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4 results on '"Alföldi, Jessica"'

1. Transcript expression-aware annotation improves rare variant discovery and interpretation

Author

Cummings, Beryl B., Karczewski, Konrad J., Kosmicki, Jack A., Seaby, Eleanor G., Watts, Nicholas A., Singer-Berk, Moriel, Mudge, Jonathan M., Karjalainen, Juha, Satterstrom, F. Kyle, O’Donnell-Luria, Anne, Poterba, Timothy, Seed, Cotton, Solomonson, Matthew, Alföldi, Jessica, Daly, Mark J., and MacArthur, Daniel G.

Subjects
0303 health sciences, 03 medical and health sciences, Annotation, 0302 clinical medicine, Computational biology, Biology, 030217 neurology & neurosurgery, 030304 developmental biology, Gene transcript, Interpretation (model theory)
Abstract

The acceleration of DNA sequencing in patients and population samples has resulted in unprecedented catalogues of human genetic variation, but the interpretation of rare genetic variants discovered using such technologies remains extremely challenging. A striking example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Through manual curation of putative loss of function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)(1), we show that one explanation for this paradox involves alternative mRNA splicing, which allows exons of a gene to be expressed at varying levels across cell types. Currently, no existing annotation tool systematically incorporates this exon expression information into variant interpretation. Here, we develop a transcript-level annotation metric, the proportion expressed across transcripts (pext), which summarizes isoform quantifications for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression project(2) (GTEx) and show that it clearly differentiates between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder (ASD) and developmental disorders and intellectual disability (DD/ID) to show that pLoF variants in weakly expressed regions have effect sizes similar to those of synonymous variants, while pLoF variants in highly expressed exons are most strongly enriched among cases versus controls. Our annotation is fast, flexible, and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for rare disease diagnosis, rare variant burden analyses in complex disorders, and curation and prioritization of variants in recall-by-genotype studies.

Published
2019

2. A high-resolution map of human evolutionary constraint using 29 mammals

Author

Lindblad-Toh, Kerstin, Garber, Manuel, Zuk, Or, Lin, Michael F, Parker, Brian J, Washietl, Stefan, Kheradpour, Pouya, Ernst, Jason, Jordan, Gregory, Mauceli, Evan, Ward, Lucas D, Lowe, Craig B, Holloway, Alisha K, Clamp, Michele, Gnerre, Sante, Alföldi, Jessica, Beal, Kathryn, Chang, Jean, Clawson, Hiram, Cuff, James, Di Palma, Federica, Fitzgerald, Stephen, Flicek, Paul, Guttman, Mitchell, Hubisz, Melissa J, Jaffe, David B, Jungreis, Irwin, Kent, W James, Kostka, Dennis, Lara, Marcia, Martins, Andre L, Massingham, Tim, Moltke, Ida, Raney, Brian J, Rasmussen, Matthew D, Robinson, Jim, Stark, Alexander, Vilella, Albert J, Wen, Jiayu, Xie, Xiaohui, Zody, Michael C, Broad Institute Sequencing Platform and Whole Genome Assembly Team, Baldwin, Jen, Bloom, Toby, Chin, Chee Whye, Heiman, Dave, Nicol, Robert, Nusbaum, Chad, Young, Sarah, Wilkinson, Jane, Worley, Kim C, Kovar, Christie L, Muzny, Donna M, Gibbs, Richard A, Baylor College of Medicine Human Genome Sequencing Center Sequencing Team, Cree, Andrew, Dihn, Huyen H, Fowler, Gerald, Jhangiani, Shalili, Joshi, Vandita, Lee, Sandra, Lewis, Lora R, Nazareth, Lynne V, Okwuonu, Geoffrey, Santibanez, Jireh, Warren, Wesley C, Mardis, Elaine R, Weinstock, George M, Wilson, Richard K, Genome Institute at Washington University, Delehaunty, Kim, Dooling, David, Fronik, Catrina, Fulton, Lucinda, Fulton, Bob, Graves, Tina, Minx, Patrick, Sodergren, Erica, Birney, Ewan, Margulies, Elliott H, Herrero, Javier, Green, Eric D, Haussler, David, Siepel, Adam, Goldman, Nick, Pollard, Katherine S, Pedersen, Jakob S, Lander, Eric S, and Kellis, Manolis

Subjects
Evolution, General Science & Technology, Genome Institute at Washington University, Genetic, Genetics, Baylor College of Medicine Human Genome Sequencing Center Sequencing Team, Animals, Humans, 2.1 Biological and endogenous factors, Disease, Aetiology, Selection, Phylogeny, Mammals, Broad Institute Sequencing Platform and Whole Genome Assembly Team, Genome, Human Genome, Molecular, Molecular Sequence Annotation, DNA, Genomics, Exons, Health, RNA, Sequence Alignment, Sequence Analysis, Human, Biotechnology
Abstract

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. 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. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.

