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1. CLSTN3β enforces adipocyte multilocularity to facilitate lipid utilization

Author

Qian, Kevin, Tol, Marcus J, Wu, Jin, Uchiyama, Lauren F, Xiao, Xu, Cui, Liujuan, Bedard, Alexander H, Weston, Thomas A, Rajendran, Pradeep S, Vergnes, Laurent, Shimanaka, Yuta, Yin, Yesheng, Jami-Alahmadi, Yasaman, Cohn, Whitaker, Bajar, Bryce T, Lin, Chia-Ho, Jin, Benita, DeNardo, Laura A, Black, Douglas L, Whitelegge, Julian P, Wohlschlegel, James A, Reue, Karen, Shivkumar, Kalyanam, Chen, Feng-Jung, Young, Stephen G, Li, Peng, and Tontonoz, Peter

Subjects
Biochemistry and Cell Biology, Biological Sciences, Diabetes, Nutrition, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Animals, Female, Humans, Mice, Adipocytes, Adipose Tissue, Brown, Calcium-Binding Proteins, Membrane Proteins, Placenta, Triglycerides, Endoplasmic Reticulum, Lipid Metabolism, Lipid Droplets, Fatty Acids, Hypothermia, Thermogenesis, General Science & Technology
Abstract

Multilocular adipocytes are a hallmark of thermogenic adipose tissue1,2, but the factors that enforce this cellular phenotype are largely unknown. Here, we show that an adipocyte-selective product of the Clstn3 locus (CLSTN3β) present in only placental mammals facilitates the efficient use of stored triglyceride by limiting lipid droplet (LD) expansion. CLSTN3β is an integral endoplasmic reticulum (ER) membrane protein that localizes to ER-LD contact sites through a conserved hairpin-like domain. Mice lacking CLSTN3β have abnormal LD morphology and altered substrate use in brown adipose tissue, and are more susceptible to cold-induced hypothermia despite having no defect in adrenergic signalling. Conversely, forced expression of CLSTN3β is sufficient to enforce a multilocular LD phenotype in cultured cells and adipose tissue. CLSTN3β associates with cell death-inducing DFFA-like effector proteins and impairs their ability to transfer lipid between LDs, thereby restricting LD fusion and expansion. Functionally, increased LD surface area in CLSTN3β-expressing adipocytes promotes engagement of the lipolytic machinery and facilitates fatty acid oxidation. In human fat, CLSTN3B is a selective marker of multilocular adipocytes. These findings define a molecular mechanism that regulates LD form and function to facilitate lipid utilization in thermogenic adipocytes.

Published
2023

2. The three major axes of terrestrial ecosystem function

Author

Migliavacca, Mirco, Musavi, Talie, Mahecha, Miguel D, Nelson, Jacob A, Knauer, Jürgen, Baldocchi, Dennis D, Perez-Priego, Oscar, Christiansen, Rune, Peters, Jonas, Anderson, Karen, Bahn, Michael, Black, T Andrew, Blanken, Peter D, Bonal, Damien, Buchmann, Nina, Caldararu, Silvia, Carrara, Arnaud, Carvalhais, Nuno, Cescatti, Alessandro, Chen, Jiquan, Cleverly, Jamie, Cremonese, Edoardo, Desai, Ankur R, El-Madany, Tarek S, Farella, Martha M, Fernández-Martínez, Marcos, Filippa, Gianluca, Forkel, Matthias, Galvagno, Marta, Gomarasca, Ulisse, Gough, Christopher M, Göckede, Mathias, Ibrom, Andreas, Ikawa, Hiroki, Janssens, Ivan A, Jung, Martin, Kattge, Jens, Keenan, Trevor F, Knohl, Alexander, Kobayashi, Hideki, Kraemer, Guido, Law, Beverly E, Liddell, Michael J, Ma, Xuanlong, Mammarella, Ivan, Martini, David, Macfarlane, Craig, Matteucci, Giorgio, Montagnani, Leonardo, Pabon-Moreno, Daniel E, Panigada, Cinzia, Papale, Dario, Pendall, Elise, Penuelas, Josep, Phillips, Richard P, Reich, Peter B, Rossini, Micol, Rotenberg, Eyal, Scott, Russell L, Stahl, Clement, Weber, Ulrich, Wohlfahrt, Georg, Wolf, Sebastian, Wright, Ian J, Yakir, Dan, Zaehle, Sönke, and Reichstein, Markus

