Author: "Alföldi, Jessica" - Searchworks@Jio Institute Digital Library Search Results

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177 results on '"Alföldi, Jessica"'

1. A genomic mutational constraint map using variation in 76,156 human genomes

Author: Chen, Siwei, Francioli, Laurent C., Goodrich, Julia K., Collins, Ryan L., Kanai, Masahiro, Wang, Qingbo, Alföldi, Jessica, Watts, Nicholas A., Vittal, Christopher, Gauthier, Laura D., Poterba, Timothy, Wilson, Michael W., Tarasova, Yekaterina, Phu, William, Grant, Riley, Yohannes, Mary T., Koenig, Zan, Farjoun, Yossi, Banks, Eric, Donnelly, Stacey, Gabriel, Stacey, Gupta, Namrata, Ferriera, Steven, Tolonen, Charlotte, Novod, Sam, Bergelson, Louis, Roazen, David, Ruano-Rubio, Valentin, Covarrubias, Miguel, Llanwarne, Christopher, Petrillo, Nikelle, Wade, Gordon, Jeandet, Thibault, Munshi, Ruchi, Tibbetts, Kathleen, O’Donnell-Luria, Anne, Solomonson, Matthew, Seed, Cotton, Martin, Alicia R., Talkowski, Michael E., Rehm, Heidi L., Daly, Mark J., Tiao, Grace, Neale, Benjamin M., MacArthur, Daniel G., and Karczewski, Konrad J.
Published: 2024
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2. Author Correction: A genomic mutational constraint map using variation in 76,156 human genomes

Author: Chen, Siwei, Francioli, Laurent C., Goodrich, Julia K., Collins, Ryan L., Kanai, Masahiro, Wang, Qingbo, Alföldi, Jessica, Watts, Nicholas A., Vittal, Christopher, Gauthier, Laura D., Poterba, Timothy, Wilson, Michael W., Tarasova, Yekaterina, Phu, William, Grant, Riley, Yohannes, Mary T., Koenig, Zan, Farjoun, Yossi, Banks, Eric, Donnelly, Stacey, Gabriel, Stacey, Gupta, Namrata, Ferriera, Steven, Tolonen, Charlotte, Novod, Sam, Bergelson, Louis, Roazen, David, Ruano-Rubio, Valentin, Covarrubias, Miguel, Llanwarne, Christopher, Petrillo, Nikelle, Wade, Gordon, Jeandet, Thibault, Munshi, Ruchi, Tibbetts, Kathleen, O’Donnell-Luria, Anne, Solomonson, Matthew, Seed, Cotton, Martin, Alicia R., Talkowski, Michael E., Rehm, Heidi L., Daly, Mark J., Tiao, Grace, Neale, Benjamin M., MacArthur, Daniel G., and Karczewski, Konrad J.
Published: 2024
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3. Progressive Cactus is a multiple-genome aligner for the thousand-genome era

Author: Armstrong, Joel, Hickey, Glenn, Diekhans, Mark, Fiddes, Ian T, Novak, Adam M, Deran, Alden, Fang, Qi, Xie, Duo, Feng, Shaohong, Stiller, Josefin, Genereux, Diane, Johnson, Jeremy, Marinescu, Voichita Dana, Alföldi, Jessica, Harris, Robert S, Lindblad-Toh, Kerstin, Haussler, David, Karlsson, Elinor, Jarvis, Erich D, Zhang, Guojie, and Paten, Benedict
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Biotechnology, Amnion, Animals, Computer Simulation, Genome, Genomics, Haplotypes, Humans, Quality Control, Sequence Alignment, Software, Vertebrates, General Science & Technology
Abstract: New genome assemblies have been arriving at a rapidly increasing pace, thanks to decreases in sequencing costs and improvements in third-generation sequencing technologies1-3. For example, the number of vertebrate genome assemblies currently in the NCBI (National Center for Biotechnology Information) database4 increased by more than 50% to 1,485 assemblies in the year from July 2018 to July 2019. In addition to this influx of assemblies from different species, new human de novo assemblies5 are being produced, which enable the analysis of not only small polymorphisms, but also complex, large-scale structural differences between human individuals and haplotypes. This coming era and its unprecedented amount of data offer the opportunity to uncover many insights into genome evolution but also present challenges in how to adapt current analysis methods to meet the increased scale. Cactus6, a reference-free multiple genome alignment program, has been shown to be highly accurate, but the existing implementation scales poorly with increasing numbers of genomes, and struggles in regions of highly duplicated sequences. Here we describe progressive extensions to Cactus to create Progressive Cactus, which enables the reference-free alignment of tens to thousands of large vertebrate genomes while maintaining high alignment quality. We describe results from an alignment of more than 600 amniote genomes, which is to our knowledge the largest multiple vertebrate genome alignment created so far.
Published: 2020

4. A structural variation reference for medical and population genetics

Author: Collins, Ryan L, Brand, Harrison, Karczewski, Konrad J, Zhao, Xuefang, Alföldi, Jessica, Francioli, Laurent C, Khera, Amit V, Lowther, Chelsea, Gauthier, Laura D, Wang, Harold, Watts, Nicholas A, Solomonson, Matthew, O’Donnell-Luria, Anne, Baumann, Alexander, Munshi, Ruchi, Walker, Mark, Whelan, Christopher W, Huang, Yongqing, Brookings, Ted, Sharpe, Ted, Stone, Matthew R, Valkanas, Elise, Fu, Jack, Tiao, Grace, Laricchia, Kristen M, Ruano-Rubio, Valentin, Stevens, Christine, Gupta, Namrata, Cusick, Caroline, Margolin, Lauren, Taylor, Kent D, Lin, Henry J, Rich, Stephen S, Post, Wendy S, Chen, Yii-Der Ida, Rotter, Jerome I, Nusbaum, Chad, Philippakis, Anthony, Lander, Eric, Gabriel, Stacey, Neale, Benjamin M, Kathiresan, Sekar, Daly, Mark J, Banks, Eric, MacArthur, Daniel G, and Talkowski, Michael E
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Human Genome, Generic health relevance, Disease, Female, Genetic Testing, Genetic Variation, Genetics, Medical, Genetics, Population, Genome, Human, Genotyping Techniques, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Racial Groups, Reference Standards, Selection, Genetic, Whole Genome Sequencing, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, General Science & Technology
Abstract: Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.
Published: 2020

5. Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals

Author: Casewell, Nicholas R., Petras, Daniel, Card, Daren C., Suranse, Vivek, Mychajliw, Alexis M., Richards, David, Koludarov, Ivan, Albulescu, Laura-Oana, Slagboom, Julien, Hempel, Benjamin-Florian, Ngum, Neville M., Kennerley, Rosalind J., Brocca, Jorge L., Whiteley, Gareth, Harrison, Robert A., Bolton, Fiona M. S., Debono, Jordan, Vonk, Freek J., Alföldi, Jessica, Johnson, Jeremy, Karlsson, Elinor K., Lindblad-Toh, Kerstin, Mellor, Ian R., Süssmuth, Roderich D., Fry, Bryan G., Kuruppu, Sanjaya, Hodgson, Wayne C., Kool, Jeroen, Castoe, Todd A., Barnes, Ian, Sunagar, Kartik, Undheim, Eivind A. B., and Turveyb, Samuel T.
Published: 2019

6. The spotted gar genome illuminates vertebrate evolution and facilitates human-teleost comparisons

Author: Braasch, Ingo, Gehrke, Andrew R, Smith, Jeramiah J, Kawasaki, Kazuhiko, Manousaki, Tereza, Pasquier, Jeremy, Amores, Angel, Desvignes, Thomas, Batzel, Peter, Catchen, Julian, Berlin, Aaron M, Campbell, Michael S, Barrell, Daniel, Martin, Kyle J, Mulley, John F, Ravi, Vydianathan, Lee, Alison P, Nakamura, Tetsuya, Chalopin, Domitille, Fan, Shaohua, Wcisel, Dustin, Cañestro, Cristian, Sydes, Jason, Beaudry, Felix EG, Sun, Yi, Hertel, Jana, Beam, Michael J, Fasold, Mario, Ishiyama, Mikio, Johnson, Jeremy, Kehr, Steffi, Lara, Marcia, Letaw, John H, Litman, Gary W, Litman, Ronda T, Mikami, Masato, Ota, Tatsuya, Saha, Nil Ratan, Williams, Louise, Stadler, Peter F, Wang, Han, Taylor, John S, Fontenot, Quenton, Ferrara, Allyse, Searle, Stephen MJ, Aken, Bronwen, Yandell, Mark, Schneider, Igor, Yoder, Jeffrey A, Volff, Jean-Nicolas, Meyer, Axel, Amemiya, Chris T, Venkatesh, Byrappa, Holland, Peter WH, Guiguen, Yann, Bobe, Julien, Shubin, Neil H, Di Palma, Federica, Alföldi, Jessica, Lindblad-Toh, Kerstin, and Postlethwait, John H
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Animals, Evolution, Molecular, Female, Fishes, Genome, Humans, Karyotype, Models, Genetic, Organ Specificity, Sequence Analysis, DNA, Transcriptome, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: To connect human biology to fish biomedical models, we sequenced the genome of spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before teleost genome duplication (TGD). The slowly evolving gar genome has conserved in content and size many entire chromosomes from bony vertebrate ancestors. Gar bridges teleosts to tetrapods by illuminating the evolution of immunity, mineralization and development (mediated, for example, by Hox, ParaHox and microRNA genes). Numerous conserved noncoding elements (CNEs; often cis regulatory) undetectable in direct human-teleost comparisons become apparent using gar: functional studies uncovered conserved roles for such cryptic CNEs, facilitating annotation of sequences identified in human genome-wide association studies. Transcriptomic analyses showed that the sums of expression domains and expression levels for duplicated teleost genes often approximate the patterns and levels of expression for gar genes, consistent with subfunctionalization. The gar genome provides a resource for understanding evolution after genome duplication, the origin of vertebrate genomes and the function of human regulatory sequences.
Published: 2016