Published
2011

3. Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication

Author

Jeremy A. Johnson, Guillaume Queney, Sarah Young, G. Bolet, Frank W. Albert, Anqi Xiong, Gerli Pielberg, Rose G. Mage, Leif Andersson, Samuel Boucher, Alvaro Martinez Barrio, Shady Younis, Carl-Johan Rubin, Nima Rafati, Kerstin Lindblad-Toh, Magali Ruffier, Eric S. Lander, Sandra Afonso, Bronwen Aken, Shumaila Sayyab, Federica Di Palma, Miguel Carneiro, Claire Rogel-Gaillard, Jessica Alföldi, Karin Forsberg-Nilsson, Jeffrey M. Good, Nuno Ferrand, Steve Searle, Rita Campos, Jean L. Chang, Luca Fontanesi, Daniel Barrell, Rafael Villafuerte, Hernán A. Burbano, Joel M. Alves, Ze Peng, Hervé Garreau, David I. Heiman, Véronique Duranthon, Jason Turner-Maier, Centro de Investigaçao em Biodiversidade e Recursos Genéticos, Science of Life Laboratory Uppsala - Department of Medical Biochemistry and Microbiology, Uppsala University, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Vertebrate and Health Genomics, Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology [Leipzig], Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Department of Human Genetics, University of California, Science of Life Laboratory Uppsala - Department of Medical Biochemistry and Microbioology, Department of Animal Bredding and Genetics, Swedish University of Agricultural Sciences (SLU), Department of Animal Production, Université Ain Shams, The Wellcome Trust Sanger Institute [Cambridge], University of Cambridge [UK] (CAM), Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Labovet Conseil, Max-Planck-Gesellschaft, Biologie du développement et reproduction (BDR), Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Department of Agricultural and Food Sciences - Division of Animal Sciences, Alma Mater Studiorum University of Bologna (UNIBO), Laboratory of Immunology, National Institute of Allergy and Infectious Deseases (NIAID), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Antagene - Animal Genomics Laboratory, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Spanish National Research Council (CSIC), Science for Life Laboratory - Department of Immunology , Genetics and Pathology, Science for Life Laboratory - Department of Immunology, Genetics and Pathology, Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, U54 HG003067 NHGRI NIH HHS, WT095908 Wellcome Trust, WT098051 Wellcome Trust, Carneiro, Miguel, Rubin, Carl-Johan, Palma, Federica Di, Albert, Frank W., Alföldi, Jessica, Barrio, Alvaro Martinez, Pielberg, Gerli, Rafati, Nima, Sayyab, Shumaila, Turner-Maier, Jason, Younis, Shady, Afonso, Sandra, Aken, Bronwen, Alves, Joel M., Barrell, Daniel, Bolet, Gerard, Boucher, Samuel, Burbano, Hernán A., Campos, Rita, Chang, Jean L., Duranthon, Veronique, Fontanesi, Luca, Garreau, Herve, Heiman, David, Johnson, Jeremy, Mage, Rose G., Peng, Ze, Queney, Guillaume, Rogel-Gaillard, Claire, Ruffier, Magali, Searle, Steve, Villafuerte, Rafael, Xiong, Anqi, Young, Sarah, Forsberg-Nilsson, Karin, Good, Jeffrey M., Lander, Eric S., Ferrand, Nuno, Lindblad-Toh, Kerstin, Andersson, Leif, Max Planck Institute for Evolutionary Anthropology, Department of Animal Breeding and Genetics, Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-École nationale supérieure agronomique de Toulouse [ENSAT], Biologie du Développement et Reproduction (BDR), and Institut National de la Recherche Agronomique (INRA)

Subjects
Molecular Sequence Data, Animals, Wild, Single-nucleotide polymorphism, Rabbit, Breeding, Biology, Polymorphism, Single Nucleotide, Genome, Article, Evolution, Molecular, Gene Frequency, Animals, Selection, Genetic, Allele, Domestication, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Gene, Allele frequency, Genetics, Multidisciplinary, Base Sequence, Behavior, Animal, Animal, Medicine (all), Sequence Analysis, DNA, Phenotype, Genetic Loci, Animals, Domestic, Rabbits, Reference genome
Abstract

Rabbits softly swept to domestication When people domesticate animals, they select for tameness and tolerance of humans. What else do they look for? To identify the selective pressures that led to rabbit domestication, Carneiro et al. sequenced a domestic rabbit genome and compared it to that of its wild brethren (see the Perspective by Lohmueller). Domestication did not involve a single gene changing, but rather many gene alleles changing in frequency between tame and domestic rabbits, known as a soft selective sweep. Many of these alleles have changes that may affect brain development, supporting the idea that tameness involves changes at multiple loci. Science , this issue p. 1074 ; see also p. 1000