Subjects
Life on Land, Carbon Cycle, Carbon Dioxide, Climate, Datasets as Topic, Ecosystem, Humidity, Plants, Principal Component Analysis, Water Cycle, General Science & Technology
Abstract

The leaf economics spectrum1,2 and the global spectrum of plant forms and functions3 revealed fundamental axes of variation in plant traits, which represent different ecological strategies that are shaped by the evolutionary development of plant species2. Ecosystem functions depend on environmental conditions and the traits of species that comprise the ecological communities4. However, the axes of variation of ecosystem functions are largely unknown, which limits our understanding of how ecosystems respond as a whole to anthropogenic drivers, climate and environmental variability4,5. Here we derive a set of ecosystem functions6 from a dataset of surface gas exchange measurements across major terrestrial biomes. We find that most of the variability within ecosystem functions (71.8%) is captured by three key axes. The first axis reflects maximum ecosystem productivity and is mostly explained by vegetation structure. The second axis reflects ecosystem water-use strategies and is jointly explained by variation in vegetation height and climate. The third axis, which represents ecosystem carbon-use efficiency, features a gradient related to aridity, and is explained primarily by variation in vegetation structure. We show that two state-of-the-art land surface models reproduce the first and most important axis of ecosystem functions. However, the models tend to simulate more strongly correlated functions than those observed, which limits their ability to accurately predict the full range of responses to environmental changes in carbon, water and energy cycling in terrestrial ecosystems7,8.

Published
2021

3. A protein assembly mediates Xist localization and gene silencing

Author

Pandya-Jones, Amy, Markaki, Yolanda, Serizay, Jacques, Chitiashvili, Tsotne, Mancia Leon, Walter R, Damianov, Andrey, Chronis, Constantinos, Papp, Bernadett, Chen, Chun-Kan, McKee, Robin, Wang, Xiao-Jun, Chau, Anthony, Sabri, Shan, Leonhardt, Heinrich, Zheng, Sika, Guttman, Mitchell, Black, Douglas L, and Plath, Kathrin

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Biological Sciences, Genetics, 1.1 Normal biological development and functioning, Generic health relevance, Animals, CELF1 Protein, Cell Line, DNA-Binding Proteins, Female, Gene Silencing, Heterogeneous-Nuclear Ribonucleoproteins, Humans, In Situ Hybridization, Fluorescence, Male, Mice, Nuclear Matrix-Associated Proteins, Polypyrimidine Tract-Binding Protein, RNA, Long Noncoding, RNA-Binding Proteins, X Chromosome Inactivation, General Science & Technology
Abstract

Nuclear compartments have diverse roles in regulating gene expression, yet the molecular forces and components that drive compartment formation remain largely unclear1. The long non-coding RNA Xist establishes an intra-chromosomal compartment by localizing at a high concentration in a territory spatially close to its transcription locus2 and binding diverse proteins3-5 to achieve X-chromosome inactivation (XCI)6,7. The XCI process therefore serves as a paradigm for understanding how RNA-mediated recruitment of various proteins induces a functional compartment. The properties of the inactive X (Xi)-compartment are known to change over time, because after initial Xist spreading and transcriptional shutoff a state is reached in which gene silencing remains stable even if Xist is turned off8. Here we show that the Xist RNA-binding proteins PTBP19, MATR310, TDP-4311 and CELF112 assemble on the multivalent E-repeat element of Xist7 and, via self-aggregation and heterotypic protein-protein interactions, form a condensate1 in the Xi. This condensate is required for gene silencing and for the anchoring of Xist to the Xi territory, and can be sustained in the absence of Xist. Notably, these E-repeat-binding proteins become essential coincident with transition to the Xist-independent XCI phase8, indicating that the condensate seeded by the E-repeat underlies the developmental switch from Xist-dependence to Xist-independence. Taken together, our data show that Xist forms the Xi compartment by seeding a heteromeric condensate that consists of ubiquitous RNA-binding proteins, revealing an unanticipated mechanism for heritable gene silencing.

Published
2020

4. The human body at cellular resolution: the NIH Human Biomolecular Atlas Program

Author

Snyder, Michael P, Lin, Shin, Posgai, Amanda, Atkinson, Mark, Regev, Aviv, Rood, Jennifer, Rozenblatt-Rosen, Orit, Gaffney, Leslie, Hupalowska, Anna, Satija, Rahul, Gehlenborg, Nils, Shendure, Jay, Laskin, Julia, Harbury, Pehr, Nystrom, Nicholas A, Silverstein, Jonathan C, Bar-Joseph, Ziv, Zhang, Kun, Börner, Katy, Lin, Yiing, Conroy, Richard, Procaccini, Dena, Roy, Ananda L, Pillai, Ajay, Brown, Marishka, Galis, Zorina S, Cai, Long, Trapnell, Cole, Jackson, Dana, Nolan, Garry, Greenleaf, William James, Plevritis, Sylvia, Ahadi, Sara, Nevins, Stephanie A, Lee, Hayan, Schuerch, Christian Martijn, Black, Sarah, Venkataraaman, Vishal Gautham, Esplin, Ed, Horning, Aaron, Bahmani, Amir, Sun, Xin, Jain, Sanjay, Hagood, James, Pryhuber, Gloria, Kharchenko, Peter, Bodenmiller, Bernd, Brusko, Todd, Clare-Salzler, Michael, Nick, Harry, Otto, Kevin, Wasserfall, Clive, Jorgensen, Marda, Brusko, Maigan, Maffioletti, Sergio, Caprioli, Richard M, Spraggins, Jeffrey M, Gutierrez, Danielle, Patterson, Nathan Heath, Neumann, Elizabeth K, Harris, Raymond, deCaestecker, Mark, Fogo, Agnes B, van de Plas, Raf, Lau, Ken, Yuan, Guo-Cheng, Zhu, Qian, Dries, Ruben, Yin, Peng, Saka, Sinem K, Kishi, Jocelyn Y, Wang, Yu, Goldaracena, Isabel, Ye, DongHye, Burnum-Johnson, Kristin E, Piehowski, Paul D, Ansong, Charles, Zhu, Ying, Desai, Tushar, Mulye, Jay, Chou, Peter, Nagendran, Monica, Teichmann, Sarah A, Paten, Benedict, Murphy, Robert F, Ma, Jian, Kiselev, Vladimir Yu, Kingsford, Carl, and Ricarte, Allyson

Subjects
Human Genome, Genetics, Networking and Information Technology R&D, Bioengineering, Aging, Atlases as Topic, Biomedical Research, Female, Health, Humans, International Cooperation, Male, Models, Anatomic, Molecular Biology, National Institutes of Health (U.S.), Organ Specificity, Single-Cell Analysis, United States, q-bio.OT, General Science & Technology
Abstract

Transformative technologies are enabling the construction of threedimensional (3D) maps of tissues with unprecedented spatial and molecularresolution. Over the next seven years, the NIH Common Fund Human BiomolecularAtlas Program (HuBMAP) intends to develop a widely accessible framework forcomprehensively mapping the human body at single-cell resolution by supportingtechnology development, data acquisition, and detailed spatial mapping. HuBMAPwill integrate its efforts with other funding agencies, programs, consortia,and the biomedical research community at large towards the shared vision of acomprehensive, accessible 3D molecular and cellular atlas of the human body, inhealth and various disease settings.

Published
2019

5. Noncoding deletions reveal a gene that is critical for intestinal function

Author

Oz-Levi, Danit, Olender, Tsviya, Bar-Joseph, Ifat, Zhu, Yiwen, Marek-Yagel, Dina, Barozzi, Iros, Osterwalder, Marco, Alkelai, Anna, Ruzzo, Elizabeth K, Han, Yujun, Vos, Erica SM, Reznik-Wolf, Haike, Hartman, Corina, Shamir, Raanan, Weiss, Batia, Shapiro, Rivka, Pode-Shakked, Ben, Tatarskyy, Pavlo, Milgrom, Roni, Schvimer, Michael, Barshack, Iris, Imai, Denise M, Coleman-Derr, Devin, Dickel, Diane E, Nord, Alex S, Afzal, Veena, van Bueren, Kelly Lammerts, Barnes, Ralston M, Black, Brian L, Mayhew, Christopher N, Kuhar, Matthew F, Pitstick, Amy, Tekman, Mehmet, Stanescu, Horia C, Wells, James M, Kleta, Robert, de Laat, Wouter, Goldstein, David B, Pras, Elon, Visel, Axel, Lancet, Doron, Anikster, Yair, and Pennacchio, Len A

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Human Genome, Biotechnology, Digestive Diseases, 1.1 Normal biological development and functioning, Oral and gastrointestinal, Animals, Chromosomes, Human, Pair 16, Diarrhea, Disease Models, Animal, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Developmental, Genes, Genes, Reporter, Genetic Loci, Humans, Intestines, Male, Mice, Mice, Knockout, Mice, Transgenic, Pedigree, Phenotype, Sequence Deletion, Transcriptional Activation, Transcriptome, Transgenes, General Science & Technology
Abstract

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.

Published
2019

6. Improved reference genome of Aedes aegypti informs arbovirus vector control

Author

Matthews, Benjamin J, Dudchenko, Olga, Kingan, Sarah B, Koren, Sergey, Antoshechkin, Igor, Crawford, Jacob E, Glassford, William J, Herre, Margaret, Redmond, Seth N, Rose, Noah H, Weedall, Gareth D, Wu, Yang, Batra, Sanjit S, Brito-Sierra, Carlos A, Buckingham, Steven D, Campbell, Corey L, Chan, Saki, Cox, Eric, Evans, Benjamin R, Fansiri, Thanyalak, Filipović, Igor, Fontaine, Albin, Gloria-Soria, Andrea, Hall, Richard, Joardar, Vinita S, Jones, Andrew K, Kay, Raissa GG, Kodali, Vamsi K, Lee, Joyce, Lycett, Gareth J, Mitchell, Sara N, Muehling, Jill, Murphy, Michael R, Omer, Arina D, Partridge, Frederick A, Peluso, Paul, Aiden, Aviva Presser, Ramasamy, Vidya, Rašić, Gordana, Roy, Sourav, Saavedra-Rodriguez, Karla, Sharan, Shruti, Sharma, Atashi, Smith, Melissa Laird, Turner, Joe, Weakley, Allison M, Zhao, Zhilei, Akbari, Omar S, Black, William C, Cao, Han, Darby, Alistair C, Hill, Catherine A, Johnston, J Spencer, Murphy, Terence D, Raikhel, Alexander S, Sattelle, David B, Sharakhov, Igor V, White, Bradley J, Zhao, Li, Aiden, Erez Lieberman, Mann, Richard S, Lambrechts, Louis, Powell, Jeffrey R, Sharakhova, Maria V, Tu, Zhijian, Robertson, Hugh M, McBride, Carolyn S, Hastie, Alex R, Korlach, Jonas, Neafsey, Daniel E, Phillippy, Adam M, and Vosshall, Leslie B

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Rare Diseases, Emerging Infectious Diseases, Biodefense, Infectious Diseases, Vector-Borne Diseases, 2.2 Factors relating to the physical environment, 3.2 Interventions to alter physical and biological environmental risks, Infection, Good Health and Well Being, Aedes, Animals, Arbovirus Infections, Arboviruses, DNA Copy Number Variations, Dengue Virus, Female, Genetic Variation, Genetics, Population, Genome, Insect, Genomics, Glutathione Transferase, Insect Control, Insecticide Resistance, Male, Molecular Sequence Annotation, Mosquito Vectors, Multigene Family, Pyrethrins, Reference Standards, Sex Determination Processes, General Science & Technology
Abstract

Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector.

Published
2018

7. Satellite DNA shapes dictate pericentromere packaging in female meiosis

Author

Dudka, Damian, Dawicki-McKenna, Jennine M., Sun, Xueqi, Beeravolu, Keagan, Akera, Takashi, Lampson, Michael A., and Black, Ben E.

Abstract

The abundance and sequence of satellite DNA at and around centromeres is evolving rapidly despite the highly conserved and essential process through which the centromere directs chromosome inheritance1, 2–3. The impact of such rapid evolution is unclear. Here we find that sequence-dependent DNA shape dictates packaging of pericentromeric satellites in female meiosis through a conserved DNA-shape-recognizing chromatin architectural protein, high mobility group AT-hook 1 (HMGA1)4,5. Pericentromeric heterochromatin in two closely related mouse species, M.musculusand M.spretus, forms on divergent satellites that differ by both density of narrow DNA minor grooves and HMGA1 recruitment. HMGA1 binds preferentially to M.musculussatellites, and depletion in M.musculusoocytes causes massive stretching of pericentromeric satellites, disruption of kinetochore organization and delays in bipolar spindle assembly. In M.musculus× spretushybrid oocytes, HMGA1 depletion disproportionately impairs M.musculuspericentromeres and microtubule attachment to their kinetochores. Thus, DNA shape affects both pericentromere packaging and the segregation machinery. We propose that rapid evolution of centromere and pericentromere DNA does not disrupt these essential processes when the satellites adopt DNA shapes recognized by conserved architectural proteins (such as HMGA1). By packaging these satellites, architectural proteins become part of the centromeric and pericentromeric chromatin, suggesting an evolutionary strategy that lowers the cost of megabase-scale satellite expansion.

Published
2025
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8. Modulation of tissue repair by regeneration enhancer elements

Author

Kang, Junsu, Hu, Jianxin, Karra, Ravi, Dickson, Amy L, Tornini, Valerie A, Nachtrab, Gregory, Gemberling, Matthew, Goldman, Joseph A, Black, Brian L, and Poss, Kenneth D

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Regenerative Medicine, Physical Injury - Accidents and Adverse Effects, Genetics, Acetylation, Animal Fins, Animals, Animals, Newborn, Cell Proliferation, Chromatin Assembly and Disassembly, Enhancer Elements, Genetic, Epigenesis, Genetic, Female, Gene Expression Profiling, Gene Expression Regulation, Heart, Histones, Leptin, Lysine, Male, Mice, Myocytes, Cardiac, Organ Specificity, Promoter Regions, Genetic, Regeneration, Transgenes, Wound Healing, Zebrafish, Zebrafish Proteins, General Science & Technology
Abstract

How tissue regeneration programs are triggered by injury has received limited research attention. Here we investigate the existence of enhancer regulatory elements that are activated in regenerating tissue. Transcriptomic analyses reveal that leptin b (lepb) is highly induced in regenerating hearts and fins of zebrafish. Epigenetic profiling identified a short DNA sequence element upstream and distal to lepb that acquires open chromatin marks during regeneration and enables injury-dependent expression from minimal promoters. This element could activate expression in injured neonatal mouse tissues and was divisible into tissue-specific modules sufficient for expression in regenerating zebrafish fins or hearts. Simple enhancer-effector transgenes employing lepb-linked sequences upstream of pro- or anti-regenerative factors controlled the efficacy of regeneration in zebrafish. Our findings provide evidence for 'tissue regeneration enhancer elements' (TREEs) that trigger gene expression in injury sites and can be engineered to modulate the regenerative potential of vertebrate organs.

Published
2016

9. Biological insights from 108 schizophrenia-associated genetic loci

Author

Ripke, Stephan, Neale, Benjamin M, Corvin, Aiden, Walters, James TR, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A Jr, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Hougaard, David M, Ikeda, Masashi, and Joa, Inge

Subjects
Human Genome, Brain Disorders, Serious Mental Illness, Prevention, Schizophrenia, Genetics, Neurosciences, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Mental health, Alleles, Brain, Enhancer Elements, Genetic, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Glutamic Acid, Humans, Immunity, Multifactorial Inheritance, Mutation, Odds Ratio, Polymorphism, Single Nucleotide, Synaptic Transmission, Schizophrenia Working Group of the Psychiatric Genomics Consortium, General Science & Technology
Abstract

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

Published
2014

10. Decoding the interplay between genetic and non-genetic drivers of metastasis.

Author

Karras, Panagiotis, Black, James R. M., McGranahan, Nicholas, and Marine, Jean-Christophe

Abstract

Metastasis is a multistep process by which cancer cells break away from their original location and spread to distant organs, and is responsible for the vast majority of cancer-related deaths. Preventing early metastatic dissemination would revolutionize the ability to fight cancer. Unfortunately, the relatively poor understanding of the molecular underpinnings of metastasis has hampered the development of effective anti-metastatic drugs. Although it is now accepted that disseminating tumour cells need to acquire multiple competencies to face the many obstacles they encounter before reaching their metastatic site(s), whether these competencies are acquired through an accumulation of metastasis-specific genetic alterations and/or non-genetic events is often debated. Here we review a growing body of literature highlighting the importance of both genetic and non-genetic reprogramming events during the metastatic cascade, and discuss how genetic and non-genetic processes act in concert to confer metastatic competencies. We also describe how recent technological advances, and in particular the advent of single-cell multi-omics and barcoding approaches, will help to better elucidate the cross-talk between genetic and non-genetic mechanisms of metastasis and ultimately inform innovative paths for the early detection and interception of this lethal process.This Review discusses the importance of genetic and non-genetic reprogramming events during the metastatic cascade. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Observed increase in local cooling effect of deforestation at higher latitudes.

Author

Lee, Xuhui, Goulden, Michael L, Hollinger, David Y, Barr, Alan, Black, T Andrew, Bohrer, Gil, Bracho, Rosvel, Drake, Bert, Goldstein, Allen, Gu, Lianhong, Katul, Gabriel, Kolb, Thomas, Law, Beverly E, Margolis, Hank, Meyers, Tilden, Monson, Russell, Munger, William, Oren, Ram, Paw U, Kyaw Tha, Richardson, Andrew D, Schmid, Hans Peter, Staebler, Ralf, Wofsy, Steven, and Zhao, Lei

Subjects
Trees, Altitude, Conservation of Natural Resources, Temperature, Atmosphere, Air, Climate, Seasons, Forestry, Canada, United States, Biophysical Phenomena, Biophysical Processes, General Science & Technology
Abstract

Deforestation in mid- to high latitudes is hypothesized to have the potential to cool the Earth's surface by altering biophysical processes. In climate models of continental-scale land clearing, the cooling is triggered by increases in surface albedo and is reinforced by a land albedo-sea ice feedback. This feedback is crucial in the model predictions; without it other biophysical processes may overwhelm the albedo effect to generate warming instead. Ongoing land-use activities, such as land management for climate mitigation, are occurring at local scales (hectares) presumably too small to generate the feedback, and it is not known whether the intrinsic biophysical mechanism on its own can change the surface temperature in a consistent manner. Nor has the effect of deforestation on climate been demonstrated over large areas from direct observations. Here we show that surface air temperature is lower in open land than in nearby forested land. The effect is 0.85 ± 0.44 K (mean ± one standard deviation) northwards of 45° N and 0.21 ± 0.53 K southwards. Below 35° N there is weak evidence that deforestation leads to warming. Results are based on comparisons of temperature at forested eddy covariance towers in the USA and Canada and, as a proxy for small areas of cleared land, nearby surface weather stations. Night-time temperature changes unrelated to changes in surface albedo are an important contributor to the overall cooling effect. The observed latitudinal dependence is consistent with theoretical expectation of changes in energy loss from convection and radiation across latitudes in both the daytime and night-time phase of the diurnal cycle, the latter of which remains uncertain in climate models.

Published
2011

12. CLSTN3β enforces adipocyte multilocularity to facilitate lipid utilization

Author

Kevin Qian, Marcus J. Tol, Jin Wu, Lauren F. Uchiyama, Xu Xiao, Liujuan Cui, Alexander H. Bedard, Thomas A. Weston, Pradeep S. Rajendran, Laurent Vergnes, Yuta Shimanaka, Yesheng Yin, Yasaman Jami-Alahmadi, Whitaker Cohn, Bryce T. Bajar, Chia-Ho Lin, Benita Jin, Laura A. DeNardo, Douglas L. Black, Julian P. Whitelegge, James A. Wohlschlegel, Karen Reue, Kalyanam Shivkumar, Feng-Jung Chen, Stephen G. Young, Peng Li, and Peter Tontonoz

Subjects
Multidisciplinary, Article
Abstract

Multilocular adipocytes are a hallmark of thermogenic adipose tissue(1,2), but the factors that enforce this cellular phenotype are largely unknown. Here, we show that an adipocyte-selective product of the Clstn3 locus (CLSTN3β) present in only placental mammals facilitates the efficient use of stored triglyceride by limiting lipid droplet (LD) expansion. CLSTN3β is an integral endoplasmic reticulum (ER) membrane protein that localizes to ER–LD contact sites through a conserved hairpin-like domain. Mice lacking CLSTN3β have abnormal LD morphology and altered substrate use in brown adipose tissue, and are more susceptible to cold-induced hypothermia despite having no defect in adrenergic signalling. Conversely, forced expression of CLSTN3β is sufficient to enforce a multilocular LD phenotype in cultured cells and adipose tissue. CLSTN3β associates with cell death-inducing DFFA-like effector proteins and impairs their ability to transfer lipid between LDs, thereby restricting LD fusion and expansion. Functionally, increased LD surface area in CLSTN3β-expressing adipocytes promotes engagement of the lipolytic machinery and facilitates fatty acid oxidation. In human fat, CLSTN3B is a selective marker of multilocular adipocytes. These findings define a molecular mechanism that regulates LD form and function to facilitate lipid utilization in thermogenic adipocytes.

