islands was usually the same as determined by expression analysis and that 12% of X-linked genes examined show tissue-specific XCI whereby a gene has a different XCI status in at least one of the four tissues examined

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Gender differences in marital status moderation of genetic and environmental influences on subjective health

From the IGEMS Consortium, data were available from 26,579 individuals aged 23 to 102 years on 3 subjective health items: self-rated health (SRH), health compared to others (COMP), and impact of health on activities (ACT). Marital status was a marker of environmental resources that may moderate genetic and environmental influences on subjective health. Results differed for the 3 subjective health items, indicating that they do not tap the same construct. Although there was little impact of marital status on variance components for women, marital status was a significant modifier of variance in all 3 subjective health measures for men. For both SRH and ACT, single men demonstrated greater shared and nonshared environmental variance than married men. For the COMP variable, genetic variance was greater for single men vs. married men. Results suggest gender differences in the role of marriage as a source of resources that are associated with subjective health

Genome-wide mapping of imprinted differentially methylated regions by DNA methylation profiling of human placentas from triploidies

Abstract Background Genomic imprinting is an important epigenetic process involved in regulating placental and foetal growth. Imprinted genes are typically associated with differentially methylated regions (DMRs) whereby one of the two alleles is DNA methylated depending on the parent of origin. Identifying imprinted DMRs in humans is complicated by species- and tissue-specific differences in imprinting status and the presence of multiple regulatory regions associated with a particular gene, only some of which may be imprinted. In this study, we have taken advantage of the unbalanced parental genomic constitutions in triploidies to further characterize human DMRs associated with known imprinted genes and identify novel imprinted DMRs. Results By comparing the promoter methylation status of over 14,000 genes in human placentas from ten diandries (extra paternal haploid set) and ten digynies (extra maternal haploid set) and using 6 complete hydatidiform moles (paternal origin) and ten chromosomally normal placentas for comparison, we identified 62 genes with apparently imprinted DMRs (false discovery rate FAM50B, as well as novel imprinted DMRs associated with known imprinted genes (for example, CDKN1C and RASGRF1) can be identified by using this approach. Furthermore, we have demonstrated how comparison of DNA methylation for known imprinted genes (for example, GNAS and CDKN1C) between placentas of different gestations and other somatic tissues (brain, kidney, muscle and blood) provides a detailed analysis of specific CpG sites associated with tissue-specific imprinting and gestational age-specific methylation. Conclusions DNA methylation profiling of triploidies in different tissues and developmental ages can be a powerful and effective way to map and characterize imprinted regions in the genome.</p

Genome-wide mapping of imprinted differentially methylated regions by DNA methylation profiling of human placentas from triploidies

Background: Genomic imprinting is an important epigenetic process involved in regulating placental and foetal growth. Imprinted genes are typically associated with differentially methylated regions (DMRs) whereby one of the two alleles is DNA methylated depending on the parent of origin. Identifying imprinted DMRs in humans is complicated by species- and tissue-specific differences in imprinting status and the presence of multiple regulatory regions associated with a particular gene, only some of which may be imprinted. In this study, we have taken advantage of the unbalanced parental genomic constitutions in triploidies to further characterize human DMRs associated with known imprinted genes and identify novel imprinted DMRs. Results: By comparing the promoter methylation status of over 14,000 genes in human placentas from ten diandries (extra paternal haploid set) and ten digynies (extra maternal haploid set) and using 6 complete hydatidiform moles (paternal origin) and ten chromosomally normal placentas for comparison, we identified 62 genes with apparently imprinted DMRs (false discovery rate <0.1%). Of these 62 genes, 11 have been reported previously as DMRs that act as imprinting control regions, and the observed parental methylation patterns were concordant with those previously reported. We demonstrated that novel imprinted genes, such as FAM50B, as well as novel imprinted DMRs associated with known imprinted genes (for example, CDKN1C and RASGRF1) can be identified by using this approach. Furthermore, we have demonstrated how comparison of DNA methylation for known imprinted genes (for example, GNAS and CDKN1C) between placentas of different gestations and other somatic tissues (brain, kidney, muscle and blood) provides a detailed analysis of specific CpG sites associated with tissue-specific imprinting and gestational age-specific methylation. Conclusions: DNA methylation profiling of triploidies in different tissues and developmental ages can be a powerful and effective way to map and characterize imprinted regions in the genome.Medical Genetics, Department ofMedicine, Faculty ofPathology and Laboratory Medicine, Department ofOther UBCNon UBCReviewedFacult

Profiling placental and fetal DNA methylation in human neural tube defects

Background: The incidence of neural tube defects (NTDs) declined by about 40 % in Canada with the introduction of a national folic acid (FA) fortification program. Despite the fact that few Canadians currently exhibit folate deficiency, NTDs are still the second most common congenital abnormality. FA fortification may have aided in reducing the incidence of NTDs by overcoming abnormal one carbon metabolism cycling, the process which provides one carbon units for methylation of DNA. We considered that NTDs persisting in a folate-replete population may also occur in the context of FA-independent compromised one carbon metabolism, and that this might manifest as abnormal DNA methylation (DNAm). Second trimester human placental chorionic villi, kidney, spinal cord, brain, and muscle were collected from 19 control, 22 spina bifida, and 15 anencephalic fetuses in British Columbia, Canada. DNA was extracted, assessed for methylenetetrahydrofolate reductase (MTHFR) genotype and for genome-wide DNAm using repetitive elements, in addition to the Illumina Infinium HumanMethylation450 (450k) array. Results: No difference in repetitive element DNAm was noted between NTD status groups. Using a false discovery rate <0.05 and average group difference in DNAm ≥0.05, differentially methylated array sites were identified only in (1) the comparison of anencephaly to controls in chorionic villi (n = 4 sites) and (2) the comparison of spina bifida to controls in kidney (n = 3342 sites). Conclusions: We suggest that the distinctive DNAm of spina bifida kidneys may be consequent to the neural tube defect or reflective of a common etiology for abnormal neural tube and renal development. Though there were some small shifts in DNAm in the other tested tissues, our data do not support the long-standing hypothesis of generalized altered genome-wide DNAm in NTDs. This finding may be related to the fact that most Canadians are not folate deficient, but it importantly opens the field to the investigation of other epigenetic and non-epigenetic mechanisms in the etiology of NTDs.Medicine, Faculty ofOther UBCMedical Genetics, Department ofObstetrics and Gynaecology, Department ofPathology and Laboratory Medicine, Department ofPsychiatry, Department ofReviewedFacult