7. The mutational constraint spectrum quantified from variation in 141,456 humans

Author: Karczewski, Konrad J., Francioli, Laurent C., Tiao, Grace, Cummings, Beryl B., Alföldi, Jessica, Wang, Qingbo, and Collins, Ryan L.
Subjects: Gene mutations -- Control -- Analysis, Gene silencing -- Analysis, Genetic variation -- Analysis, Human genome -- Identification and classification -- Analysis, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes.sup.1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases. A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes., Author(s): Konrad J. Karczewski [sup.1] [sup.2] , Laurent C. Francioli [sup.1] [sup.2] , Grace Tiao [sup.1] [sup.2] , Beryl B. Cummings [sup.1] [sup.2] [sup.3] , Jessica Alföldi [sup.1] [sup.2] , [...]
Published: 2020
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8. Evaluating drug targets through human loss-of-function genetic variation

Author: Minikel, Eric Vallabh, Karczewski, Konrad J., Martin, Hilary C., Cummings, Beryl B., Whiffin, Nicola, Rhodes, Daniel, and Alföldi, Jessica
Subjects: Gene silencing -- Analysis -- Genetic aspects, Drug targeting -- Analysis -- Genetic aspects, Genetic variation -- Analysis -- Genetic aspects, Genetic engineering -- Analysis -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of human gene inactivation that complements knockout studies in cells and model organisms. Here we report three key findings regarding the assessment of candidate drug targets using human loss-of-function variants. First, even essential genes, in which loss-of-function variants are not tolerated, can be highly successful as targets of inhibitory drugs. Second, in most genes, loss-of-function variants are sufficiently rare that genotype-based ascertainment of homozygous or compound heterozygous 'knockout' humans will await sample sizes that are approximately 1,000 times those presently available, unless recruitment focuses on consanguineous individuals. Third, automated variant annotation and filtering are powerful, but manual curation remains crucial for removing artefacts, and is a prerequisite for recall-by-genotype efforts. Our results provide a roadmap for human knockout studies and should guide the interpretation of loss-of-function variants in drug development. Analysis of predicted loss-of-function variants from 125,748 human exomes and 15,708 whole genomes in the Genome Aggregation Database (gnomAD) provides a roadmap for human 'knockout' studies and a guide for future research into disease biology and drug-target selection., Author(s): Eric Vallabh Minikel [sup.1] [sup.2] [sup.3] [sup.4] [sup.5] [sup.6] [sup.7] [sup.8] , Konrad J. Karczewski [sup.1] [sup.4] , Hilary C. Martin [sup.9] , Beryl B. Cummings [sup.1] [sup.4] [sup.5] [...]
Published: 2020
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9. The effect of LRRK2 loss-of-function variants in humans

Author: Whiffin, Nicola, Armean, Irina M., Kleinman, Aaron, Marshall, Jamie L., Minikel, Eric V., Goodrich, Julia K., Quaife, Nicholas M., Cole, Joanne B., Wang, Qingbo, Karczewski, Konrad J., Cummings, Beryl B., Francioli, Laurent, Laricchia, Kristen, Guan, Anna, Alipanahi, Babak, Morrison, Peter, Baptista, Marco A. S., Merchant, Kalpana M., Ware, James S., Havulinna, Aki S., Iliadou, Bozenna, Lee, Jung-Jin, Nadkarni, Girish N., Whiteman, Cole, Daly, Mark, Esko, Tõnu, Hultman, Christina, Loos, Ruth J. F., Milani, Lili, Palotie, Aarno, Pato, Carlos, Pato, Michele, Saleheen, Danish, Sullivan, Patrick F., Alföldi, Jessica, Cannon, Paul, and MacArthur, Daniel G.
Published: 2020
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10. Convergent evolution of the genomes of marine mammals

Author: Foote, Andrew D, Liu, Yue, Thomas, Gregg WC, Vinař, Tomáš, Alföldi, Jessica, Deng, Jixin, Dugan, Shannon, van Elk, Cornelis E, Hunter, Margaret E, Joshi, Vandita, Khan, Ziad, Kovar, Christie, Lee, Sandra L, Lindblad-Toh, Kerstin, Mancia, Annalaura, Nielsen, Rasmus, Qin, Xiang, Qu, Jiaxin, Raney, Brian J, Vijay, Nagarjun, Wolf, Jochen BW, Hahn, Matthew W, Muzny, Donna M, Worley, Kim C, Gilbert, M Thomas P, and Gibbs, Richard A
Subjects: Microbiology, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Human Genome, Adaptation, Physiological, Amino Acid Substitution, Animals, Evolution, Molecular, Genome, Humans, Mammals, Phenotype, Phylogeny, Selection, Genetic, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: Marine mammals from different mammalian orders share several phenotypic traits adapted to the aquatic environment and therefore represent a classic example of convergent evolution. To investigate convergent evolution at the genomic level, we sequenced and performed de novo assembly of the genomes of three species of marine mammals (the killer whale, walrus and manatee) from three mammalian orders that share independently evolved phenotypic adaptations to a marine existence. Our comparative genomic analyses found that convergent amino acid substitutions were widespread throughout the genome and that a subset of these substitutions were in genes evolving under positive selection and putatively associated with a marine phenotype. However, we found higher levels of convergent amino acid substitutions in a control set of terrestrial sister taxa to the marine mammals. Our results suggest that, whereas convergent molecular evolution is relatively common, adaptive molecular convergence linked to phenotypic convergence is comparatively rare.
Published: 2015

11. The genomic substrate for adaptive radiation in African cichlid fish.

Author: Brawand, David, Wagner, Catherine E, Li, Yang I, Malinsky, Milan, Keller, Irene, Fan, Shaohua, Simakov, Oleg, Ng, Alvin Y, Lim, Zhi Wei, Bezault, Etienne, Turner-Maier, Jason, Johnson, Jeremy, Alcazar, Rosa, Noh, Hyun Ji, Russell, Pamela, Aken, Bronwen, Alföldi, Jessica, Amemiya, Chris, Azzouzi, Naoual, Baroiller, Jean-François, Barloy-Hubler, Frederique, Berlin, Aaron, Bloomquist, Ryan, Carleton, Karen L, Conte, Matthew A, D'Cotta, Helena, Eshel, Orly, Gaffney, Leslie, Galibert, Francis, Gante, Hugo F, Gnerre, Sante, Greuter, Lucie, Guyon, Richard, Haddad, Natalie S, Haerty, Wilfried, Harris, Rayna M, Hofmann, Hans A, Hourlier, Thibaut, Hulata, Gideon, Jaffe, David B, Lara, Marcia, Lee, Alison P, MacCallum, Iain, Mwaiko, Salome, Nikaido, Masato, Nishihara, Hidenori, Ozouf-Costaz, Catherine, Penman, David J, Przybylski, Dariusz, Rakotomanga, Michaelle, Renn, Suzy CP, Ribeiro, Filipe J, Ron, Micha, Salzburger, Walter, Sanchez-Pulido, Luis, Santos, M Emilia, Searle, Steve, Sharpe, Ted, Swofford, Ross, Tan, Frederick J, Williams, Louise, Young, Sarah, Yin, Shuangye, Okada, Norihiro, Kocher, Thomas D, Miska, Eric A, Lander, Eric S, Venkatesh, Byrappa, Fernald, Russell D, Meyer, Axel, Ponting, Chris P, Streelman, J Todd, Lindblad-Toh, Kerstin, Seehausen, Ole, and Di Palma, Federica
Subjects: Animals, Cichlids, MicroRNAs, DNA Transposable Elements, Genomics, Evolution, Molecular, Phylogeny, Gene Expression Regulation, Gene Duplication, Polymorphism, Genetic, Genome, Africa, Eastern, Genetic Speciation, Lakes, Africa, Eastern, Evolution, Molecular, Polymorphism, Genetic, General Science & Technology
Abstract: Cichlid fishes are famous for large, diverse and replicated adaptive radiations in the Great Lakes of East Africa. To understand the molecular mechanisms underlying cichlid phenotypic diversity, we sequenced the genomes and transcriptomes of five lineages of African cichlids: the Nile tilapia (Oreochromis niloticus), an ancestral lineage with low diversity; and four members of the East African lineage: Neolamprologus brichardi/pulcher (older radiation, Lake Tanganyika), Metriaclima zebra (recent radiation, Lake Malawi), Pundamilia nyererei (very recent radiation, Lake Victoria), and Astatotilapia burtoni (riverine species around Lake Tanganyika). We found an excess of gene duplications in the East African lineage compared to tilapia and other teleosts, an abundance of non-coding element divergence, accelerated coding sequence evolution, expression divergence associated with transposable element insertions, and regulation by novel microRNAs. In addition, we analysed sequence data from sixty individuals representing six closely related species from Lake Victoria, and show genome-wide diversifying selection on coding and regulatory variants, some of which were recruited from ancient polymorphisms. We conclude that a number of molecular mechanisms shaped East African cichlid genomes, and that amassing of standing variation during periods of relaxed purifying selection may have been important in facilitating subsequent evolutionary diversification.
Published: 2014

12. 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: Broad Institute Sequencing Platform and Whole Genome Assembly Team, Baylor College of Medicine Human Genome Sequencing Center Sequencing Team, Genome Institute at Washington University, Animals, Mammals, Humans, Disease, RNA, Sequence Alignment, Sequence Analysis, DNA, Genomics, Evolution, Molecular, Phylogeny, Genome, Genome, Human, Exons, Health, Selection, Genetic, Molecular Sequence Annotation, Sequence Analysis, DNA, Evolution, Molecular, Human, Selection, Genetic, General Science & Technology
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