Published
2022
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13. Organization of the human intestine at single-cell resolution

Author

Hickey, John W., primary, Becker, Winston R., additional, Nevins, Stephanie A., additional, Horning, Aaron, additional, Perez, Almudena Espin, additional, Zhu, Chenchen, additional, Zhu, Bokai, additional, Wei, Bei, additional, Chiu, Roxanne, additional, Chen, Derek C., additional, Cotter, Daniel L., additional, Esplin, Edward D., additional, Weimer, Annika K., additional, Caraccio, Chiara, additional, Venkataraaman, Vishal, additional, Schürch, Christian M., additional, Black, Sarah, additional, Brbić, Maria, additional, Cao, Kaidi, additional, Chen, Shuxiao, additional, Zhang, Weiruo, additional, Monte, Emma, additional, Zhang, Nancy R., additional, Ma, Zongming, additional, Leskovec, Jure, additional, Zhang, Zhengyan, additional, Lin, Shin, additional, Longacre, Teri, additional, Plevritis, Sylvia K., additional, Lin, Yiing, additional, Nolan, Garry P., additional, Greenleaf, William J., additional, and Snyder, Michael, additional

Published
2023
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14. Formation of the methyl cation by photochemistry in a protoplanetary disk

Author

Berné, Olivier, primary, Martin-Drumel, Marie-Aline, additional, Schroetter, Ilane, additional, Goicoechea, Javier R., additional, Jacovella, Ugo, additional, Gans, Bérenger, additional, Dartois, Emmanuel, additional, Coudert, Laurent H., additional, Bergin, Edwin, additional, Alarcon, Felipe, additional, Cami, Jan, additional, Roueff, Evelyne, additional, Black, John H., additional, Asvany, Oskar, additional, Habart, Emilie, additional, Peeters, Els, additional, Canin, Amelie, additional, Trahin, Boris, additional, Joblin, Christine, additional, Schlemmer, Stephan, additional, Thorwirth, Sven, additional, Cernicharo, Jose, additional, Gerin, Maryvonne, additional, Tielens, Alexander, additional, Zannese, Marion, additional, Abergel, Alain, additional, Bernard-Salas, Jeronimo, additional, Boersma, Christiaan, additional, Bron, Emeric, additional, Chown, Ryan, additional, Cuadrado, Sara, additional, Dicken, Daniel, additional, Elyajouri, Meriem, additional, Fuente, Asunción, additional, Gordon, Karl D., additional, Issa, Lina, additional, Kannavou, Olga, additional, Khan, Baria, additional, Lacinbala, Ozan, additional, Languignon, David, additional, Le Gal, Romane, additional, Maragkoudakis, Alexandros, additional, Meshaka, Raphael, additional, Okada, Yoko, additional, Onaka, Takashi, additional, Pasquini, Sofia, additional, Pound, Marc W., additional, Robberto, Massimo, additional, Röllig, Markus, additional, Schefter, Bethany, additional, Schirmer, Thiébaut, additional, Sidhu, Ameek, additional, Tabone, Benoit, additional, Van De Putte, Dries, additional, Vicente, Sílvia, additional, and Wolfire, Mark G., additional

Published
2023
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16. Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Author

