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

Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes

BACKGROUND:DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. METHODS:Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. RESULTS:Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. CONCLUSIONS:Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes

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

bioSyntax: syntax highlighting for computational biology

Background: Computational biology requires the reading and comprehension of biological data files. Plain-text formats such as SAM, VCF, GTF, PDB and FASTA, often contain critical information which is obfuscated by the data structure complexity. Results: bioSyntax ( https://biosyntax.org/ ) is a freely available suite of biological syntax highlighting packages for vim, gedit, Sublime, VSCode, and less. bioSyntax improves the legibility of low-level biological data in the bioinformatics workspace. Conclusion: bioSyntax supports computational scientists in parsing and comprehending their data efficiently and thus can accelerate research output.Medicine, Faculty ofScience, Faculty ofOther UBCNon UBCMedical Genetics, Department ofReviewedFacult

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

DNA methylation analysis identifies novel genetic loci associated with circulating fibrinogen levels in blood

BACKGROUND: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa. METHODS: We performed an epigenome-wide association study (EWAS) of circulating fibrinogen levels in 18,037 White, Black, American Indian, and Hispanic participants representing 14 studies from the CHARGE consortium. Circulating leukocyte DNA methylation was measured in 12,904 participants using the Illumina 450K array, and in 5,133 participants using the EPIC array. Each study performed an EWAS of fibrinogen using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without C-reactive protein (CRP) adjustment to examine the role of inflammation. RESULTS: We identified 208 and 87 significant CpG sites associated with fibrinogen from the 450K (p-value<1.03×10(-7)) and EPIC arrays (p-value<5.78×10(-8)), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for the overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. Examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations for all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. CONCLUSION: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP