Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome

Background The functional impact of genetic variation has been extensively surveyed, revealing that genetic changes correlated to phenotypes lie mostly in non-coding genomic regions. Studies have linked allele-specific genetic changes to gene expression, DNA methylation, and histone marks but these investigations have only been carried out in a limited set of samples. Results We describe a large-scale coordinated study of allelic and non-allelic effects on DNA methylation, histone mark deposition, and gene expression, detecting the interrelations between epigenetic and functional features at unprecedented resolution. We use information from whole genome and targeted bisulfite sequencing from 910 samples to perform genotype-dependent analyses of allele-specific methylation (ASM) and non-allelic methylation (mQTL). In addition, we introduce a novel genotype-independent test to detect methylation imbalance between chromosomes. Of the ~2.2 million CpGs tested for ASM, mQTL, and genotype-independent effects, we identify ~32% as being genetically regulated (ASM or mQTL) and ~14% as being putatively epigenetically regulated. We also show that epigenetically driven effects are strongly enriched in repressed regions and near transcription start sites, whereas the genetically regulated CpGs are enriched in enhancers. Known imprinted regions are enriched among epigenetically regulated loci, but we also observe several novel genomic regions (e.g., HOX genes) as being epigenetically regulated. Finally, we use our ASM datasets for functional interpretation of disease-associated loci and show the advantage of utilizing naïve T cells for understanding autoimmune diseases. Conclusions Our rich catalogue of haploid methylomes across multiple tissues will allow validation of epigenome association studies and exploration of new biological models for allelic exclusion in the human genome.This work was supported by a Canadian Institute of Health Research (CIHR) team grant awarded to E.G. and M.L. (TEC-128093) and the CIHR funded Epigenome Mapping Centre at McGill University (EP1-120608) awarded to T.P. and M.L. The work was also supported in part by a grant to M.L. from Génome Québec, le Ministère de l’Enseignement supérieur, de la Recherche, de la Science et de la Technologie Québec (MESRST), and McGill University as well as by the RESERt-AID grant (ANR-15-EPIG-0004-05) awarded to T.P and F.D. and by a grant from the French national clinical research program (PHRC) awarded to I.P. which also covered salary support to D.A. and X.S. E.G. is Tier 2 Canada Research Chair in Disease Genomics and Epigenomics, T.P. is Tier 2 Canada Research Chair in Human Genomics, and M.-C.V. is Tier 1 Canada Research Chair in Genomics Applied to Nutrition and Health. W.C. and A.M. are supported by a fellowship from the Fonds de Recherche du Quebec (FRSQ-32203 and FRSQ-27644). X.S. is supported by a fellowship from the Research Institute of the MUHC (McGill University Health Centre). D.S.P. and The Cardiovascular Epidemiology Unit are supported by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), and NIHR Cambridge Biomedical Research Centre

Dva zanimljiva terminološka rječnika

Authors thank United States Fleet Forces Command and Naval Facilities Engineering Command Atlantic for funding and support for the development of this gap analysis.Heterogeneous data collection in the marine environment has led to large gaps in our knowledge of marine species distributions. To fill these gaps, models calibrated on existing data may be used to predict species distributions in unsampled areas, given that available data are sufficiently representative. Our objective was to evaluate the feasibility of mapping cetacean densities across the entire Mediterranean Sea using models calibrated on available survey data and various environmental covariates. We aggregated 302,481 km of line transect survey effort conducted in the Mediterranean Sea within the past 20 years by many organisations. Survey coverage was highly heterogeneous geographically and seasonally: large data gaps were present in the eastern and southern Mediterranean and in non-summer months. We mapped the extent of interpolation versus extrapolation and the proportion of data nearby in environmental space when models calibrated on existing survey data were used for prediction across the entire Mediterranean Sea. Using model predictions to map cetacean densities in the eastern and southern Mediterranean, characterised by warmer, less productive waters, and more intense eddy activity, would lead to potentially unreliable extrapolations. We stress the need for systematic surveys of cetaceans in these environmentally unique Mediterranean waters, particularly in non-summer months.Publisher PDFPeer reviewe

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Epigenome-wide association study identifies DNA methylation markers for asthma remission in blood and nasal epithelium

Background: Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission. Methods: Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n=72) and nasal brushing samples (n=97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and EGEA. Results: We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P<0.05) and the same direction of effect in nasal brushes. Conclusion: We identified DNA methylation markers possibly associated with clinical and complete asthma remission in nasal brushes and whole blood

Epigenome-wide association study identifies DNA methylation markers for asthma remission in whole blood and nasal epithelium.

BACKGROUND: Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission. METHODS: Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n = 72) and nasal brushing samples (n = 97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and Epidemiological study on the Genetics and Environment of Asthma (EGEA). RESULTS: We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P < 0.05) and the same direction of effect in nasal brushes. CONCLUSION: We identified DNA methylation markers possibly associated with clinical and complete asthma remission in nasal brushes and whole blood, and two CpG sites identified from whole blood can be replicated in independent cohorts and may play a role in peroxisome proliferation and Wnt signaling pathway

Genetic variation 25.1 Mb upstream of tissue factor pathway inhibitor is associated with TFPI plasma levels and venous thromboembolism

International audienceBackgroundTissue factor pathway inhibitor (TFPI) regulates fibrin clot formation, and low TFPI plasma levels increase the risk of arterial and venous thromboembolism (VTE). TFPI plasma levels are also heritable, and a previous linkage scan implicated the chromosome 2q region, but no specific genes.ObjectivesWe sought to replicate the linkage region in an independent sample and to identify the causal locus. MethodsWe first ran a linkage analysis of microsatellite markers and TFPI plasma levels in 251 individuals from the F5L Family Study and replicated the linkage peak on chromosome 2q (LOD=3.06). We next defined a follow-up region that included 112603 SNPs under the linkage peak, and meta-analyzed associations between these SNPs and TFPI plasma levels across the F5L Family Study and MARTHA, a study of 1033 unrelated VTE patients. SNPs with FDR q<0.10 were tested for association with TFPI plasma levels in 892 patients with coronary artery disease in the AtheroGene study.Results and ConclusionsOne SNP, rs62187992, was associated with TFPI plasma levels in all three samples (β=+0.14 P=4.23x10-6 combined; β=+0.16, P=0.02 in F5L Family Study; β=+0.13, P=6.3x10-4 in MARTHA; β=+0.17, P=0.03 in AtheroGene) and contributed to the linkage peak in the F5L Family Study. rs62187992 was also associated with clinical VTE (odds ratio=0.90, P=0.03) in the INVENT consortium of over 7000 cases and their controls and was marginally associated with TFPI expression (β=+0.19, P=0.08) in human aortic endothelial cells, a primary site of TFPI synthesis. The biological mechanisms underlying these associations remain to be elucidated

An integrated approach for cetacean knowledge and conservation in the central Mediterranean Sea using research and social media data sources

1. Sources of data other than those derived from conventional research protocols may contribute valuable information to fill gaps in knowledge about cetacean occurrences and diversity in a given area and help address conservation issues. 2. The performance of a method to examine cetacean communities based on presence records systematically derived from shared photographs and videos posted by boaters and maritime operators on social media (e.g. YouTube and Facebook) combined with patchy distributed visual/acoustic data collected by researchers has been evaluated. 3. Records (N = 1,274) gathered over a 10‐year period (2008–2017) have been used to obtain insights into species' presence and habitat selection in a scattered study area of the central Mediterranean Sea (Italy). The effectiveness of the method, practical and theoretical advantages, limitations, and challenges of using data originated from social media for research and conservation purposes are discussed. 4. Seven out of the eight cetacean species regularly residing in the Mediterranean have been reported in the area, with different relative densities. Maximum entropy modelling techniques have been applied to the datasets derived from (a) social media, (b) research surveys, and (c) the combination of the two, using six fixed variables as proxies for cetacean presence. Distance from the coast and depth emerged as the main variables predicting encounters, with specificities related to the ecology of the species. 5. The approach was reliable enough to obtain broad‐scale, baseline information on cetacean communities in the region, on the basis of which initial conservation recommendations and future research programmes can be proposed. 6. With the increasing need for studying whale and dolphin population ecology coming from national/international directives, support from citizens to aid research may act as a practical, inexpensive solution to gathering extensive spatial–temporal data for regional‐scale monitoring and for the development of management priorities

DNA methylation and body-mass index: a genome-wide analysis

BACKGROUND Obesity is a major health problem that is determined by interactions between lifestyle and environmental and genetic factors. Although associations between several genetic variants and body-mass index (BMI) have been identified, little is known about epigenetic changes related to BMI. We undertook a genome-wide analysis of methylation at CpG sites in relation to BMI. METHODS 479 individuals of European origin recruited by the Cardiogenics Consortium formed our discovery cohort. We typed their whole-blood DNA with the Infinium HumanMethylation450 array. After quality control, methylation levels were tested for association with BMI. Methylation sites showing an association with BMI at a false discovery rate q value of 0·05 or less were taken forward for replication in a cohort of 339 unrelated white patients of northern European origin from the MARTHA cohort. Sites that remained significant in this primary replication cohort were tested in a second replication cohort of 1789 white patients of European origin from the KORA cohort. We examined whether methylation levels at identified sites also showed an association with BMI in DNA from adipose tissue (n=635) and skin (n=395) obtained from white female individuals participating in the MuTHER study. Finally, we examined the association of methylation at BMI-associated sites with genetic variants and with gene expression. FINDINGS 20 individuals from the discovery cohort were excluded from analyses after quality-control checks, leaving 459 participants. After adjustment for covariates, we identified an association (q value ≤0·05) between methylation at five probes across three different genes and BMI. The associations with three of these probes--cg22891070, cg27146050, and cg16672562, all of which are in intron 1 of HIF3A--were confirmed in both the primary and second replication cohorts. For every 0·1 increase in methylation β value at cg22891070, BMI was 3·6% (95% CI 2·4-4·9) higher in the discovery cohort, 2·7% (1·2-4·2) higher in the primary replication cohort, and 0·8% (0·2-1·4) higher in the second replication cohort. For the MuTHER cohort, methylation at cg22891070 was associated with BMI in adipose tissue (p=1·72 × 10(-5)) but not in skin (p=0·882). We observed a significant inverse correlation (p=0·005) between methylation at cg22891070 and expression of one HIF3A gene-expression probe in adipose tissue. Two single nucleotide polymorphisms--rs8102595 and rs3826795--had independent associations with methylation at cg22891070 in all cohorts. However, these single nucleotide polymorphisms were not significantly associated with BMI. INTERPRETATION Increased BMI in adults of European origin is associated with increased methylation at the HIF3A locus in blood cells and in adipose tissue. Our findings suggest that perturbation of hypoxia inducible transcription factor pathways could have an important role in the response to increased weight in people. FUNDING The European Commission, National Institute for Health Research, British Heart Foundation, and Wellcome Trust