We have developed quantitative metrics for the evolutionary signatures specific to protein-coding regions and applied them genome-wide, resulting in 1193 candidate new protein-coding exons in the D. melanogaster genome. We previously developed PhyloCSF, a widely-used tool to identify evolutionary signatures of protein-coding regions using multi-species genome alignments. Bioinformatics. We analyse over 1000 high-scoring human PhyloCSF regions, and confidently add 144 conserved protein-coding genes to the GENCODE gene set, as well as additional coding regions within 236 previously-annotated protein-coding genes, and 169 pseudogenes, most of them disabled after primates diverged. However, heterogeneous EHR data types and biased ascertainment impose computational challenges. Given a good program for this fundamental subroutine, the algorithm is quite easy to implement. Here we map the genome-wide binding locations of 165 human, 93 worm and 52 fly transcription regulatory factors, generating a total of 1,019 data sets from diverse cell types, developmental stages, or conditions in the three species, of which 498 (48.9%) are presented here for the first time. In a fifth cohort of older subjects with or without neurological disease (n = 438, ages 67-108), we show that subjects with brains deviating in the older direction from what would be expected based on chronological age show an increase in AD, Parkinson's disease, and cognitive decline. Rather, in mice engineered to develop Alzheimerâs-like symptoms, they found that immune cells start to change even before neural changes are observed, Kellis is a member of the Genotype-Tissue Expression (GTEx) project that seeks to elucidate the basis of disease predisposition. Manolis Kellis Despite large experimental and computational efforts aiming to dissect the mechanisms underlying disease risk, mapping cis-regulatory elements to target genes remains a challenge. Existing approaches for evaluating RNA structure have been largely limited to in vitro systems, yet the thermodynamic forces which drive RNA folding in vitro may not be sufficient to predict stable RNA structures in vivo5. Here we present a general method for inferring direct effects from an observed correlation matrix containing both direct and indirect effects. In 2004, Kellis became a member of the MIT faculty, the Computer Science and Artificial Intelligence Laboratory (CSAIL) and the Broad Institute. These results affect >10% of annotated fly genes and demonstrate the power of comparative genomics to enhance our understanding of genome organization, even in a model organism as intensively studied as Drosophila melanogaster. 2015 Dec 10. pii: gkv1340. In simulation, RiVIERA promising power in detecting causal variants and causal annotations, the multi-trait joint inference further improved the detection power. 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. Schizophrenia is a devastating mental disorder with a high societal burden, complex pathophysiology, and diverse genetic and environmental risk factors. MIT CSAIL Professor Manolis Kellis discusses how the symbiotic relationship between computer science and biology helps us to better understand the complex programming language that is our DNA. Furthermore, our methods suggest a variety of refinements to hundreds of existing gene models, such as modifications to translation start codons and exon splice boundaries. Software Engineer Prawal Gangwar. “Obesity has traditionally been seen as the result of an imbalance between the amount of food we eat and how much we exercise, but this view ignores the contribution of genetics to each individual’s metabolism,” says senior author Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and of the Broad Institute. Several years after the initial sequencing of the genomes from human and other organisms, the vast majority of each genome remains unannotated, and it is still unclear how to translate genomic information into a functional map of cellular and developmental programs. Head, MIT Computational Biology Group. We then wondered whether the inclusion of codon usage codon autocorrelation patterns, which reflects the non-random distribution of codon occurrences throughout a transcript, might improve the classification performance of our algorithm. It combines multiple genome-wide epigenomic maps, and uses combinatorial and spatial mark patterns to infer a complete annotation for each cell type. Manolis Kellis is a professor at MIT and head of the MIT Computational Biology Group. We introduce the Enhancing GTEx (eGTEx) project that extends the GTEx project to combine gene expression with additional intermediate molecular measurements on the same tissues to provide a resource for studying how genetic differences cascade through molecular phenotypes to impact human health, Ernst, Melnikov, Zhang, Wang, Rogov, Mikkelsen, Kellis. 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. The variation of recombination rate at both fine and large scales cannot be fully explained by DNA sequences alone. 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 define over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalogue of human enhancers and highlighting the role of these elements in cell-type-specific gene expression. 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. doi: 10.7554/eLife.10557. 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. 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. Dec 1, 2017. doi.org/10.1101/219428, Nature Communications 10(1):4902, Oct 25 2019. doi: 10.1038/s41467-019-12780-8, Genome Research, Sep 19, 2019, gr.246462.118, Nature Methods. Furthermore, dynamic 3'-UTR structures contain RNA-decay elements, such as the regulatory elements in nanog and ccna1, two genes encoding key maternal factors orchestrating the maternal-to-zygotic transition. The algorithm is the first for this problem with provable guarantees. 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. Computer Science & Artificial Intelligence Laboratory. In this issue, Alipanahi et al describe the use of a deep learning strategy to calculate protein-nucleic acid interactions from diverse experimental data sets. Ultimately, advances in regulatory and systems genomics can help unleash the value of whole-genome sequencing for personalized genomic risk assessment, diagnosis and treatment. With hundreds of epigenomic maps, the opportunity arises to exploit the correlated nature of epigenetic signals, across both marks and samples, for large-scale prediction of additional datasets. Here, we characterized mRNA structure dynamics during zebrafish development. Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects, A fundamental unit of gene-regulatory control is the contact between a regulatory protein and its target DNA or RNA molecule. Some coronavirus advice for my friends: 1. Epub 2007 Nov 7, Nature. We use SCINET to analyze the human cortex, reconstructing interactomes for the major cell types of the adult human brain. 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. Epub 2009 Mar 18, Nature. 10.1093/molbev/msz124, Life Sci Alliance 2(3). Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease. Butler, Rasmussen, Lin, Santos, Sakthikumar, Munro, Rheinbay, Grabherr, Forche, Reedy, Agrafioti, Arnaud, Bates, Brown, Brunke, Costanzo, Fitzpatrick, de, Harris, Hoyer, Hube, Klis, Kodira, Lennard, Logue, Martin, Neiman, Nikolaou, Quail, Quinn, Santos, Schmitzberger, Sherlock, Shah, Silverstein, Skrzypek, Soll, Staggs, Stansfield, Stumpf, Sudbery, Srikantha, Zeng, Berman, Berriman, Heitman, Gow, Lorenz, Birren, Kellis, Cuomo. We then exploit this finding, and show that domain-specific codon bias signatures can be used to classify a given sequence into its corresponding domain of life with high accuracy. Moreover, the variants from the 95% credible sets exhibited high conservation and enrichments for GTEx whole-blood eQTLs located within transcription-factor-binding-sites and DNA-hypersensitive-sites. Within enhancer elements specifically active in relevant cell types matrix factorization framework to physical! 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