Functional genomics assays based on high-throughput sequencing greatly expand our ability to understand the genome. Here, we define the ENCODE blacklist- a comprehensive set of regions in the human, ...mouse, worm, and fly genomes that have anomalous, unstructured, or high signal in next-generation sequencing experiments independent of cell line or experiment. The removal of the ENCODE blacklist is an essential quality measure when analyzing functional genomics data.
The 2015 Paris Agreement on climate change is relevant to human rights law, not for what it says about human rights— which is next to nothing—but for what it says about the need to address the risk ...of climate change taking global temperatures above 1.5 or 2 °C. The Agreement could work, or it could fail by a large margin, but those who want to influence the outcome can still do so. That includes the human rights community. Since climate change is plainly a threat to human rights, how should the UN human rights institutions respond? Should they use their existing powers of oversight to focus attention on how States parties implement (or fail to implement) commitments made in the Paris Agreement? Or should they recognize a right to the enjoyment of a safe, clean, healthy and sustainable environment? Either choice would represent a significant contribution to the debate on human rights and climate change, giving humanity as a whole a voice that at present is scarcely heard.
Abstract
Inter-state litigation is a weapon employed by weaker states with limited diplomatic leverage over their bigger, more powerful opponents. An authoritative judgment may facilitate a ...settlement of some kind, whether directly, by further negotiation, or simply by legitimising the claims made. The LOSC was negotiated at a time when climate change was not yet part of the international agenda; however, it must be interpreted and applied with subsequent developments in international law and policy in mind. The harmful, toxic, and persistent effects of climate change more than satisfy the test for marine pollution established by Article 1 of LOSC. Part XII applies to climate change insofar as it has or is likely to have deleterious effects on the marine environment. This article will discuss the role that Part XII of LOSC may play in enforcing states' obligations to protect and preserve the marine environment from the effects of climate change.
Here we present a computational model, Score of Unified Regulatory Features (SURF), that predicts functional variants in enhancer and promoter elements. SURF is trained on data from massively ...parallel reporter assays and predicts the effect of variants on reporter expression levels. It achieved the top performance in the Fifth Critical Assessment of Genome Interpretation “Regulation Saturation” challenge. We also show that features queried through RegulomeDB, which are direct annotations from functional genomics data, help improve prediction accuracy beyond transfer learning features from DNA sequence‐based deep learning models. Some of the most important features include DNase footprints, especially when coupled with complementary ChIP‐seq data. Furthermore, we found our model achieved good performance in predicting allele‐specific transcription factor binding events. As an extension to the current scoring system in RegulomeDB, we expect our computational model to prioritize variants in regulatory regions, thus help the understanding of functional variants in noncoding regions that lead to disease.
Importance of procedural rights - right to a decent environment - application of human rights treaties to transboundary pollution and global climate change - pollution control - Aarhus Convention.
Different trans-acting factors (TFs) collaborate and act in concert at distinct loci to perform accurate regulation of their target genes. To date, the cobinding of TF pairs has been investigated in ...a limited context both in terms of the number of factors within a cell type and across cell types and the extent of combinatorial colocalizations. Here, we use an approach to analyze TF colocalization within a cell type and across multiple cell lines at an unprecedented level. We extend this approach with large-scale mass spectrometry analysis of immunoprecipitations of 50 TFs. Our combined approach reveals large numbers of interesting TF-TF associations. We observe extensive change in TF colocalizations both within a cell type exposed to different conditions and across multiple cell types. We show distinct functional annotations and properties of different TF cobinding patterns and provide insights into the complex regulatory landscape of the cell.
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•Colocalization patterns of 128 TFs in human cells•An application of SOMs to study high-dimensional TF colocalization patterns•Colocalization patterns are dynamic through stimulation and across cell types•Many TF colocalizations can be explained by protein-protein interaction
An integrative analysis of large, high-throughput datasets reveals the properties and dynamics of transcription factor complex colocalization binding patterns in human cell lines.
Chromatin looping is important for gene regulation, and studies of 3D chromatin structure across species and cell types have improved our understanding of the principles governing chromatin looping. ...However, 3D genome evolution and its relationship with natural selection remains largely unexplored. In mammals, the CTCF protein defines the boundaries of most chromatin loops, and variations in CTCF occupancy are associated with looping divergence. While many CTCF binding sites fall within transposable elements (TEs), their contribution to 3D chromatin structural evolution is unknown. Here we report the relative contributions of TE-driven CTCF binding site expansions to conserved and divergent chromatin looping in human and mouse. We demonstrate that TE-derived CTCF binding divergence may explain a large fraction of variable loops. These variable loops contribute significantly to corresponding gene expression variability across cells and species, possibly by refining sub-TAD-scale loop contacts responsible for cell-type-specific enhancer-promoter interactions.
Portability of trans-ancestral polygenic risk scores is often confounded by differences in linkage disequilibrium and genetic architecture between ancestries. Recent literature has shown that ...prioritizing GWAS SNPs with functional genomic evidence over strong association signals can improve model portability. We leveraged three RegulomeDB-derived functional regulatory annotations—SURF, TURF, and TLand—to construct polygenic risk models across a set of quantitative and binary traits highlighting functional mutations tagged by trait-associated tissue annotations. Tissue-specific prioritization by TURF and TLand provide a significant improvement in model accuracy over standard polygenic risk score (PRS) models across all traits. We developed the Trans-ancestral Iterative Tissue Refinement (TITR) algorithm to construct PRS models that prioritize functional mutations across multiple trait-implicated tissues. TITR-constructed PRS models show increased predictive accuracy over single tissue prioritization. This indicates our TITR approach captures a more comprehensive view of regulatory systems across implicated tissues that contribute to variance in trait expression.
Genome-wide association studies have been successful in identifying single nucleotide polymorphisms (SNPs) associated with a large number of phenotypes. However, an associated SNP is likely part of a ...larger region of linkage disequilibrium. This makes it difficult to precisely identify the SNPs that have a biological link with the phenotype. We have systematically investigated the association of multiple types of ENCODE data with disease-associated SNPs and show that there is significant enrichment for functional SNPs among the currently identified associations. This enrichment is strongest when integrating multiple sources of functional information and when highest confidence disease-associated SNPs are used. We propose an approach that integrates multiple types of functional data generated by the ENCODE Consortium to help identify "functional SNPs" that may be associated with the disease phenotype. Our approach generates putative functional annotations for up to 80% of all previously reported associations. We show that for most associations, the functional SNP most strongly supported by experimental evidence is a SNP in linkage disequilibrium with the reported association rather than the reported SNP itself. Our results show that the experimental data sets generated by the ENCODE Consortium can be successfully used to suggest functional hypotheses for variants associated with diseases and other phenotypes.
Abstract
Understanding the functional consequences of genetic variation in the non-coding regions of the human genome remains a challenge. We introduce h ere a computational tool, TURF, to prioritize ...regulatory variants with tissue-specific function by leveraging evidence from functional genomics experiments, including over 3000 functional genomics datasets from the ENCODE project provided in the RegulomeDB database. TURF is able to generate prediction scores at both organism and tissue/organ-specific levels for any non-coding variant on the genome. We present that TURF has an overall top performance in prediction by using validated variants from MPRA experiments. We also demonstrate how TURF can pick out the regulatory variants with tissue-specific function over a candidate list from associate studies. Furthermore, we found that various GWAS traits showed the enrichment of regulatory variants predicted by TURF scores in the trait-relevant organs, which indicates that these variants can be a valuable source for future studies.
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