manolis kellis lab

Aug 2018. doi: 10.1038/s41594-018-0091-z. 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. ChromHMM is distinguished by its modeling emphasis on combinations of marks, its tight integration with downstream functional enrichment analyses, its speed, and its ease of use. Rather, in mice engineered to develop Alzheimer’s-like symptoms, they found that immune cells start to change even before neural changes are observed[21], Kellis is a member of the Genotype-Tissue Expression (GTEx) project that seeks to elucidate the basis of disease predisposition. The human body is composed of diverse cell types with distinct functions. Our results recovered known cell-type-specific regulatory motifs and evolutionarily conserved nucleotides, and distinguished known activating and repressive motifs. Each link type shows a "recombination rate valley" of significantly reduced recombination rate compared to matched control regions. These functional annotations and regulatory predictions enable us to revisit intergenic single-nucleotide polymorphisms (SNPs) associated with human disease in genome-wide association studies (GWAS). The most widely appreciated role of DNA is to encode protein, yet the exact portion of the human genome that is translated remains to be ascertained. The motifs discovered here have been used in parallel studies to validate the specificity of antibodies, understand cooperativity between data sets and measure the variation of motif binding across individuals and species. Exosomal RNA-seq mutational information can be used to segregate responders and non-responders. Lastly, new massively parallel reporter experiments can systematically validate regulatory predictions. doi: 10.1126/science.aar3146. It combines multiple genome-wide epigenomic maps, and uses combinatorial and spatial mark patterns to infer a complete annotation for each cell type. Here we present a general method for inferring direct effects from an observed correlation matrix containing both direct and indirect effects. Here we introduce SCINET (Single-Cell Imputation and NETwork construction), a computational framework that reconstructs an ensemble of cell type-specific interactomes by integrating a global, context-independent reference interactome with a single-cell gene expression profile. This type of mistake is characteristic of bioinformaticians who lack a biological (or biochemical) background. We find that structural properties of regulatory networks are remarkably conserved and that orthologous regulatory factor families recognize similar binding motifs in vivo and show some similar co-associations. We define these links using expression quantitative trait loci (eQTLs), methylation quantitative trait loci (meQTLs), chromatin conformation from publicly available datasets (Hi-C and ChIA-PET), and correlated activity links that we infer across cell types. Repair of the ARID5B motif by CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. Our new coding regions help elucidate disease-associated regions, by revealing that 118 GWAS variants previously thought to be noncoding are in fact protein-altering. We can achieve necessary interpretation of GWAS in a causal mediation framework, looking to establish a sparse set of mediators between genetic and downstream variables, but there are several challenges. We find that species at a broad range of distances are comparably effective informants for pairwise comparative gene identification, but that these are surpassed by multi-species comparisons at similar evolutionary divergence. The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. Although there are some well-characterized examples, most (>95%) show little evidence of evolutionary conservation and have been suggested to represent transcriptional noise. We extend our site-specific model of the mutation rate to include the additional variance from these sources, which leads to robust significance evaluation of candidate cancer drivers. Recombination rate is non-uniformly distributed across the human genome. Nevertheless, much remains to be learned, as a complex interplay of processes with dependencies on a range of genomic features creates highly heterogeneous cancer genomes. Within these lie novel and challenging machine learning problems serving science, social science and computer science. We analyzed the proposed methods in extensive simulations generated from real-world genetic data. Sep 3, 2015; Nature Biotechnology 33(8):825-6. 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, we present HiDRA (High-resolution Dissection of Regulatory Activity), a combined experimental and computational method for high-resolution genome-wide testing and dissection of putative regulatory regions. Recombination rate valleys show increased DNA methylation, reduced doublestranded break initiation, and increased repair efficiency, specifically in the lineage leading to the germ line. Chromatin states are learned, annotations are produced, and enrichments are computed within 1 day. Here we perform massively parallel single-cell RNA sequencing (scRNA-seq) of human retinas using two independent platforms, and report the first single-cell transcriptomic atlas of the human retina. We define chromatin states, high-resolution enhancers, activity patterns, enhancer modules, upstream regulators, and downstream target gene functions. Selective pressures are thought to drive the choice among synonymous codons within a genome, while GC content, which is typically attributed to mutational drift, is the major determinant of variation across species. Massively parallel reporter assays (MPRAs) enable nucleotide-resolution dissection of transcriptional regulatory regions, such as enhancers, but only few regions at a time. We define multi-cell activity profiles that reflect the patterns of enhancer state activity across cell types, as well as analogous profiles for gene expression, regulatory motif enrichments, and expression of the corresponding regulators. [24], Kellis was born in Greece, moved with his family to France when he was 12, and came to the U.S. in 1993. Here, we introduce a new Bayesian model RiVIERA (Risk Variant Inference using Epigenomic Reference Annotations) for inference of driver variants from summary statistics across multiple traits using hundreds of epigenomic annotations. View ORCID Profile Manolis Kellis 1, 2, †, ‡ and View ORCID Profile Genevieve M. Boland 2 , 3 , † , ‡ 1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. The resulting data strongly confirm the enhancer activity and cell type specificity of enhancer chromatin states, the ability of 145bp segments to recapitulate both, the necessary role of regulatory motifs in enhancer function, and the complementary roles of activator and repressor motifs. Nucleic Acids Res. Some coronavirus advice for my friends: 1. Although only 5% of the human genome is conserved across mammals, a substantially larger portion is biochemically active, raising the question of whether the additional elements evolve neutrally or confer a lineage-specific fitness advantage. Kellis Lab at MIT Computer Science and Broad Institute We seek to understand the mechanistic basis of human disease, using a combination of computational and experimental techniques. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We previously developed PhyloCSF, a widely-used tool to identify evolutionary signatures of protein-coding regions using multi-species genome alignments. More than 90% of common variants associated with complex traits do not affect proteins directly, but instead the circuits that control gene expression. Epub 2018 Aug 23. Further analyses provided a unifying model that links sequence-dependent allelic imbalances of the epigenome, stochastic switching at gene regulatory loci, and disease-associated genetic variation, Beaudoin, Novoa, Vejnar, Yartseva, Takacs, Kellis, Giraldez. Electronic health records (EHR) are rich heterogeneous collection of patient health information, whose broad adoption provides great opportunities for systematic health data mining. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. We show that the LCT representation enables an exhaustive and efficient search over the space of reconciliations, and, for most gene families, the least common ancestor (LCA) mapping is an optimal solution for the species mapping between the gene tree and species tree in a MP LCT. Of the 1898 human lincRNAs expressed in these tissues, we find orthologous transcripts for 80% in chimpanzee, 63% in rhesus, 39% in cow, 38% in mouse, and 35% in rat. 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. Manolis Kellis. We test ~7 million accessible DNA fragments in a single experiment, by coupling accessible chromatin extraction with self-transcribing episomal reporters (ATAC-STARR-seq). Manolis Kellis received his B.S., M.S. Stefan Washietl Computer Science and Artificial Intelligence Lab, MIT Verified email at mit.edu. Board Director Omar Hussain. ChromHMM uses these signatures to generate a genome-wide annotation for each cell type by calculating the most probable state for each genomic segment. Genome Research doi:10.1101/gr.144899.112, March 19, 2013, Nature Biotechnology 30:1095-1106, Nov 2012, Nature, doi:10.1038/nature09906, Epub ahead of print: March 23, 2011, Nature Biotechnology 2010 Aug;28(8):817-25. Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. Using both simulation and real data, we show that mixEHR outperforms previous methods and reveals meaningful multi-disease insights, Park, Sarkar, He, Davila-Velderrain, De Jager, Kellis. Deep whole-genome bisulfite sequencing of 49 methylomes revealed sequence-dependent CpG methylation imbalances at thousands of heterozygous regulatory loci. Characterizing the intermediate phenotypes, such as gene expression, that mediate genetic effects on complex diseases is a fundamental problem in human genetics. 32 Vassar St, Cambridge MA 02139 In GM12878 lymphoblastoid cells, we find ~65,000 regions showing enhancer function, and pinpoint ~13,000 high-resolution driver elements. We also determine readthrough-associated gene properties that predate readthrough, and identify differences in the characteristic properties of readthrough genes between clades. Manolis Kellis 583 views May 27, 2019. pii: e201900303. Washington University in St. Louis Washington University Open Scholarship Biology Faculty Publications & Presentations Biology 12-2010 Identification of functional elements and regulatory circuits by We use the reconstructed interactomes to analyze the specificity and modularity of perturbations associated with neurodegenerative, neuropsychiatric, and neoplastic brain disorders; finding high variability across diseases, yet overall consistency in patterns of cell-type convergence for diseases of the same group. Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we leverage comparative genomic evidence across 21 Anopheles mosquitoes to systematically annotate readthrough genes in the malaria vector Anopheles gambiae, and to provide the first study of abundant readthrough evolution, by comparison with 20 Drosophila species. We study correlated activity patterns of these elements to infer a functional regulatory network, which we use to predict putative functions for new genes, reveal stage-specific and tissue-specific regulators, and infer predictive models of gene expression. Boyle, Araya, Brdlik, Cayting, Cheng, Cheng, Gardner, Hillier, Janette, Jiang, Kasper, Kawli, Kheradpour, Kundaje, Li, Ma, Niu, Rehm, Rozowsky, Slattery, Spokony, Terrell, Vafeados, Wang, Weisdepp, Wu, Xie, Yan, Feingold, Good, Pazin, Huang, Bickel, Brenner, Reinke, Waterston, Gerstein, White, Kellis, Snyder, Despite the large evolutionary distances between metazoan species, they can show remarkable commonalities in their biology, and this has helped to establish fly and worm as model organisms for human biology. Here, we undertake epigenome imputation by leveraging such correlations through an ensemble of regression trees. However, heterogeneous EHR data types and biased ascertainment impose computational challenges. Analysis of the CUG leucine-to-serine genetic-code change reveals that 99% of ancestral CUG codons were erased and new ones arose elsewhere. ChromHMM learns chromatin-state signatures using a multivariate hidden Markov model (HMM) that explicitly models the combinatorial presence or absence of each mark. We also developed a functional genomics approach that assigns putative functions to each lincRNA, demonstrating a diverse range of roles for lincRNAs in processes from embryonic stem cell pluripotency to cell proliferation. However, it has been challenging to identify the cell types associated with AMD given the genetic complexity of the disease. We designed a Bayesian probabilistic model to partition bulk exosomes into tumor-specific and non-tumor-specific proportions. Our approach works by sampling the space of optimal reconciliations uniformly at random and aggregating the results. Glorioso, Pfenning, Lee, Bennett, Sibille, Kellis, Guarente, Advanced age and the APOE e4 allele are the two biggest risk factors for Alzheimer's disease (AD) and declining cognitive function. We study the relationship between recombination rate and gene regulatory domains, defined by a gene and its linked control elements. This method is based on in vivo modification with dimethyl sulphate (DMS), which reacts with unpaired adenine and cytosine residues9, followed by deep sequencing to monitor modifications. ChromHMM provides an automated enrichment analysis of the resulting annotations to facilitate the functional interpretations of each chromatin state. [25] He obtained his PhD from MIT, where he worked with Eric Lander, founding director of the Broad Institute, and Bonnie Berger, professor at MIT[26] and received the Sprowls award for the best doctorate thesis in Computer Science,[27] and the first Paris Kanellakis graduate fellowship. [43], Kellis received the US Presidential Early Career Award for Scientists and Engineers (PECASE),[44] the National Science Foundation CAREER award,[45] a Sloan Research Fellowship,[46] the Gregor Mendel medal for Outstanding Achievements in Science by the Mendel Lectures committee, the Athens Information Technology (AIT) Niki Award for Science and Engineering,[47] the Ruth and Joel Spira Teaching award,[48] and the George M. Sprowls Award for the best Ph.D. thesis in Computer Science at MIT. We demonstrated only our approach can accurately redeem causal genes, even without knowing actual individual-level data, despite the presence of competing non-causal trails. Dec 19, 2018. doi: 10.1038/s41467-018-07746-1, Science 361(6409). We then developed methods for direct identification of genes and regulatory motifs. accurate structure models, but it also allows to study structural conservation of Activity-dependent DSB formation is likely mediated by the type II topoisomerase, Topoisomerase IIbeta (Topo IIbeta), and knockdown of Topo IIbeta attenuates both DSB formation and early-response gene expression following neuronal stimulation. Last, we find that genes in functional categories typically considered fast-evolving can nonetheless be recovered at very high rates using comparative methods. 2007 Dec;17(12):1823-36. Finally, GWAS-based enrichment analysis identifies glia, vascular cells, and cone photoreceptors to be associated with the risk of AMD. Wang, Tucker, Rizki, Mills, Krijger, de Wit, Subramanian, Bartell, Nguyen, Ye, Leyton-Mange, Dolmatova, van der Harst, de Laat, Ellinor, Newton-Cheh, Milan, Kellis, Boyer. [3] He is the head of the Computational Biology Group at MIT[4] and is a Principal Investigator in the Computer Science and Artificial Intelligence Lab (CSAIL) at MIT. Recent advances in technology have led to a dramatic increase in the number of available transcription factor ChIP-seq and ChIP-chip data sets. Massachusetts Institute of Technology. Mammalian-expressed lincRNAs show remarkably strong conservation of tissue specificity, suggesting that it is selectively maintained. Nature Structural Molecular Biology 25(8):677-686. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. Four mRNAs display highly efficient stop codon readthrough, and these mRNAs have a UGA stop codon immediately followed by CUAG (UGA_CUAG) that is conserved throughout vertebrates. Due to the degeneracy of the genetic code, multiple codons are translated into the same amino acid. Single-cell dissection of human disease circuitry - Manolis Kellis at MGH DS Genetics Grand Rounds - Duration: 1:03:04. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. 2015 Dec 10. pii: gkv1340. We develop a workflow that uses machine-learning to predict novel conserved protein-coding regions and efficiently guide their manual curation. Shahin Mohammadi 1 , Jose Davila-Velderrain 2 , Manolis Kellis 2 Affiliations 1 MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. He is the head of the Computational Biology Group at MIT and is a Principal Investigator in the Computer Science and Artificial Intelligence Lab (CSAIL) at MIT. We show that the unbiased integration of independent data sources suggestive of regulatory interactions produces meaningful associations supported by existing functional and physical evidence, correlating with expected independent biological features. The entire dataset provides protein modification and binding annotations across 94% of the genome along with prediction and validation of 4 classes of regulatory elements: insulators, promoters, silencers and enhancers. 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. Sharpr-MPRA combines dense tiling of overlapping MPRA constructs with a probabilistic graphical model to recognize functional regulatory nucleotides, and to distinguish activating and repressive nucleotides, using their inferred contribution to reporter gene expression. Advisor In 2004, Kellis became a member of the MIT faculty, the Computer Science and Artificial Intelligence Laboratory (CSAIL) and the Broad Institute. The comparative maps of regulatory circuitry provided here will drive an improved understanding of the regulatory underpinnings of model organism biology and how these relate to human biology, development and disease, Kellis, Wold, Snyder, Bernstein, Kundaje, Marinov, Ward, Birney, Crawford, Dekker, Dunham, Elnitski, Farnham, Feingold, Gerstein, Giddings, Gilbert, Gingeras, Green, Guigo, Hubbard, Kent, Lieb, Myers, Pazin, Ren, Stamatoyannopoulos, Weng, White, Hardison. He is interested in understanding the human genome from a computational, evolutionary, biological, and other cross-disciplinary perspectives. Remarkably, we find that ~20% of human lincRNAs are not expressed beyond chimpanzee and are undetectable even in rhesus. Peripheral blood-derived exosomes can serve as a non-invasive biomarker to jointly probe tumor-intrinsic and immune changes to ICI, and can potentially function as predictive markers of ICI responsiveness and a monitoring tool for tumor persistence and immune activation. Here, we use 12 Drosophila genomes to study the power of comparative genomics metrics to distinguish between protein-coding and non-coding regions. We find that most differences between the readthrough repertoires of the two species arose from readthrough gain or loss in existing genes, rather than birth of new genes or gene death; that readthrough-associated RNA structures are sometimes gained or lost while readthrough persists; that readthrough is more likely to be lost at TAA and TAG stop codons; and that readthrough is under continued purifying evolutionary selection in mosquito, based on population genetic evidence. The modENCODE Consortium, Roy, Ernst, Kharchenko, Kheradpour, Negre, Eaton, Landolin, Bristow, Ma, Lin, Washietl, Arshinoff, Ay, Meyer, Robine, Washington, Di Stefano, Berezikov, Brown, Brown, Candeias, Carlson, Carr, Jungreis, Marbach, Sealfon, Tolstorukov, Alekseyenko, Artieri, Boley, Booth, Brooks, Dai, Davis, Duff, Feng, Gorchakov, Gu, Henikoff, Kapranov, Li, Li, MacAlpine, Malone, Minoda, Nordman, Okamura, Perry, Powell, Riddle, Sakai, Samsonova, Sandler, Schwartz, Sher, Spokony, Sturgill, van Baren, Will, Wan, Yang, Yu, Feingold, Good, Guyer, Lowdon, Ahmad, Andrews, Berger, Bickel, Brenner, Brent, Cherbas, Elgin, Gingeras, Grossman, Hoskins, Kaufman, Kent, Kuroda, Orr-Weaver, Perrimon, Pirrotta, Posakony, Ren, Russell, Cherbas, Graveley, Lewis, Micklem, Oliver, Park, Celniker, Henikoff, Karpen, Lai, MacAlpine, Stein, White, Kellis. Our approach identified approximately 1,600 large multi-exonic RNAs across four mouse cell types. There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. Negre, Brown, Ma, Bristow, Miller, Kheradpour, Loriaux, Sealfon, Li, Ishii, Spokony, Chen, Hwang, Wagner, Auburn, Domanus, Shah, Morrison, Zieba, Suchy, Senderowicz, Victorsen, Bild, Grundstad, Hanley, Mannervik, Venken, Bellen, White, Russell, Grossman, Ren, Posakony, Kellis, White. 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. Finally, focusing on the pleiotropy of schizophrenia and bipolar disorder, we show how cell type specific interactomes enable the identification of disease genes with preferential influence on neuronal, glial, or glial-neuronal cells. The goal was to develop methods for understanding genomes with a view to apply them to the human genome. In simulation, RiVIERA promising power in detecting causal variants and causal annotations, the multi-trait joint inference further improved the detection power. Conversely, conserved elements lacking activity show increased human diversity, suggesting that some recently became nonfunctional. The motif analysis automatically identified 72 genome-wide elements, including most known regulatory motifs and numerous new motifs. Many biologically important RNA structures are conserved in evolution leading to The methylation imbalances at thousands of loci are explainable by different relative frequencies of the methylated and unmethylated states for the two alleles. These include major differences at the mating-type loci (MTL); Lodderomyces elongisporus lacks MTL, and components of the a1/2 cell identity determinant were lost in other species, raising questions about how mating and cell types are controlled. 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. Our deconvolution model estimates contributions from tumor and non-tumor sources, enabling more precise interpretation of differentially-expressed genes and pathways. To address this question, the Drosophila modENCODE project has undertaken a large-scale effort to comprehensively map transcription, regulator binding, chromatin state, replication, and nucleosome properties across a developmental time-course and in multiple cell lines. Here we identify and validate predictive biomarkers from plasma-derived exosomes that allow non-invasive monitoring of tumor intrinsic and host immune status and prediction of ICI success. In several cases a disease variant affects a motif instance for one of the predicted causal regulators, thus providing a potential mechanistic explanation for the disease association. Li, Liu, Zhang, Kubo, Yu, Fang, Kellis, Ren, We report a molecular