Published
2014

4. The African coelacanth genome provides insights into tetrapod evolution

Author

Mariko Forconi, Tereza Manousaki, Peter F. Stadler, Anna Maria Fausto, Simon D. M. White, Shigehiro Kuraku, Sumir Panji, Marcia Lara, Andreas Gnirke, Hervé Philippe, Shaohua Fan, Axel Meyer, Jean Nicolas Volff, Tsutomu Miyake, Sante Gnerre, Thorsten Burmester, Anne Nitsche, Igor Schneider, John J. Stegeman, Alison P. Lee, Kerstin Lindblad-Toh, Peter van Heusden, Chris T. Amemiya, Michael S. Campbell, Ettore Olmo, Vydianathan Ravi, Jason Turner-Maier, Denis Baurain, Gary W. Litman, Federica Di Palma, Nicolas Rohner, Manfred Schartl, Giuseppe Scapigliati, Oleg Simakov, Aaron M. Berlin, Barbara Picone, Ingo Braasch, Byrappa Venkatesh, David R. Nelson, Wilfried Haerty, Diana Tabbaa, M. Gail Mueller, Francesco Buonocore, Eric S. Lander, Gianluca De Moro, Uljana Hesse, Chris P. Ponting, Nathalie Feiner, Junaid Gamieldien, Clifford J. Tabin, Gregory L. Blatch, Tatsuya Ota, Steve Hoffmann, Maria Assunta Biscotti, John H. Postlethwait, Chris L. Organ, Jessica Alföldi, Lin Fan, Mark Robinson, Stephen M. J. Searle, Louise Williams, Mark E. Hahn, Sonja J. Prohaska, Jared V. Goldstone, Dariusz Przybylski, Iain MacCallum, Rosemary A. Dorrington, Joshua Z. Levin, Tatjana Sauka-Spengler, Kenta Sumiyama, Nil Ratan Saha, Henner Brinkmann, Jeremy Johnson, John P. Cannon, Filipe J. Ribeiro, Marco Gerdol, David B. Jaffe, Adriana Canapa, Hakim Tafer, Marco Barucca, Mark Yandell, Evan Mauceli, Alan Christoffels, Sibel I. Karchner, Adrienne L. Edkins, J. Joshua Smith, Bronwen Aken, Neil H. Shubin, Ted Sharpe, Domitille Chalopin, Alberto Pallavicini, Molecular Genetics Program, Benaroya Research Institute, Department of Biology, Northern Arizona University [Flagstaff], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Partenaires INRAE, Université de Montréal (UdeM), Institute of Neuroscience, University of Oregon [Eugene], University of Konstanz, Instituto de Ciências Biológicas, Federal University of Para - Universidade Federal do Para [Belem - Brésil], Department of Genetics [Boston], Harvard Medical School [Boston] (HMS), Utah State University (USU), Institut de Génomique Fonctionnelle de Lyon (IGFL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), Rhodes University, Grahamstown, Department of Life Sciences, Università degli studi di Trieste, Wellcome Trust Sanger Institute, Università Politecnica delle Marche [Ancona] (UNIVPM), Université de Liège, Victoria University [Melbourne], Department for Innovation in Biological, Agro-Food and Forest Systems, Tuscia University, University of Hamburg, Eccles Institute of Human Genetics, University of Utah, University of South Florida [Tampa] (USF), South African National Bioinformatics Institute (SANBI), University of the Western Cape, International Max Planck Research School for Organismal Biology (IMPRS), Max Planck Institute for Ornithology, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft-University of Konstanz, Biology Department (WHOI), Woods Hole Oceanographic Institution (WHOI), University of Oxford [Oxford], Leipzig University, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA, Keio University, All Children’s Hospital, University of Tennessee, Bioinformatics Group, Department of Computer Science, Universität Leipzig [Leipzig], Graduate University for Advanced Studies, Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore 138673, Singapore, European Molecular Biology Laboratory (EMBL), National Institute of Genetics (NIG), University of Chicago, Department Physiological Chemistry, Biocenter, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), South African National Department of Science and Technology, National Human Genome Research Institute (NHGRI), European Science Foundation, Amemiya, Chris T., Alföldi, Jessica, Meyer, Axel, Lindblad-Toh, Kerstin, Federal University of Para - Universidade Federal do Pará - UFPA [Belém, Brazil] (UFPA), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Trieste = University of Trieste, Università degli studi della Tuscia [Viterbo], University of the Western Cape (UWC), University of Oxford, Universität Leipzig, Julius-Maximilians-Universität Würzburg (JMU), Chris T., Amemiya, Jessica, Alföldi, Alison P., Lee, Shaohua, Fan, Hervé, Philippe, Iain, Maccallum, Ingo, Braasch, Tereza, Manousaki, Igor, Schneider, Nicolas, Rohner, Chris, Organ, Domitille, Chalopin, Jeramiah J., Smith, Mark, Robinson, Rosemary A., Dorrington, Gerdol, Marco, Bronwen, Aken, Maria Assunta, Biscotti, Marco, Barucca, Denis, Baurain, Aaron M., Berlin, Gregory L., Blatch, Francesco, Buonocore, Thorsten, Burmester, Michael S., Campbell, Adriana, Canapa, John P., Cannon, Alan, Christoffel, DE MORO, Gianluca, Adrienne L., Edkin, Lin, Fan, Anna Maria, Fausto, Nathalie, Feiner, Mariko, Forconi, Junaid, Gamieldien, Sante, Gnerre, Andreas, Gnirke, Jared V., Goldstone, Wilfried, Haerty, Mark E., Hahn, Uljana, Hesse, Steve, Hoffmann, Jeremy, Johnson, Sibel I., Karchner, Shigehiro, Kuraku, Marcia, Lara, Joshua Z., Levin, Gary W., Litman, Evan, Mauceli, Tsutomu, Miyake, M., Gail Mueller, David R., Nelson, Anne, Nitsche, Ettore, Olmo, Tatsuya, Ota, Pallavicini, Alberto, Sumir, Panji, Barbara, Picone, Chris P., Ponting, Sonja J., Prohaska, Dariusz, Przybylski, Nil Ratan, Saha, Vydianathan, Ravi, Filipe J., Ribeiro, Tatjana Sauka, Spengler, Giuseppe, Scapigliati, Stephen M. J., Searle, Ted, Sharpe, Oleg, Simakov, Peter F., Stadler, John J., Stegeman, Kenta, Sumiyama, Diana, Tabbaa, Hakim, Tafer, Jason Turner, Maier, Peter van, Heusden, Simon, White, Louise, William, Mark, Yandell, Henner, Brinkmann, Jean Nicolas, Volff, Clifford J., Tabin, Neil, Shubin, Manfred, Schartl, David B., Jaffe, John H., Postlethwait, Byrappa, Venkatesh, Federica Di, Palma, Eric S., Lander, Axel, Meyer, and Kerstin Lindblad, Toh

