Previously our analysis of conserved protein coding signatures that extend beyond annotated stop codons predicted stop codon readthrough of several mammalian genes, all of which have been validated experimentally.  This course is aimed at exploring the computational challenges associated with interpreting how sequence differences between individuals lead to phenotypic differences such as gene expression, disease predisposition, or response to treatment. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples from patients. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Our study presents a general framework for applying multi-cell chromatin state analysis to decipher cis-regulatory connections and their role in health and disease. 2019 Aug 5. doi: 10.1038/s41592-019-0502-z, Nucleic Acids Research 47(14):7235-7246, Aug 22 2019. doi: 10.1093/nar/gkz538, Molecular Biology and Evolution. Massachusetts Institute of Technology. Exosomal profiles reflect several key biological drivers of ICI resistance or melanoma progression, exhibit significantly differentially expressed genes and pathways, and correlate with and are predictive of clinical response to therapy. Here we describe the theory and applications of the RNAalifold algorithm. A plethora of epigenetic modifications have been described in the human genome and shown to play diverse roles in gene regulation, cellular differentiation and the onset of disease. First, we study the relative power of different comparative metrics and their relationship to single-species metrics. Comparison between in vivo and in vitro data reveals that in rapidly dividing cells there are vastly fewer structured mRNA regions in vivo than in vitro. Our results suggest a general strategy for deciphering cis-regulatory elements by systematic large-scale experimental manipulation, and provide quantitative enhancer activity measurements across thousands of constructs that can be mined to generate and test predictive models of gene expression, Association studies provide genome-wide information about the genetic basis of complex disease, but medical research has focused primarily on protein-coding variants, owing to the difficulty of interpreting noncoding mutations. More than 90% of common variants associated with complex traits do not affect proteins directly, but instead the circuits that control gene expression. Our analysis confirms the known specificity of 41 of the 56 analyzed factor groups and reveals motifs of potential cofactors. Although individual modifications have been linked to the activity levels of various genetic functional elements, their combinatorial patterns are still unresolved and their potential for systematic de novo genome annotation remains untapped. Here, we use 12 Drosophila genomes to study the power of comparative genomics metrics to distinguish between protein-coding and non-coding regions. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Shi, Kasumova, Michaud, Cintolo-Gonzales, Mart�nez, Ohmura, Mehta, Chien, Frederick, Cohen, Plana, Johnson, Flaherty, Sullivan, Kellis, Boland. Here, we characterized mRNA structure dynamics during zebrafish development. Using improved comparative genomics methods for detecting readthrough, we identify evolutionary signatures of conserved, functional readthrough of 353 stop codons in the malaria vector, Anopheles gambiae, and of 51 additional Drosophila melanogaster stop codons, including several cases of double and triple readthrough and of readthrough of two adjacent stop codons. Sep 3, 2015; Nature Biotechnology 33(8):825-6. Our single-cell transcriptomic resource provides a blueprint for interrogating the molecular and cellular basis of Alzheimer's disease, Wang, He, Goggin, Saadat, Wang, Sinnott-Armstrong, Claussnitzer*, Kellis*, Genome-wide epigenomic maps have revealed millions of putative enhancers and promoters, but experimental validation of their function and high-resolution dissection of their driver nucleotides remain limited. Kasowski, Kyriazopoulou-Panagiotopoulou, Grubert, Zaugg, Kundaje, Liu, Boyle, Zhang, Zakharia, Spacek, Li, Xie, Olarerin-George, Steinmetz, Hogenesch, Kellis, Batzoglou, Snyder. RiVIERA identified meaningful tissue-specific enrichments for enhancer regions defined by H3K4me1 and H3K27ac for Blood T-Cell specifically in the nine autoimmune diseases and Brain-specific enhancer activities exclusively in Schizophrenia. Here, using both molecular and genome-wide next-generation sequencing methods, we report that neuronal activity stimulation triggers the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including Fos, Npas4, and Egr1. Generation of targeted DNA DSBs within Fos and Npas4 promoters is sufficient to induce their expression even in the absence of an external stimulus. Juul, Madsen, Guo, Bertl, Hobolth, Kellis, Pedersen, Understanding the mutational processes that act during cancer development is a key topic of cancer biology. Here, we report our initial integrative analysis of the first phase of the project, encompassing more than 1000 datasets generated over four years across six production centers.  They showed that this mechanism operates in the fat cells of both humans and mice and detailed how changes within the relevant genomic regions cause a shift from dissipating energy as heat (thermogenesis) to storing energy as fat. This picture has changed with advances in the systematic annotation of functional noncoding elements. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. Stefan Washietl Computer Science and Artificial Intelligence Lab, MIT Verified email at mit.edu. They show that their algorithm, called DeepBind, is broadly applicable and results in increased predictive power compared to traditional single-domain methods, and they use its predictions to discover regulatory motifs, to predict RNA editing and alternative splicing, and to interpret genetic variants. The VDR is a member of the nuclear receptor superfamily of ligand-inducible transcription factors and binds its major ligand, calcitriol, via its C-terminal ligand-binding domain. We use a systematic pipeline for calculating motif enrichment in each data set, providing a principled way for choosing between motif variants found in the literature and for flagging potentially problematic data sets. Board Director Omar Hussain. Some coronavirus advice for my friends: 1. In 2004, Kellis became a member of the MIT faculty, the Computer Science and Artificial Intelligence Laboratory (CSAIL) and the Broad Institute. Manolis Kellis received his B.S., M.S. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. Given a good program for this fundamental subroutine, the algorithm is quite easy to implement. We infer for each disorder group disease gene networks with preferential cell-type specific activity that can aid the design and interpretation of cell-type resolution experiments. The goal was to develop methods for understanding genomes with a view to apply them to the human genome. However, heterogeneous EHR data types and biased ascertainment impose computational challenges. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. 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