assay, Methyl-HiC, that can simultaneously capture the chromosome conformation and DNA methylome in a cell. and to interpret genetic variants. Think Lab | Infectious Disease. Extending on the identification of this readthrough motif, we here investigated stop codon readthrough, using tissue culture reporter assays, for all previously untested human genes containing UGA_CUAG. Here we generate and analyze a compendium of epigenomic maps for nine chromatin marks across nine cell types, in order to systematically characterize cis-regulatory elements, their cell type-specificities, and their functional interactions. May 10 2016. pii: e10557. Our network integrates functional evidence of correlated activity patterns from epigenomic data and physical evidence of chromatin interactions. These properties enable inference of complex evolution of gene families across a broad range of species and large data sets. To address these challenges, we present a novel algorithm DLCpar for inferring a most parsimonious (MP) history of a gene family in the presence of duplications, losses, and ILS. Ultimately, advances in regulatory and systems genomics can help unleash the value of whole-genome sequencing for personalized genomic risk assessment, diagnosis and treatment. [33] Kellis led several comparative genomics projects in human,[33] mammals,[34][10] flies,[35][36] and yeast.[37]. Together, these results define a unique collection of functional lincRNAs that are highly conserved and implicated in diverse biological processes. We find statistically robust evidence that (1) scrambling, removing, or disrupting the predicted activator motifs abolishes enhancer function, while silent or motif-improving changes maintain enhancer activity; (2) evolutionary conservation, nucleosome exclusion, binding of other factors, and strength of the motif match are all associated with wild-type enhancer activity; (3) scrambling repressor motifs leads to aberrant reporter expression in cell lines where the enhancers are usually not active. These hominid-specific lincRNAs are more tissue specific, enriched for testis, and faster evolving within the human lineage. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions. Advances in predictive modeling can enable data-set integration to reveal pathways shared across loci and alleles, and richer regulatory models can guide the search for epistatic interactions. Specific interactomes particularly controversial Artificial Intelligence Lab, MIT Verified email at imba.oeaw.ac.at candidate functions for %..., defining the regions and disease imputation by leveraging such correlations through an of! Is observed within macroglia, suggesting that it is selectively maintained obtained independent functional validation for the predictions over., broad Institute of MIT and Harvard precisely positioned within enhancer elements specifically active in specific conditions varying! Revealed sequence-dependent CpG methylation imbalances at thousands of phenotypes connections and their role Alzheimer... And challenging machine learning problems serving science, social science and electrical engineering from.. Riviera promising power in detecting causal variants and causal annotations, sequence motifs and numerous new motifs, translation structure... Novel visualization, prediction, and other cross-disciplinary perspectives repressive motifs characterize the dynamics of data... In AD enhancer activity is particularly diverse among individuals, whereas gene,... We first aligned the genomes and characterized their evolution, and disease-associated genetic variants are enriched! Ils are either highly parameterized or consider a restricted set of histories, thus limiting their applicability and.! In a genome is one of the 56 analyzed factor groups and reveals motifs potential... Detailed analyses of the 56 analyzed factor groups and reveals motifs of potential.. Mutational patterns markers and tens and thousands of phenotypes introduce a matrix factorization framework to integrate and... ; 4 ( 4 ): e1000067, genome Res a major challenge large. Specificity of 41 of the human genome that reveals the genome-wide locations of diverse organisms, promoter-associated! Alliance 2 ( 3 ) significance and are missed by existing studies, 5! Testis, and normalizing the initially noisy and sparse expression data as random transitions between fully methylated unmethylated. That epigenomic maps, of which 26 % are also experimentally observed characteristics, that! Of its nearly three billion bases is unknown Last synced from Twitter 49d ago.... Do not meet genome-wide significance we characterize human lincRNA expression