13. Supplementary Figures 1-8 from SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma

Author: Sakthikumar, Sharadha, primary, Elvers, Ingegerd, primary, Kim, Jaegil, primary, Arendt, Maja L., primary, Thomas, Rachael, primary, Turner-Maier, Jason, primary, Swofford, Ross, primary, Johnson, Jeremy, primary, Schumacher, Steven E., primary, Alföldi, Jessica, primary, Axelsson, Erik, primary, Couto, C. Guillermo, primary, Kisseberth, William C., primary, Pettersson, Mats E., primary, Getz, Gad, primary, Meadows, Jennifer R.S., primary, Modiano, Jaime F., primary, Breen, Matthew, primary, Kierczak, Marcin, primary, Forsberg-Nilsson, Karin, primary, Marinescu, Voichita D., primary, and Lindblad-Toh, Kerstin, primary
Published: 2023
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14. Additional methods for putative drive genes discovery and oaCGH results from SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma

Author: Sakthikumar, Sharadha, primary, Elvers, Ingegerd, primary, Kim, Jaegil, primary, Arendt, Maja L., primary, Thomas, Rachael, primary, Turner-Maier, Jason, primary, Swofford, Ross, primary, Johnson, Jeremy, primary, Schumacher, Steven E., primary, Alföldi, Jessica, primary, Axelsson, Erik, primary, Couto, C. Guillermo, primary, Kisseberth, William C., primary, Pettersson, Mats E., primary, Getz, Gad, primary, Meadows, Jennifer R.S., primary, Modiano, Jaime F., primary, Breen, Matthew, primary, Kierczak, Marcin, primary, Forsberg-Nilsson, Karin, primary, Marinescu, Voichita D., primary, and Lindblad-Toh, Kerstin, primary
Published: 2023
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15. Supplementary Tables 1-14 from SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma

Author: Sakthikumar, Sharadha, primary, Elvers, Ingegerd, primary, Kim, Jaegil, primary, Arendt, Maja L., primary, Thomas, Rachael, primary, Turner-Maier, Jason, primary, Swofford, Ross, primary, Johnson, Jeremy, primary, Schumacher, Steven E., primary, Alföldi, Jessica, primary, Axelsson, Erik, primary, Couto, C. Guillermo, primary, Kisseberth, William C., primary, Pettersson, Mats E., primary, Getz, Gad, primary, Meadows, Jennifer R.S., primary, Modiano, Jaime F., primary, Breen, Matthew, primary, Kierczak, Marcin, primary, Forsberg-Nilsson, Karin, primary, Marinescu, Voichita D., primary, and Lindblad-Toh, Kerstin, primary
Published: 2023
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16. Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication

Author: Carneiro, Miguel, Rubin, Carl-Johan, Di Palma, Federica, 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, Hervé, 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, and Andersson, Leif
Published: 2014

17. Author Correction: The mutational constraint spectrum quantified from variation in 141,456 humanS

Author: Karczewski, Konrad J., Francioli, Laurent C., Tiao, Grace, Cummings, Beryl B., Alföldi, Jessica, Wang, Qingbo, Collins, Ryan L., Laricchia, Kristen M., Ganna, Andrea, Birnbaum, Daniel P., Gauthier, Laura D., Brand, Harrison, Solomonson, Matthew, Rhodes, Daniel, Singer-Berk, Moriel, England, Eleina M., Seaby, Eleanor G., Kosmicki, Jack A., Walters, Raymond K., Tashman, Katherine, Farjoun, Yossi, Banks, Eric, Poterba, Timothy, Wang, Arcturus, Seed, Cotton, Whiffin, Nicola, Chong, Jessica X., Samocha, Kaitlin E., Pierce-Hoffman, Emma, Zappala, Zachary, O’Donnell-Luria, Anne H., Minikel, Eric Vallabh, Weisburd, Ben, Lek, Monkol, Ware, James S., Vittal, Christopher, Armean, Irina M., Bergelson, Louis, Cibulskis, Kristian, Connolly, Kristen M., Covarrubias, Miguel, Donnelly, Stacey, Ferriera, Steven, Gabriel, Stacey, Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Llanwarne, Christopher, Munshi, Ruchi, Novod, Sam, Petrillo, Nikelle, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Schleicher, Molly, Soto, Jose, Tibbetts, Kathleen, Tolonen, Charlotte, Wade, Gordon, Talkowski, Michael E., Aguilar Salinas, Carlos A., Ahmad, Tariq, Albert, Christine M., Ardissino, Diego, Atzmon, Gil, Barnard, John, Beaugerie, Laurent, Benjamin, Emelia J., Boehnke, Michael, Bonnycastle, Lori L., Bottinger, Erwin P., Bowden, Donald W., Bown, Matthew J., Chambers, John C., Chan, Juliana C., Chasman, Daniel, Cho, Judy, Chung, Mina K., Cohen, Bruce, Correa, Adolfo, Dabelea, Dana, Daly, Mark J., Darbar, Dawood, Duggirala, Ravindranath, Dupuis, Josée, Ellinor, Patrick T., Elosua, Roberto, Erdmann, Jeanette, Esko, Tõnu, Färkkilä, Martti, Florez, Jose, Franke, Andre, Getz, Gad, Glaser, Benjamin, Glatt, Stephen J., Goldstein, David, Gonzalez, Clicerio, Groop, Leif, Haiman, Christopher, Hanis, Craig, Harms, Matthew, Hiltunen, Mikko, Holi, Matti M., Hultman, Christina M., Kallela, Mikko, Kaprio, Jaakko, Kathiresan, Sekar, Kim, Bong Jo, Kim, Young Jin, Kirov, George, Kooner, Jaspal, Koskinen, Seppo, Krumholz, Harlan M., Kugathasan, Subra, Kwak, Soo Heon, Laakso, Markku, Lehtimäki, Terho, Loos, Ruth J.F., Lubitz, Steven A., Ma, Ronald C.W., MacArthur, Daniel G., Marrugat, Jaume, Mattila, Kari M., McCarthy, Mark I., McGovern, Dermot, McPherson, Ruth, Meigs, James B., Melander, Olle, Metspalu, Andres, Neale, Benjamin M., Nilsson, Peter M., O’Donovan, Michael C., Ongur, Dost, Orozco, Lorena, Palotie, Aarno, Park, Kyong Soo, Pato, Carlos, Pulver, Ann E., Rahman, Nazneen, Remes, Anne M., Rioux, John D., Ripatti, Samuli, Roden, Dan M., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Scharf, Jeremiah, Schunkert, Heribert, Shoemaker, Moore B., Sklar, Pamela, Soininen, Hilkka, Sokol, Harry, Spector, Tim, Sullivan, Patrick F., Suvisaari, Jaana, Tai, E. Shyong, Teo, Yik Ying, Tiinamaija, Tuomi, Tsuang, Ming, Turner, Dan, Tusie-Luna, Teresa, Vartiainen, Erkki, Vawter, Marquis P., Watkins, Hugh, Weersma, Rinse K., Wessman, Maija, and Xavier, Ramnik J.
Subjects: Multidisciplinary, Science & Technology, General Science & Technology, Spectrum (functional analysis), Rare variants, Biology, Constraint (information theory), Multidisciplinary Sciences, Variation (linguistics), Genome Aggregation Database Consortium, Science & Technology - Other Topics, Author Correction, Medical genomics, Algorithm
Abstract: In this Article, author Marquis P. Vawter was missing from the Genome Aggregation Database Consortium list. They are associated with the affiliation: ‘Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, CA, USA’, and contributed to the generation of the primary data incorporated into the gnomAD resource. In addition, in the legend to Fig. 1, ‘ten’ should have been ‘seven’ in the sentence: “a, Uniform manifold approximation and projection (UMAP)46,47 plot depicting the ancestral diversity of all individuals in gnomAD, using seven principal components.” The original Article has been corrected online.
Published: 2021

18. The Naked Mole Rat Genome Resource: facilitating analyses of cancer and longevity-related adaptations

Author: Keane, Michael, Craig, Thomas, Alföldi, Jessica, Berlin, Aaron M., Johnson, Jeremy, Seluanov, Andrei, Gorbunova, Vera, Di Palma, Federica, Lindblad-Toh, Kerstin, Church, George M., and de Magalhães, João Pedro
Published: 2014
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19. Author Correction: Evaluating drug targets through human loss-of-function genetic variation

Author: Minikel, Eric Vallabh, Karczewski, Konrad J., Martin, Hilary C., Cummings, Beryl B., Whiffin, Nicola, Rhodes, Daniel, and Alföldi, Jessica
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03177-5, Author(s): Eric Vallabh Minikel [sup.1] [sup.2] [sup.3] [sup.4] [sup.5] [sup.6] [sup.7] [sup.8] , Konrad J. Karczewski [sup.1] [sup.4] , Hilary C. Martin [sup.9] , Beryl B. Cummings [sup.1] [sup.4] [sup.5] [...]
Published: 2021
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20. Author Correction: A structural variation reference for medical and population genetics

Author: Collins, Ryan L., Brand, Harrison, Karczewski, Konrad J., Zhao, Xuefang, Alföldi, Jessica, Francioli, Laurent C., and Khera, Amit V.
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03176-6., Author(s): Ryan L. Collins [sup.1] [sup.2] [sup.3] , Harrison Brand [sup.1] [sup.2] [sup.4] , Konrad J. Karczewski [sup.1] [sup.5] , Xuefang Zhao [sup.1] [sup.2] [sup.4] , Jessica Alföldi [sup.1] [sup.5] [...]
Published: 2021
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21. EVOLUTIONARY GENOMICS: Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication

Author: Carneiro, Miguel, Rubin, Carl-Johan, Di Palma, Federica, 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, Hervé, 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, and Andersson, Leif
Published: 2014
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22. Transcript expression-aware annotation improves rare variant interpretation

Author: Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, 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 H., Poterba, Timothy, Seed, Cotton, Solomonson, Matthew, Alföldi, Jessica, Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, Collins, Ryan L., Connolly, Kristen M., Covarrubias, Miguel, Daly, Mark J., Donnelly, Stacey, Farjoun, Yossi, Ferriera, Steven, Francioli, Laurent, Gabriel, Stacey, Gauthier, Laura D., Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Laricchia, Kristen M., Llanwarne, Christopher, Minikel, Eric V., Munshi, Ruchi, Neale, Benjamin M., Novod, Sam, Petrillo, Nikelle, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Lehtimäki, Terho, Mattila, Kari M., Suvisaari, Jaana, Tampere University, Clinical Medicine, Department of Clinical Chemistry, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Department of Medicine, Clinicum, Gastroenterologian yksikkö, HUS Psychiatry, Department of Psychiatry, HUS Neurocenter, Department of Neurosciences, Neurologian yksikkö, Institute for Molecular Medicine Finland, Department of Public Health, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Biosciences, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, and Biostatistics Helsinki
Subjects: Male, Transcription, Genetic, Autism Spectrum Disorder, Developmental Disabilities, Datasets as Topic, Haploinsufficiency, Human genetic variation, Genome, Exon, 0302 clinical medicine, Loss of Function Mutation, Disease, Poisson Distribution, Exome sequencing, 0303 health sciences, education.field_of_study, Multidisciplinary, Disease genetics, ARRHYTHMIA, 1184 Genetics, developmental biology, physiology, Genome Aggregation Database Production Team, Exons, Female, Medical genomics, GENES, Genotype, General Science & Technology, Population, Computational biology, Biology, 3121 Internal medicine, Article, DNA sequencing, 03 medical and health sciences, Rare Diseases, Intellectual Disability, Exome Sequencing, Humans, RNA, Messenger, Author Correction, Transcriptomics, education, Gene, 030304 developmental biology, MUTATIONS, Alternative splicing, Reproducibility of Results, Molecular Sequence Annotation, Genome Aggregation Database Consortium, 3111 Biomedicine, Transcriptome, 030217 neurology & neurosurgery
Abstract: The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Here, by 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 splicing of mRNA, which allows exons of a gene to be expressed at varying levels across different cell types. Currently, no existing annotation tool systematically incorporates information about exon expression into the interpretation of variants. We develop a transcript-level annotation metric known as the ‘proportion expressed across transcripts’, which quantifies isoform expression for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression (GTEx) project2 and show that it can differentiate 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 and intellectual disability or developmental disorders to show that pLoF variants in weakly expressed regions have similar effect sizes to those of synonymous variants, whereas pLoF variants in highly expressed exons are most strongly enriched among cases. 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 the genetic diagnosis of rare diseases, the analysis of rare variant burden in complex disorders, and the curation and prioritization of variants in recall-by-genotype studies., A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation.
Published: 2020

23. The meadow jumping mouse genome and transcriptome suggest mechanisms of hibernation

Author: Cong, Qian, primary, Brem, Ethan A., additional, Zhang, Jing, additional, Alföldi, Jessica, additional, Johnson, Jeremy, additional, Karlsson, Elinor K., additional, Lindblad-Toh, Kerstin, additional, Malaney, Jason L., additional, and Israelsen, William J., additional
Published: 2020
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24. The African coelacanth genome provides insights into tetrapod evolution

Author: Amemiya, Chris T., Alföldi, Jessica J, Lee, Alison P., Fan, Shaohua S, Philippe, Hervé H, MacCallum, Iain I, Braasch, Ingo I, Manousaki, Tereza T, Schneider, Igor I, Rohner, Nicolas N, Organ, Chris C, Chalopin, Domitille D, Smith, Jeramiah J., Robinson, Mark M, Dorrington, Rosemary A., Gerdol, Marco M, Aken, Bronwen B, Biscotti, Maria Assunta, Barucca, Marco M, Baurain, Denis D, Berlin, Aaron M., Blatch, Gregory L., Buonocore, Francesco F, Burmester, Thorsten T, Campbell, Michael S., Canapa, Adriana A, Cannon, John P., Christoffels, Alan A, De Moro, Gianluca G, Edkins, Adrienne L., Fan, Lin L, Fausto, Anna Maria, Feiner, Nathalie N, Forconi, Mariko M, Gamieldien, Junaid J, Gnerre, Sante S, Gnirke, Andreas A, Goldstone, Jared V., Haerty, Wilfried W, Hahn, Mark E., Hesse, Uljana U, Hoffmann, Steve S, Johnson, Jeremy J, Karchner, Sibel I., Kuraku, Shigehiro S, Lara, Marcia M, Levin, Joshua Z., Litman, Gary W., Mauceli, Evan E, Miyake, Tsutomu T, Mueller, Gail M., Nelson, David R., Nitsche, Anne A, Olmo, Ettore E, Ota, Tatsuya T, Pallavicini, Alberto A, Panji, Sumir S, Picone, Barbara B, Ponting, Chris P., Prohaska, Sonja J., Przybylski, Dariusz D, Saha, Nil Ratan, Ravi, Vydianathan V, Ribeiro, Filipe J., Sauka-Spengler, Tatjana T, Scapigliati, Giuseppe G, Searle, Stephen M. J., Sharpe, Ted T, Simakov, Oleg O, Stadler, Peter F., Stegeman, John J., Sumiyama, Kenta K, Tabbaa, Diana D, Tafer, Hakim H, Turner-Maier, Jason J, van Heusden, Peter P, White, Simon S, Williams, Louise L, Yandell, Mark M, Brinkmann, Henner H, Volff, Jean-Nicolas J, Tabin, Clifford J., Shubin, Neil N, Schartl, Manfred M, Jaffe, David B., Postlethwait, John H., Venkatesh, Byrappa B, Di Palma, Federica F, Lander, Eric S., Meyer, Axel A, and Lindblad-Toh, Kerstin K
Published: 2013
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25. The European Rabbit Genome

Author: Alföldi, Jessica, primary, Palma, Federica Di, additional, and Lindblad-Toh, Kerstin, additional
Published: 2009
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26. The genome of the green anole lizard and a comparative analysis with birds and mammals

Author: Alföldi, Jessica, Di Palma, Federica, Grabherr, Manfred, Williams, Christina, Kong, Lesheng, Mauceli, Evan, Russell, Pamela, Lowe, Craig B., Glor, Richard E., Jaffe, Jacob D., Ray, David A., Boissinot, Stephane, Shedlock, Andrew M., Botka, Christopher, Castoe, Todd A., Colbourne, John K., Fujita, Matthew K., Moreno, Ricardo Godinez, ten Hallers, Boudewijn F., Haussler, David, Heger, Andreas, Heiman, David, Janes, Daniel E., Johnson, Jeremy, de Jong, Pieter J., Koriabine, Maxim Y., Lara, Marcia, Novick, Peter A., Organ, Chris L., Peach, Sally E., Poe, Steven, Pollock, David D., de Queiroz, Kevin, Sanger, Thomas, Searle, Steve, Smith, Jeremy D., Smith, Zachary, Swofford, Ross, Turner-Maier, Jason, Wade, Juli, Young, Sarah, Zadissa, Amonida, Edwards, Scott V., Glenn, Travis C., Schneider, Christopher J., Losos, Jonathan B., Lander, Eric S., Breen, Matthew, Ponting, Chris P., and Lindblad-Toh, Kerstin
Published: 2011
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27. Genome-wide synteny through highly sensitive sequence alignment

Author: Grabherr, Manfred G., Russell, Pamela, Meyer, Miriah, Mauceli, Evan, Alföldi, Jessica, Di Palma, Federica, and Lindblad-Toh, Kerstin
Published: 2010
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28. Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals

Author: Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Whiffin, Nicola, Karczewski, Konrad J., Zhang, Xiaolei, Chothani, Sonia, Smith, Miriam J., Evans, D. Gareth, Roberts, Angharad M., Quaife, Nicholas M., Schafer, Sebastian, Rackham, Owen, Alföldi, Jessica, O’Donnell-Luria, Anne H., Francioli, Laurent C., Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, Collins, Ryan L., Connolly, Kristen M., Covarrubias, Miguel, Cummings, Beryl, Daly, Mark J., Donnelly, Stacey, Farjoun, Yossi, Ferriera, Steven, Gabriel, Stacey, Gauthier, Laura D., Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Laricchia, Kristen M., Llanwarne, Christopher, Minikel, Eric V., Munshi, Ruchi, Neale, Benjamin M., Novod, Sam, Petrillo, Nikelle, Poterba, Timothy, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Samocha, Kaitlin E., Schleicher, Molly, Seed, Cotton, Solomonson, Matthew, Soto, Jose, Lehtimäki, Terho, Mattila, Kari M., Suvisaari, Jaana, Imper, Rosetrees Trust, Wellcome Trust, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Department of Medicine, Clinicum, Gastroenterologian yksikkö, Institute for Molecular Medicine Finland, Biosciences, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Psychiatry, HUS Neurocenter, Department of Neurosciences, Neurologian yksikkö, Department of Public Health, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Doctoral Programme in Social Sciences, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, University Management, Biostatistics Helsinki, Faculty of Medicine, University of Helsinki, Tampere University, Clinical Medicine, Department of Clinical Chemistry, BioMediTech, Fondation Leducq, Department of Health, Leducq Foundation for Cardiovascular Research, British Heart Foundation, and Royal Brompton & Harefield NHS Foundation Trust
Subjects: 0301 basic medicine, Untranslated region, Five prime untranslated region, General Physics and Astronomy, Genome informatics, Negative selection, 0302 clinical medicine, Loss of Function Mutation, Genetics research, Coding region, lcsh:Science, education.field_of_study, Multidisciplinary, 1184 Genetics, developmental biology, physiology, Genome Aggregation Database Production Team, Genomics, Multidisciplinary Sciences, Genome Aggregation Database (gnomAD) Consortium, Science & Technology - Other Topics, 5'-UNTRANSLATED REGIONS, Medical genomics, Genome Aggregation Database (gnomAD) Production Team, OPEN READING FRAMES, Science, Population, WOUDE, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, ORFS, Frameshift mutation, 03 medical and health sciences, Humans, Author Correction, education, Gene, Science & Technology, Base Sequence, Genome, Human, MUTATIONS, Genetic Variation, Proteins, General Chemistry, 030104 developmental biology, INITIATION CODON, Genome Aggregation Database Consortium, Human genome, lcsh:Q, 3111 Biomedicine, TRANSLATION, 5' Untranslated Regions, 030217 neurology & neurosurgery, VAN
Abstract: Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes., Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.
Published: 2019

29. An open resource of structural variation for medical and population genetics

Author: Collins, Ryan L., Brand, Harrison, Karczewski, Konrad J., Zhao, Xuefang, Alföldi, Jessica, Francioli, Laurent C., Khera, Amit V., Lowther, Chelsea, Gauthier, Laura D., Wang, Harold, Watts, Nicholas A., Solomonson, Matthew, O’Donnell-Luria, Anne, Baumann, Alexander, Munshi, Ruchi, Walker, Mark, Whelan, Christopher, Huang, Yongqing, Brookings, Ted, Sharpe, Ted, Stone, Matthew R., Valkanas, Elise, Fu, Jack, Tiao, Grace, Laricchia, Kristen M., Ruano-Rubio, Valentin, Stevens, Christine, Gupta, Namrata, Margolin, Lauren, Taylor, Kent D., Lin, Henry J., Rich, Stephen S., Post, Wendy, Chen, Yii-Der Ida, Rotter, Jerome I., Nusbaum, Chad, Philippakis, Anthony, Lander, Eric, Gabriel, Stacey, Neale, Benjamin M., Kathiresan, Sekar, Daly, Mark J., Banks, Eric, MacArthur, Daniel G., and Talkowski, Michael E.
Subjects: Structural variation, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Resource (biology), business.industry, Environmental resource management, Population genetics, Biology, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: SUMMARYStructural variants (SVs) rearrange large segments of the genome and can have profound consequences for evolution and human diseases. As national biobanks, disease association studies, and clinical genetic testing grow increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral for interpreting genetic variation. To date, no large-scale reference maps of SVs exist from high-coverage sequencing comparable to those available for point mutations in protein-coding genes. Here, we constructed a reference atlas of SVs across 14,891 genomes from diverse global populations (54% non-European) as a component of gnomAD. We discovered a rich landscape of 433,371 distinct SVs, including 5,295 multi-breakpoint complex SVs across 11 mutational subclasses, and examples of localized chromosome shattering, as in chromothripsis. The average individual harbored 7,439 SVs, which accounted for 25-29% of all rare protein-truncating events per genome. We found strong correlations between constraint against damaging point mutations and rare SVs that both disrupt and duplicate protein-coding sequence, suggesting intolerance to reciprocal dosage alterations for a subset of tightly regulated genes. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than any effect on noncoding SVs. Finally, we benchmarked carrier rates for medically relevant SVs, finding very large (≥1Mb) rare SVs in 3.8% of genomes (~1:26 individuals) and clinically reportable incidental SVs in 0.18% of genomes (~1:556 individuals). These data have been integrated directly into the gnomAD browser (https://gnomad.broadinstitute.org) and will have broad utility for population genetics, disease association, and diagnostic screening.
Published: 2019
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30. Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinson’s disease

Author: Whiffin, Nicola, Armean, Irina M., Kleinman, Aaron, Marshall, Jamie L., Minikel, Eric V., Karczewski, Konrad J., Cummings, Beryl B., Francioli, Laurent, Laricchia, Kristen, Wang, Qingbo, Guan, Anna, Alipanahi, Babak, Morrison, Peter, Baptista, Marco A.S., Merchant, Kalpana M., Ware, James S., Havulinna, Aki S., Iliadou, Bozenna, Lee, Jung-Jin, Nadkarni, Girish N., Whiteman, Cole, Daly, Mark, Esko, Tõnu, Hultman, Christina, Loos, Ruth J.F., Milani, Lili, Palotie, Aarno, Pato, Carlos, Pato, Michele, Saleheen, Danish, Sullivan, Patrick F., Alföldi, Jessica, Cannon, Paul, and MacArthur, Daniel G.
Subjects: Oncology, 0303 health sciences, medicine.medical_specialty, Parkinson's disease, business.industry, medicine.disease, LRRK2, language.human_language, 3. Good health, nervous system diseases, Danish, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, language, business, 030217 neurology & neurosurgery, Loss function, 030304 developmental biology, Therapeutic strategy
Abstract: Human genetic variants causing loss-of-function (LoF) of protein-coding genes provide natural in vivo models of gene inactivation, which are powerful indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. Whilst preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here we systematically analyse LoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9 and over 4 million participants in the 23andMe genotyped dataset, to assess their impact at a molecular and phenotypic level. After thorough variant curation, we identify 1,358 individuals with high-confidence predicted LoF variants in LRRK2, several with experimental validation. We show that heterozygous LoF of LRRK2 reduces LRRK2 protein level by ~50% but is not associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that downregulate LRRK2 levels or kinase activity by up to 50% are unlikely to have major on-target safety liabilities. Our results demonstrate the value of large scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.
Published: 2019
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31. 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

32. Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 15,708 individuals

Author: Whiffin, Nicola, Karczewski, Konrad J, Zhang, Xiaolei, Chothani, Sonia, Smith, Miriam J, Evans, D Gareth, Roberts, Angharad M, Quaife, Nicholas M, Schafer, Sebastian, Rackham, Owen, Alföldi, Jessica, O’Donnell-Luria, Anne H, Francioli, Laurent C, Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, Collins, Ryan L, Connolly, Kristen M., Covarrubias, Miguel, Cummings, Beryl, Daly, Mark J., Donnelly, Stacey, Farjoun, Yossi, Ferriera, Steven, Francioli, Laurent, Gabriel, Stacey, Gauthier, Laura D., Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Karczewski, Konrad J., Laricchia, Kristen M., Llanwarne, Christopher, Minikel, Eric V., Munshi, Ruchi, Neale, Benjamin M, Novod, Sam, O’Donnell-Luria, Anne H., Petrillo, Nikelle, Poterba, Timothy, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Samocha, Kaitlin E., Schleicher, Molly, Seed, Cotton, Solomonson, Matthew, Soto, Jose, Tiao, Grace, Tibbetts, Kathleen, Tolonen, Charlotte, Vittal, Christopher, Wade, Gordon, Wang, Arcturus, Wang, Qingbo, Ware, James S, Watts, Nicholas A, Weisburd, Ben, Salinas, Carlos A Aguilar, Ahmad, Tariq, Albert, Christine M., Ardissino, Diego, Atzmon, Gil, Barnard, John, Beaugerie, Laurent, Benjamin, Emelia J., Boehnke, Michael, Bonnycastle, Lori L., Bottinger, Erwin P., Bowden, Donald W, Bown, Matthew J, Chambers, John C, Chan, Juliana C., Chasman, Daniel, Cho, Judy, Chung, Mina K., Cohen, Bruce, Correa, Adolfo, Dabelea, Dana, Darbar, Dawood, Duggirala, Ravindranath, Dupuis, Josée, Ellinor, Patrick T., Elosua, Roberto, Erdmann, Jeanette, Esko, Tõnu, Färkkilä, Martti, Florez, Jose, Franke, Andre, Getz, Gad, Glaser, Benjamin, Glatt, Stephen J., Goldstein, David, Gonzalez, Clicerio, Groop, Leif, Haiman, Christopher, Hanis, Craig, Harms, Matthew, Hiltunen, Mikko, Holi, Matti M., Hultman, Christina M., Kallela, Mikko, Kaprio, Jaakko, Kathiresan, Sekar, Kim, Bong-Jo, Kim, Young Jin, Kirov, George, Kooner, Jaspal, Koskinen, Seppo, Krumholz, Harlan M., Kugathasan, Subra, Kwak, Soo Heon, Laakso, Markku, Lehtimäki, Terho, Loos, Ruth J.F., Lubitz, Steven A., Ma, Ronald C.W., MacArthur, Daniel G., Marrugat, Jaume, Mattila, Kari M., McCarroll, Steven, McCarthy, Mark I, McGovern, Dermot, McPherson, Ruth, Meigs, James B., Melander, Olle, Metspalu, Andres, Nilsson, Peter M, O’Donovan, Michael C, Ongur, Dost, Orozco, Lorena, Owen, Michael J, Palmer, Colin N.A., Palotie, Aarno, Park, Kyong Soo, Pato, Carlos, Pulver, Ann E., Rahman, Nazneen, Remes, Anne M., Rioux, John D., Ripatti, Samuli, Roden, Dan M., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Scharf, Jeremiah, Schunkert, Heribert, Shoemaker, Moore B., Sklar, Pamela, Soininen, Hilkka, Soko, Harry, Spector, Tim, Sullivan, Patrick F., Suvisaari, Jaana, Tai, E Shyong, Teo, Yik Ying, Tiinamaija, Tuomi, Tsuang, Ming, Turner, Dan, Tusie-Luna, Teresa, Vartiainen, Erkki, Watkins, Hugh, Weersma, Rinse K, Wessman, Maija, Wilson, James G., Xavier, Ramnik J., Cook, Stuart A, Barton, Paul J R, and MacArthur, Daniel G
Subjects: 0303 health sciences, education.field_of_study, Five prime untranslated region, Population, Computational biology, Biology, Genome, DNA sequencing, Frameshift mutation, 03 medical and health sciences, Negative selection, 0302 clinical medicine, Coding region, education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Upstream open reading frames (uORFs) are important tissue-specific cis-regulators of protein translation. Although isolated case reports have shown that variants that create or disrupt uORFs can cause disease, genetic sequencing approaches typically focus on protein-coding regions and ignore these variants. Here, we describe a systematic genome-wide study of variants that create and disrupt human uORFs, and explore their role in human disease using 15,708 whole genome sequences collected by the Genome Aggregation Database (gnomAD) project. We show that 14,897 variants that create new start codons upstream of the canonical coding sequence (CDS), and 2,406 variants disrupting the stop site of existing uORFs, are under strong negative selection. Furthermore, variants creating uORFs that overlap the CDS show signals of selection equivalent to coding loss-of-function variants, and uORF-perturbing variants are under strong selection when arising upstream of known disease genes and genes intolerant to loss-of-function variants. Finally, we identify specific genes where perturbation of uORFs is likely to represent an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in families with neurofibromatosis. Our results highlight uORF-perturbing variants as an important and under-recognised functional class that can contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data to study the deleteriousness of specific classes of non-coding variants.
Published: 2019
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33. Evaluating potential drug targets through human loss-of-function genetic variation

Author: Minikel, Eric Vallabh, Karczewski, Konrad J, Martin, Hilary C, Cummings, Beryl B, Whiffin, Nicola, Alföldi, Jessica, Trembath, Richard C, van Heel, David A, Daly, Mark J, Schreiber, Stuart L, and MacArthur, Daniel G
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Human genetics has informed the clinical development of new drugs, and is beginning to influence the selection of new drug targets. Large-scale DNA sequencing studies have created a catalogue of naturally occurring genetic variants predicted to cause loss of function in human genes, which in principle should provide powerfulin vivomodels of human genetic “knockouts” to complement model organism knockout studies and inform drug development. Here, we consider the use of predicted loss-of-function (pLoF) variation catalogued in the Genome Aggregation Database (gnomAD) for the evaluation of genes as potential drug targets. Many drug targets, including the targets of highly successful inhibitors such as aspirin and statins, are under natural selection at least as extreme as known haploinsufficient genes, with pLoF variants almost completely depleted from the population. Thus, metrics of gene essentiality should not be used to eliminate genes from consideration as potential targets. The identification of individual humans harboring “knockouts” (biallelic gene inactivation), followed by individual recall and deep phenotyping, is highly valuable to study gene function. In most genes, pLoF alleles are sufficiently rare that ascertainment will be largely limited to heterozygous individuals in outbred populations. Sampling of diverse bottlenecked populations and consanguineous individuals will aid in identification of total “knockouts”. Careful filtering and curation of pLoF variants in a gene of interest is necessary in order to identify true LoF individuals for follow-up, and the positional distribution or frequency of true LoF variants may reveal important disease biology. Our analysis suggests that the value of pLoF variant data for drug discovery lies in deep curation informed by the nature of the drug and its indication, as well as the biology of the gene, followed by recall-by-genotype studies in targeted populations.
Published: 2019
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34. Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes

Author: Karczewski, Konrad J., Francioli, Laurent C., Tiao, Grace, Cummings, Beryl B., Alföldi, Jessica, Wang, Qingbo, Collins, Ryan L., Laricchia, Kristen M., Ganna, Andrea, Birnbaum, Daniel P., Gauthier, Laura D., Brand, Harrison, Solomonson, Matthew, Watts, Nicholas A., Rhodes, Daniel, Singer-Berk, Moriel, Seaby, Eleanor G., Kosmicki, Jack A., Walters, Raymond K., Tashman, Katherine, Farjoun, Yossi, Banks, Eric, Poterba, Timothy, Wang, Arcturus, Seed, Cotton, Whiffin, Nicola, Chong, Jessica X., Samocha, Kaitlin E., Pierce-Hoffman, Emma, Zappala, Zachary, O’Donnell-Luria, Anne H., Minikel, Eric Vallabh, Weisburd, Ben, Lek, Monkol, Ware, James S., Vittal, Christopher, Armean, Irina M., Bergelson, Louis, Cibulskis, Kristian, Connolly, Kristen M., Covarrubias, Miguel, Donnelly, Stacey, Ferriera, Steven, Gabriel, Stacey, Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Llanwarne, Christopher, Munshi, Ruchi, Novod, Sam, Petrillo, Nikelle, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Schleicher, Molly, Soto, Jose, Tibbetts, Kathleen, Tolonen, Charlotte, Wade, Gordon, Talkowski, Michael E., Neale, Benjamin M., Daly, Mark J., and MacArthur, Daniel G.
Abstract: Summary Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes critical for an organism’s function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here, we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence pLoF variants in this cohort after filtering for sequencing and annotation artifacts. Using an improved model of human mutation, we classify human protein-coding genes along a spectrum representing intolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve gene discovery power for both common and rare diseases.
Published: 2019
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35. Genome reannotation of the lizard Anolis carolinensis based on 14 adult and embryonic deep transcriptomes

Author: Eckalbar Walter L, Hutchins Elizabeth D, Markov Glenn J, Allen April N, Corneveaux Jason J, Lindblad-Toh Kerstin, Di Palma Federica, Alföldi Jessica, Huentelman Matthew J, and Kusumi Kenro
Subjects: Annotation, Lizard, Anolis carolinensis, Transcriptome, Genome, RNA-Seq, Gene, Vertebrate, Embryo, Tissue-specific, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract: Abstract Background The green anole lizard, Anolis carolinensis, is a key species for both laboratory and field-based studies of evolutionary genetics, development, neurobiology, physiology, behavior, and ecology. As the first non-avian reptilian genome sequenced, A. carolinesis is also a prime reptilian model for comparison with other vertebrate genomes. The public databases of Ensembl and NCBI have provided a first generation gene annotation of the anole genome that relies primarily on sequence conservation with related species. A second generation annotation based on tissue-specific transcriptomes would provide a valuable resource for molecular studies. Results Here we provide an annotation of the A. carolinensis genome based on de novo assembly of deep transcriptomes of 14 adult and embryonic tissues. This revised annotation describes 59,373 transcripts, compared to 16,533 and 18,939 currently for Ensembl and NCBI, and 22,962 predicted protein-coding genes. A key improvement in this revised annotation is coverage of untranslated region (UTR) sequences, with 79% and 59% of transcripts containing 5’ and 3’ UTRs, respectively. Gaps in genome sequence from the current A. carolinensis build (Anocar2.0) are highlighted by our identification of 16,542 unmapped transcripts, representing 6,695 orthologues, with less than 70% genomic coverage. Conclusions Incorporation of tissue-specific transcriptome sequence into the A. carolinensis genome annotation has markedly improved its utility for comparative and functional studies. Increased UTR coverage allows for more accurate predicted protein sequence and regulatory analysis. This revised annotation also provides an atlas of gene expression specific to adult and embryonic tissues.
Published: 2013
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36. Progressive alignment with Cactus: a multiple-genome aligner for the thousand-genome era

Author: Armstrong, Joel, primary, Hickey, Glenn, additional, Diekhans, Mark, additional, Deran, Alden, additional, Fang, Qi, additional, Xie, Duo, additional, Feng, Shaohong, additional, Stiller, Josefin, additional, Genereux, Diane, additional, Johnson, Jeremy, additional, Marinescu, Voichita Dana, additional, Haussler, David, additional, Alföldi, Jessica, additional, Lindblad-Toh, Kerstin, additional, Karlsson, Elinor, additional, Jarvis, Erich D., additional, Zhang, Guojie, additional, and Paten, Benedict, additional
Published: 2019
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37. FEELnc: a tool for long non-coding RNA annotation and its application to the dog transcriptome

Author: Wucher, Valentin, Legeai, Fabrice, Hédan, Benoît, Rizk, Guillaume, Lagoutte, Lætitia, Leeb, Tosso, Jagannathan, Vidhya, Cadieu, Edouard, David, Audrey, Lohi, Hannes, Cirera, Susanna, Fredholm, Merete, Botherel, Nadine, Leegwater, Peter A J, Le Béguec, Céline, Fieten, Hille, Johnson, Jeremy, Alföldi, Jessica, André, Catherine, Lindblad-Toh, Kerstin, Hitte, Christophe, Derrien, Thomas, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Scalable, Optimized and Parallel Algorithms for Genomics (GenScale), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut de Génétique, Environnement et Protection des Plantes (IGEPP), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-AGROCAMPUS OUEST, Institute of Genetics, University of Bern, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Folkhälsan Institute of Genetics, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), IT University of Copenhagen (ITU), Universiteit Utrecht, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Science for Life Laboratory, Uppsala University-Department of Medical Biochemistry and Microbiology, 7th PCRD 'Health programs' LUPA consortium [FP7] [GA: 201370], French National Research Agency [ANR-11-INBS-0003], European Young Investigator Award from European Science Foundation, European Research Council, ANR-11-INBS-0003,CRB-Anim,Réseau de Centres de Ressources Biologiques pour les animaux domestiques(2011), European Project: 201370,EC:FP7:HEALTH,FP7-HEALTH-2007-A,LUPA(2008), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), University of Helsinki, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), IT University of Copenhagen, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), ANR-11-INBS-0003/11-INBS-0003,CRB-Anim,Réseau de Centres de Ressources Biologiques pour les animaux domestiques(2011), Research Programs Unit, Hannes Tapani Lohi / Principal Investigator, Veterinary Biosciences, Veterinary Genetics, and Research Programme for Molecular Neurology
Subjects: COMPARATIVE GENOMICS, PREDICTION, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy), 610 Medicine & health, arn non codant, Mice, Open Reading Frames, Dogs, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, RECONSTRUCTION, RNA, Messenger, analyse du transcriptome, Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci), Genome, IDENTIFICATION, Sequence Analysis, RNA, HUMAN-CELLS, génome, Decision Trees, Molecular Sequence Annotation, QUANTIFICATION, GENE, CANCER, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], EVOLUTION, Benchmarking, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, DIFFERENTIATION, Gene Expression Regulation, 1182 Biochemistry, cell and molecular biology, Methods Online, 570 Life sciences, biology, 590 Animals (Zoology), RNA, Long Noncoding, Transcriptome, Software
Abstract: International audience; Whole transcriptome sequencing (RNA-seq) has become a standard for cataloguing and monitoring RNA populations. One of the main bottlenecks, however, is to correctly identify the different classes of RNAs among the plethora of reconstructed transcripts, particularly those that will be translated (mRNAs) from the class of long non-coding RNAs (lncRNAs). Here, we present FEELnc (FlExible Extraction of LncRNAs), an alignment-free program that accurately annotates lncRNAs based on a Random Forest model trained with general features such as multi k-mer frequencies and relaxed open reading frames. Benchmarking versus five state-of-the-art tools shows that FEELnc achieves similar or better classification performance on GENCODE and NONCODE data sets. The program also provides specific modules that enable the user to fine-tune classification accuracy, to formalize the annotation of lncRNA classes and to identify lncRNAs even in the absence of a training set of non-coding RNAs. We used FEELnc on a real data set comprising 20 canine RNA-seq samples produced by the European LUPA consortium to substantially expand the canine genome annotation to include 10 374 novel lncRNAs and 58 640 mRNA transcripts. FEELnc moves beyond conventional coding potential classifiers by providing a standardized and complete solution for annotating lncRNAs and is freely available at https://github.com/tderrien/FEELnc.
Published: 2017

38. Transcript expression-aware annotation improves rare variant 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 H., Poterba, Timothy, Seed, Cotton, Solomonson, Matthew, Alföldi, Jessica, Genome Aggregation Database Production Team, Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, and Collins, Ryan L.
Abstract: The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Here, by 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 splicing of mRNA, which allows exons of a gene to be expressed at varying levels across different cell types. Currently, no existing annotation tool systematically incorporates information about exon expression into the interpretation of variants. We develop a transcript-level annotation metric known as the 'proportion expressed across transcripts', which quantifies isoform expression for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression (GTEx) project2 and show that it can differentiate 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 and intellectual disability or developmental disorders to show that pLoF variants in weakly expressed regions have similar effect sizes to those of synonymous variants, whereas pLoF variants in highly expressed exons are most strongly enriched among cases. 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 the genetic diagnosis of rare diseases, the analysis of rare variant burden in complex disorders, and the curation and prioritization of variants in recall-by-genotype studies. A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation. [ABSTRACT FROM AUTHOR]
Published: 2020
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39. Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes.

Author: Wang, Qingbo, Pierce-Hoffman, Emma, Cummings, Beryl B., Alföldi, Jessica, Francioli, Laurent C., Gauthier, Laura D., Hill, Andrew J., O'Donnell-Luria, Anne H., Genome Aggregation Database Production Team, Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, Collins, Ryan L., Connolly, Kristen M., Covarrubias, Miguel, Daly, Mark J., Donnelly, Stacey, Farjoun, Yossi, and Ferriera, Steven
Subjects: AMINO acid sequence, GENOMES, DEAMINATION, EXOMES
Abstract: Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs. Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate. [ABSTRACT FROM AUTHOR]
Published: 2020
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40. Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals.

Author: Whiffin, Nicola, Karczewski, Konrad J., Zhang, Xiaolei, Chothani, Sonia, Smith, Miriam J., Evans, D. Gareth, Roberts, Angharad M., Quaife, Nicholas M., Schafer, Sebastian, Rackham, Owen, Alföldi, Jessica, O'Donnell-Luria, Anne H., Francioli, Laurent C., Genome Aggregation Database Production Team, Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, Collins, Ryan L., and Connolly, Kristen M.
Subjects: GENETIC translation, NUCLEOTIDE sequencing, GENETIC code, GENOMES, EXOMES
Abstract: Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes. Upstream open reading frames (uORFs), located in 5' untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs. [ABSTRACT FROM AUTHOR]
Published: 2020
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41. SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma

Author: Sakthikumar, Sharadha, primary, Elvers, Ingegerd, additional, Kim, Jaegil, additional, Arendt, Maja L., additional, Thomas, Rachael, additional, Turner-Maier, Jason, additional, Swofford, Ross, additional, Johnson, Jeremy, additional, Schumacher, Steven E., additional, Alföldi, Jessica, additional, Axelsson, Erik, additional, Couto, C. Guillermo, additional, Kisseberth, William C., additional, Pettersson, Mats E., additional, Getz, Gad, additional, Meadows, Jennifer R.S., additional, Modiano, Jaime F., additional, Breen, Matthew, additional, Kierczak, Marcin, additional, Forsberg-Nilsson, Karin, additional, Marinescu, Voichita D., additional, and Lindblad-Toh, Kerstin, additional
Published: 2018
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42. Corrigendum: The spotted gar genome illuminates vertebrate evolution and facilitates human-teleost comparisons

Author: Braasch, Ingo, Gehrke, Andrew R., Smith, Jeramiah J., Kawasaki, Kazuhiko, Manousaki, Tereza, Pasquier, Jérémy, Amores, Angel, Desvignes, Thomas, Batzel, Peter, Catchen, Julian, Berlin, Aaron M., Campbell, Michael S., Barrell, Daniel, Martin, Kyle J., Mulley, John F., Ravi, Vydianathan, Lee, Alison P., Nakamura, Tetsuya, Chalopin, Domitille, Fan, Shaohua, Wcisel, Dustin, Cañestro, Cristian, Sydes, Jason, Beaudry, Felix E.G., Sun, Yi, Hertel, Jana, Beam, Michael J., Fasold, Mario, Ishiyama, Mikio, Johnson, Jeremy, Kehr, Steffi, Lara, Marcia, Letaw, John H., Litman, Gary W., Litman, Ronda T., Mikami, Masato, Ota, Tatsuya, Saha, Nil Ratan, Williams, Louise, Stadler, Peter F., Wang, Han, Taylor, John S., Fontenot, Quenton, Ferrara, Allyse, Searle, Stephen M.J., Aken, Bronwen, Yandell, Mark, Schneider, Igor, Yoder, Jeffrey A, Volff, Jean-Nicolas, Meyer, Axel, Amemiya, Chris T, Venkatesh, Byrappa, Holland, Peter W.H., Guiguen, Yann, Bobe, Julien, Shubin, Neil H., Di Palma, Federica, Alföldi, Jessica, Lindblad-Toh, Kerstin, Postlethwait, John H., Institute of Neuroscience, National Research Council [Italy] (CNR), Department of Integrative Biology [Berkeley] (IB), University of California [Berkeley], University of California-University of California, Department of Organismal Biology and Anatomy, University of Chicago, Department of Biology, Northern Arizona University [Flagstaff], Department of Anthropology, University of California, Pennsylvania State University (Penn State), Penn State System, Hellenic Centre for Marine Research, Hellenic Center for Marine Research (HCMR), Laboratoire de Physiologie et Génomique des Poissons (LPGP), Institut National de la Recherche Agronomique (INRA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Department of Animal Biology, University of Pennsylvania [Philadelphia], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Eccles Institute of Human Genetics, University of Utah, Cold Spring Harbor, Cold Spring Harbor Laboratory, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Department of Zoology, Auburn University (AU), Department of Animal and Plant Sciences [Sheffield], University of Sheffield [Sheffield], School of Biological Sciences [Bangor], Bangor University, Comparative Genomics Laboratory, Agency for Science, Technology and Research (A*STAR), International Institute of Molecular and Cell Biology, Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS 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), Department of Genetics, The University of Texas M.D. Anderson Cancer Center [Houston], Department of Molecular Biomedical Sciences Raleigh, North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), Center for Comparative Medicine and Translational Research Raleigh, Departament de Genètica, Universitat Autònoma de Barcelona [Barcelona] (UAB), Institut de Recerca de la Biodiversitat, University of Barcelona, University of Victoria, Center for Circadian Clocks, Soochow University, School of Biology and Basic Medical Sciences, Medical College, Bioinformatics Group, Department of Computer Science, Universität Leipzig [Leipzig], Young Investigators Group Bioinformatics and Transcriptomics, Department of Proteomics, Helmholtz Centre for Environmental Research (UFZ), Department of Dental Hygiene, Nippon Dental University, Morsani College of Medicine, Department of Pediatrics, University of South Florida (USF), Department of Microbiology, Department of Evolutionary Studies of Biosystems, SOKENDAI, Graduate University for Advanced Studies, Molecular Genetics Program, Benaroya Research Institute, Department of Biological Sciences, The Open University [Milton Keynes] (OU), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, European Bioinformatics Institute, Instituto de Ciências Biológicas, Federal University of Para - Universidade Federal do Para [Belem - Brésil], Department of Molecular Biomedical Sciences, University of North Carolina System (UNC)-University of North Carolina System (UNC)-College of Veterinary Medicine Raleigh, Center for Comparative Medicine and Translational Research, International Max Planck Research School for Organismal Biology (IMPRS), University of Konstanz, Genome Analysis Center, Vertebrate and Health Genomics, Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Recherche Agronomique (INRA), Hellenic Centre for Marine Research (HCMR), 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), Universitat Autònoma de Barcelona (UAB), University of Victoria [Canada] (UVIC), Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), University of South Florida [Tampa] (USF), University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), University of California (UC), University of Pennsylvania, École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Universität Leipzig, and Federal University of Para - Universidade Federal do Pará - UFPA [Belém, Brazil] (UFPA)
Subjects: [SDV]Life Sciences [q-bio], analyse phylogénétique, reproduction, poisson, analyse génomique, human, chromosome, analyse du transcriptome, genome, duplication des génomes, miRNA, fish, teleost, physiologie animale, séquence régulatrice, vertébré, homme, lepisosteus oculatus, interaction animal homme, lépisosté tacheté, évolution du génome, fonction des gènes, teleosteen, regulatory sequence, vertebrates, immunité, expression des gènes
Abstract: The spotted gar genome illuminates vertebrate evolution and facilitates human-teleost comparisons (vol 48, pg 427, 2016); As we intended, other researchers have been able to use the draft spotted gar genome sequence available from the Broad Institute website since December 2011, the assembly LepOcu1 publicly available from NCBI since 13 January 2012 under accession code GCA000242695.1, and the Ensembl gene annotation (version 74, December 2013; http://www.ensembl.org/Lepisosteus_oculatus/Info/Annotation) and recent annotation by NCBI on 15 May 2014 guided by RNA sequence data from ten tissues. While this article was in review, a paper (Nature 526, 108–111, 2015) was published that arrives at conclusions similar to some of our own analyses, and we wish to acknowledge that publication, which used our unpublished data and genome annotations, emphasizing the importance of the strategy of early release of sequence data. The correction has been made to the HTML and PDF versions of the article.
Published: 2016

43. An Improved microRNA Annotation of the Canine Genome

Author: Penso-Dolfin, Luca, primary, Swofford, Ross, additional, Johnson, Jeremy, additional, Alföldi, Jessica, additional, Lindblad-Toh, Kerstin, additional, Swarbreck, David, additional, Moxon, Simon, additional, and Di Palma, Federica, additional
Published: 2016
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44. The genome of the green anole lizard and a comparative analysis with birds and mammals

Author: Grabherr, Manfred, Fujita, Matthew K., Russell, Pamela, Jaffe, Jacob D., Mauceli, Evan, Pollock, David D., Novick, Peter A., Lowe, Craig B., Koriabine, Maxim Y., Haussler, David, ten Hallers, Boudewijn F., Shedlock, Andrew M., Peach, Sally E., Moreno, Ricardo Godinez, Colbourne, John K., Glor, Richard E., Boissinot, Stephane, Poe, Steven, Kong, Lesheng, Lara, Marcia, Janes, Daniel E., Di Palma, Federica, Castoe, Todd A., Williams, Christina, Heiman, David, Ray, David A., Alföldi, Jessica, Botka, Christopher, Johnson, Jeremy, Heger, Andreas, de Jong, Pieter J., and Organ, Chris L.
Abstract: The evolution of the amniotic egg was one of the great evolutionary innovations in the history of life, freeing vertebrates from an obligatory connection to water and thus permitting the conquest of terrestrial environments1. Among amniotes, genome sequences are available for mammals2 and birds3–5, but not for non-avian reptiles. Here we report the genome sequence of the North American green anole lizard, Anolis carolinensis. We find that A. carolinensis microchromosomes are highly syntenic with chicken microchromosomes, yet do not exhibit the high GC and low repeat content that are characteristic of avian microchromosomes3. Also, A. carolinensis mobile elements are very young and diverse – more so than in any other sequenced amniote genome. This lizard genome’s GC content is also unusual in its homogeneity, unlike the regionally variable GC content found in mammals and birds6. We describe and assign sequence to the previously unknown A. carolinensis X chromosome. Comparative gene analysis shows that amniote egg proteins have evolved significantly more rapidly than other proteins. An anole phylogeny resolves basal branches to illuminate the history of their repeated adaptive radiations.
Published: 2011
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45. Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

Author: Elvers, Ingegerd, primary, Turner-Maier, Jason, additional, Swofford, Ross, additional, Koltookian, Michele, additional, Johnson, Jeremy, additional, Stewart, Chip, additional, Zhang, Cheng-Zhong, additional, Schumacher, Steven E., additional, Beroukhim, Rameen, additional, Rosenberg, Mara, additional, Thomas, Rachael, additional, Mauceli, Evan, additional, Getz, Gad, additional, Palma, Federica Di, additional, Modiano, Jaime F., additional, Breen, Matthew, additional, Lindblad-Toh, Kerstin, additional, and Alföldi, Jessica, additional
Published: 2015
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46. The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease

Author: Peng, Xinxia, primary, Alföldi, Jessica, additional, Gori, Kevin, additional, Eisfeld, Amie J, additional, Tyler, Scott R, additional, Tisoncik-Go, Jennifer, additional, Brawand, David, additional, Law, G Lynn, additional, Skunca, Nives, additional, Hatta, Masato, additional, Gasper, David J, additional, Kelly, Sara M, additional, Chang, Jean, additional, Thomas, Matthew J, additional, Johnson, Jeremy, additional, Berlin, Aaron M, additional, Lara, Marcia, additional, Russell, Pamela, additional, Swofford, Ross, additional, Turner-Maier, Jason, additional, Young, Sarah, additional, Hourlier, Thibaut, additional, Aken, Bronwen, additional, Searle, Steve, additional, Sun, Xingshen, additional, Yi, Yaling, additional, Suresh, M, additional, Tumpey, Terrence M, additional, Siepel, Adam, additional, Wisely, Samantha M, additional, Dessimoz, Christophe, additional, Kawaoka, Yoshihiro, additional, Birren, Bruce W, additional, Lindblad-Toh, Kerstin, additional, Di Palma, Federica, additional, Engelhardt, John F, additional, Palermo, Robert E, additional, and Katze, Michael G, additional
Published: 2014
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47. Sequencing the Mouse Y Chromosome Reveals Convergent Gene Acquisition and Amplification on Both Sex Chromosomes

Author: Soh, Y.Q. Shirleen, primary, Alföldi, Jessica, additional, Pyntikova, Tatyana, additional, Brown, Laura G., additional, Graves, Tina, additional, Minx, Patrick J., additional, Fulton, Robert S., additional, Kremitzki, Colin, additional, Koutseva, Natalia, additional, Mueller, Jacob L., additional, Rozen, Steve, additional, Hughes, Jennifer F., additional, Owens, Elaine, additional, Womack, James E., additional, Murphy, William J., additional, Cao, Qing, additional, de Jong, Pieter, additional, Warren, Wesley C., additional, Wilson, Richard K., additional, Skaletsky, Helen, additional, and Page, David C., additional
Published: 2014
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48. Erratum: Corrigendum: Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators

Author: Bellott, Daniel W., primary, Hughes, Jennifer F., additional, Skaletsky, Helen, additional, Brown, Laura G., additional, Pyntikova, Tatyana, additional, Cho, Ting-Jan, additional, Koutseva, Natalia, additional, Zaghlul, Sara, additional, Graves, Tina, additional, Rock, Susie, additional, Kremitzki, Colin, additional, Fulton, Robert S., additional, Dugan, Shannon, additional, Ding, Yan, additional, Morton, Donna, additional, Khan, Ziad, additional, Lewis, Lora, additional, Buhay, Christian, additional, Wang, Qiaoyan, additional, Watt, Jennifer, additional, Holder, Michael, additional, Lee, Sandy, additional, Nazareth, Lynne, additional, Alföldi, Jessica, additional, Rozen, Steve, additional, Muzny, Donna M., additional, Warren, Wesley C., additional, Gibbs, Richard A., additional, Wilson, Richard K., additional, and Page, David C., additional
Published: 2014
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49. Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators

Author: Bellott, Daniel W., primary, Hughes, Jennifer F., additional, Skaletsky, Helen, additional, Brown, Laura G., additional, Pyntikova, Tatyana, additional, Cho, Ting-Jan, additional, Koutseva, Natalia, additional, Zaghlul, Sara, additional, Graves, Tina, additional, Rock, Susie, additional, Kremitzki, Colin, additional, Fulton, Robert S., additional, Dugan, Shannon, additional, Ding, Yan, additional, Morton, Donna, additional, Khan, Ziad, additional, Lewis, Lora, additional, Buhay, Christian, additional, Wang, Qiaoyan, additional, Watt, Jennifer, additional, Holder, Michael, additional, Lee, Sandy, additional, Nazareth, Lynne, additional, Alföldi, Jessica, additional, Rozen, Steve, additional, Muzny, Donna M., additional, Warren, Wesley C., additional, Gibbs, Richard A., additional, Wilson, Richard K., additional, and Page, David C., additional
Published: 2014
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50. An Improved Canine Genome and a Comprehensive Catalogue of Coding Genes and Non-Coding Transcripts

Author: Hoeppner, Marc P., primary, Lundquist, Andrew, additional, Pirun, Mono, additional, Meadows, Jennifer R. S., additional, Zamani, Neda, additional, Johnson, Jeremy, additional, Sundström, Görel, additional, Cook, April, additional, FitzGerald, Michael G., additional, Swofford, Ross, additional, Mauceli, Evan, additional, Moghadam, Behrooz Torabi, additional, Greka, Anna, additional, Alföldi, Jessica, additional, Abouelleil, Amr, additional, Aftuck, Lynne, additional, Bessette, Daniel, additional, Berlin, Aaron, additional, Brown, Adam, additional, Gearin, Gary, additional, Lui, Annie, additional, Macdonald, J. Pendexter, additional, Priest, Margaret, additional, Shea, Terrance, additional, Turner-Maier, Jason, additional, Zimmer, Andrew, additional, Lander, Eric S., additional, di Palma, Federica, additional, Lindblad-Toh, Kerstin, additional, and Grabherr, Manfred G., additional
Published: 2014
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