Subjects
0106 biological sciences, terrestrial environment, adaptation, ancestry, brain, excretion, finfish, gene expression, genome, immunity, olfaction, phylogenetics, protein, terrestrial environment, tetrapod, [SDV]Life Sciences [q-bio], LATIMERIA-MENADOENSIS, adaptation, Chick Embryo, MITOCHONDRIAL GENOME, LIVING FOSSIL, SEQUENCE, GENES, MODEL, TRANSCRIPTION, CHROMOSOMES, RETENTION, CHALUMNAE, 01 natural sciences, Genome, Animals, Genetically Modified, Mice, poisson, Coelacanth, Conserved Sequence, Phylogeny, Lungfish, 0303 health sciences, Multidisciplinary, biology, Latimeria, Fishes, Genes, Homeobox, Vertebrate, Genomics, Biological Evolution, phylogenetics, Enhancer Elements, Genetic, évolution du génome, Vertebrates, excretion, Comperative genomics, Living fossil, olfaction, Genome evolution, finfish, brain, Molecular Sequence Data, tetrapod, 010603 evolutionary biology, Article, Evolution, Molecular, 03 medical and health sciences, ddc:570, biology.animal, Animals, [INFO]Computer Science [cs], 14. Life underwater, 030304 developmental biology, Comparative genomics, ancestry, génome, Extremities, Molecular Sequence Annotation, Sequence Analysis, DNA, biology.organism_classification, immunity, body regions, Immunoglobulin M, Evolutionary biology, gene expression, protein, Sequence Alignment
Abstract

Acquisition and storage of Latimeria chalumnae samples was supported by grants from the African Coelacanth Ecosystem Programme of the South African National Department of Science and Technology. Generation of the Latimeria chalumnae and Protopterus annectens sequences by the Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University was supported by grants from the National Human Genome Research Institute (NHGRI). K.L.T. is the recipient of a EURYI award from the European Science Foundation. We would also like to thank the Genomics Sequencing Platform of the Broad Institute for sequencing the L. chalumnae genome and L. chalumnae and P. annectens transcriptomes, S. Ahamada, R. Stobbs and the Association pour le Protection de Gombesa (APG) for their help in obtaining coelacanth samples, Y. Zhao for the use of data from Rana chensinensis, and L. Gaffney, C. Hamilton and J. Westlund for assistance with figure preparation. 10; International audience; The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.

Published
2013

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