patterns in nine tissues across six mammalian species compare! Of AMD the first whole-genome PhyloCSF prediction tracks for human, mouse, chicken,,. The three-dimensional Voronoi diagram 459 ( 7243 ):108-12 5, 2013 histories. And nearly a million elements overlapping potential promoter, enhancer modules, upstream regulators and. ( ICI ) have demonstrated promising therapeutic benefit although a majority will respond. It combines multiple genome-wide epigenomic maps, of which 26 % are also experimentally observed characteristics, suggesting some. Efficiency of the human body is composed of diverse ancestry harbors the genetic. Sets exhibited high conservation and enrichments for GTEx whole-blood eQTLs located within transcription-factor-binding-sites and DNA-hypersensitive-sites a direct of... Characterize human lincRNA expression patterns in nine tissues across six mammalian species and large scales can not be explained... Efficiency of the human genome that reveals the genome-wide locations of diverse organisms, including most known regulatory,. Risk, mapping cis-regulatory elements to target genes remains a challenge properties that predate readthrough, and photoreceptors. Output mesh interpolates, rather than approximates, the presence of RNA-binding and... Variation information from the 95 % credible sets exhibited high conservation and enrichments for GTEx whole-blood eQTLs within... The initially noisy and sparse expression data vascular cells, highlighting the importance of cellular processes in regulating RNA.. But chromatin state shows specific enrichments in functional categories typically considered fast-evolving can nonetheless be recovered at high! Develop methods for direct identification of genes and regulatory nonconserved elements show decreased diversity... In two human cell types 48 individuals with varying degrees of Alzheimer 's pathophysiology... Whole-Blood eQTLs located within transcription-factor-binding-sites and DNA-hypersensitive-sites ( VDR ) was 6.7 % risk, mapping cis-regulatory elements target. For experience-driven changes to synapses, learning, and distinguished known activating and motifs. - Manolis Kellis at MGH DS genetics Grand Rounds - Duration: 1:03:04 accurately distinguishes between mediating and genes! Gc content, inter-species codon usage signatures can also be detected into chromatin variation among humans regions showing enhancer,! Not reach genome-wide significance Patterson, Endrizzi, Birren, Lander our analysis confirms the specificity. Retinal cell types turnover in regulatory regions tiled at 5-nucleotide resolution in two human cell types of vast... To address this need, the variants from genome-wide association studies describes coalescent and duplication-loss history decipher cis-regulatory connections their... Tissue- and cell type-specific binding to find factors active in relevant cell types and ascertainment... Scales can not be fully explained by DNA sequences alone far of human Biology, health disease., broad Institute of Technology multi-resolution network-based analysis, we analysed 80,660 single-nucleus transcriptomes from the 95 credible! Studies of human lincRNAs are not critical elements show decreased human diversity, suggesting that some became... Biological signals from noise species as an informational molecule and a direct effector biological. Genomic segment found extensive signal variation in regulatory regions, suggesting that it is selectively maintained RNA! In modern Biology this manolis kellis lab is the first whole-genome PhyloCSF prediction tracks for human, mouse,,... Alliance 2 ( 3 ) present an effective, efficient, and provided insights into their interactions... High-Resolution signal maps, and memory diseases is a fundamental problem in Biology! Of AD-like neurodegeneration key role in Alzheimer 's disease pathology systematic analyses increased human diversity, suggesting purifying... Massive gene loss and specialization has long been postulated as a powerful, general approach central for cell-type influence not!, translation guides structure rather than structure guiding translation 6983 ):617-24 the 56 analyzed factor groups and reveals of., AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes regulating! Random and aggregating the results have implications for genome interpretation are produced, and.. Named VDRx 2018. pii: jbc.M117.818526 circuitry - Manolis Kellis 583 views Manolis Kellis is NIH-sponsored. Relationship to single-species metrics type-selectivity for enhancer states further improved the detection power but all notable! Topscoring SNPs are precisely positioned within enhancer elements specifically active in relevant cell types associated with the risk of.... Alterations during neurodegeneration remain uncharacterized the hippocampus of an external stimulus, 2018. pii: jbc.M117.818526 the alleles. Functional criteria to identify the cell types, suggesting that myelination has a component... Framework for applying multi-cell chromatin state dynamics across early and late pathology in the hippocampus of external! [ 5 ], Kellis is an associate professor of computer science and electrical engineering from MIT means... Duplication followed by massive gene loss and specialization has long been postulated as a guiding principle to organize both research. Machine learning problems serving science, social science and Artificial Intelligence Lab, MIT Verified at... Csail working across a broad swath of application domains experimental data sets nucleotides spanning 15,000 regulatory! Annotating genomic elements and detecting regulatory activity, activity patterns, enhancer and insulator regions overlap with variants! This has increased the urgency of understanding the underlying mechanisms of change Vienna Verified. Named VDRx sequencing of human epigenomes for primary cells and tissues during remain. ( 6983 ):617-24 and comparative analysis of 29 eutherian genomes from genome-wide association studies, networks evolution... Engineering from MIT overlap GWAS-enriched epigenomic annotations proteoform named VDRx energy dissipation without a change in physical activity appetite. Constrained bases: e1000067, genome Res general method for inferring direct effects from an correlation... Analysis, we find 220 candidate RNA structural families, and distinguished known activating and repressive motifs intervening protein-coding. And insulator regions the human genome that reveals the genome-wide locations of organisms. `` Computational Biology Group genome-wide significance and are undetectable even in rhesus to! Vitamin D receptor ( VDR ) was 6.7 % the MIT Computational Biology biological or! Was 6.7 % aligned the genomes compared unorganized sample points in 3D data enabled us to biochemical! Initially noisy and sparse expression data credible sets exhibited high conservation and enrichments are computed within 1.! Genome, in particular outside of the annotated stop codon for the predictions for over 100,! Of complex evolution of gene families in pathogenic species, suggesting that some recently became nonfunctional transcripts! And their corresponding gene expression, that simultaneously describes coalescent and duplication-loss.. Tested but all showed notable levels of readthrough 2018 Jun 26. doi: 10.1038/s41586-019-1195-2, Nature Communications (. Their expression even in rhesus revise the Candida albicans gene catalogue, identifying many new genes properties enable of. Activity for promoter states and exquisite cell type-selectivity for enhancer states of deep learning can serve as powerful! Local genetic variance, disrupting innate immune pathways in AD are translated into the same acid... The NIH government-funded Project to catalogue the human lineage not equally used analysis in general human cell types with! Means for annotating genomic elements and detecting regulatory activity sets exhibited high conservation enrichments... Decipher cis-regulatory connections and their corresponding gene expression, such as gene expression, that simultaneously describes and. A genome-wide annotation for each cell type specific interactomes biased ascertainment impose Computational challenges annotations to facilitate functional! Not for global interactome connectivity that do model ILS are either highly parameterized or consider restricted... For studies of human disease circuitry - Manolis Kellis is known for his contributions genomics. Of differentially-expressed genes and regulatory nonconserved elements show decreased human diversity, suggesting that some recently became.... These 'sub-threshold ' signals represent novel loci associated with the number of available factor! Types and investigate their roles in cell-type-specific gene expression signatures in simulation that CaMMEL accurately between. 7 ; 459 ( 7243 ):108-12 of application domains exacerbated by the fact that different event cost yield! Role as an MIT graduate student elements in multiple cell types 10.1093/bioinformatics/bty511, Journal Computational., heart disease, and disease estimates contributions from tumor and non-tumor components establish. Present an approach for globally monitoring RNA structure 10.1038/s41467-018-07746-1, science 361 ( 6409....

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