Trubetskoy, Vassily, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Braun, Alice, Kraft, Julia, Skarabis, Nora, Walter, Henrik, Ripke, Stephan, Pardiñas, Antonio F., Dennison, Charlotte A., Hall, Lynsey S., Harwood, Janet C., Richards, Alexander L., Legge, Sophie E., Lynham, Amy, Williams, Nigel M., Bray, Nicholas J., Escott-Price, Valentina, Kirov, George, Holmans, Peter A., Pocklington, Andrew J., Owen, Michael J., Walters, James T. R., O’Donovan, Michael C., Qi, Ting, Sidorenko, Julia, Wu, Yang, Zeng, Jian, Gratten, Jacob, Visscher, Peter M., Yang, Jian, Wray, Naomi R., Bigdeli, Tim B., Fanous, Ayman H., Bryois, Julien, Bergen, Sarah E., Kähler, Anna K., Magnusson, Patrik K. E., Hultman, Christina M., Sullivan, Patrick F., Chen, Chia-Yen, Atkinson, Elizabeth G., Goldstein, Jacqueline I., Howrigan, Daniel P., Martin, Alicia R., Daly, Mark J., Huang, Hailiang, Neale, Benjamin M., Ge, Tian, Lam, Max, Belliveau, Richard A., Chambert, Kimberley D., Genovese, Giulio, Lee, Phil H., Pietiläinen, Olli, McCarroll, Steven A., Moran, Jennifer L., Smoller, Jordan W., Brown, Tyler C., Feng, Guoping, Hyman, Steven E., Sheng, Morgan, Chong, Siow Ann, Subramaniam, Mythily, Lencz, Todd, Malhotra, Anil K., Watanabe, Kyoko, Frei, Oleksandr, Agartz, Ingrid, Athanasiu, Lavinia, Melle, Ingrid, Andreassen, Ole A., Steen, Nils Eiel, DeLisi, Lynn E., Mesholam-Gately, Raquelle I., Seidman, Larry J., Koopmans, Frank, Magnusson, Sigurdur, Stefánsson, Hreinn, Stefansson, Kari, Grove, Jakob, Agerbo, Esben, Als, Thomas D., Bybjerg-Grauholm, Jonas, Demontis, Ditte, Hougaard, David M., Mors, Ole, Mortensen, Preben B., Nordentoft, Merete, Børglum, Anders D., Mattheisen, Manuel, Kim, Minsoo, Gandal, Michael J., Li, Zhiqiang, Shi, Yongyong, Zhou, Wei, Qin, Shengying, Voloudakis, Georgios, Zhang, Wen, Roussos, Panos, Adams, Mark, McIntosh, Andrew, Söderman, Erik, Jönsson, Erik G., McGrath, John J., Al Eissa, Mariam, Bass, Nicholas J., Fiorentino, Alessia, O’Brien, Niamh Louise, Pimm, Jonathan, Sharp, Sally Isabel, McQuillin, Andrew, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z., Bruggeman, Richard, Alptekin, Köksal, Amin, Farooq, Arolt, Volker, Lencer, Rebecca, Rothermundt, Matthias, Baune, Bernhard T., Arrojo, Manuel, Azevedo, Maria Helena, Bacanu, Silviu A., Webb, Bradley T., Wormley, Brandon K., Riley, Brien P., Kendler, Kenneth S., Begemann, Martin, Mitjans, Marina, Steixner-Kumar, Agnes A., Ehrenreich, Hannelore, Bene, Judit, Benyamin, Beben, Blasi, Giuseppe, Rampino, Antonio, Torretta, Silvia, Bertolino, Alessandro, Bobes, Julio, Bonassi, Stefano, Bressan, Rodrigo Affonseca, Gadelha, Ary, Noto, Cristiano, Ota, Vanessa Kiyomi, Santoro, Marcos Leite, Belangero, Sintia Iole, Bromet, Evelyn J., Buckley, Peter F., Buckner, Randy L., Cahn, Wiepke, Kahn, René S., Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Schall, Ulrich, Calkins, Monica E., Gur, Raquel E., Gur, Ruben C., Turetsky, Bruce I., Carr, Vaughan J., Castle, David, Harvey, Carol, Catts, Stanley V., Chan, Raymond C. K., Chaumette, Boris, Kebir, Oussama, Krebs, Marie-Odile, Cheng, Wei, Cheung, Eric F. C., Cohen, David, Consoli, Angèle, Giannitelli, Marianna, Laurent-Levinson, Claudine, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Quattrone, Diego, Breen, Gerome, Collier, David A., Di Forti, Marta, Vassos, Evangelos, Mondelli, Valeria, van Amelsvoort, Therese, Murray, Robin M., Davidson, Michael, Davis, Kenneth L., Haroutunian, Vahram, Malaspina, Dolores, Reichenberg, Abraham, Siever, Larry J., Silverman, Jeremy M., Buxbaum, Joseph D., de Haan, Lieuwe, Degenhardt, Franziska, Forstner, Andreas, Nöthen, Markus M., Dickerson, Faith, Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Gejman, Pablo V., Sanders, Alan R., Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanás, Lourdes, Peñas, Javier González, González-Pinto, Ana, Molto, María Dolores, Moreno, Carmen, Parellada, Mara, Sanjuan, Julio, Crepo-Facorro, Benedicto, Mata, Ignacio, Arango, Celso, Faraone, Stephen V., Frank, Josef, Streit, Fabian, Witt, Stephanie H., Rietschel, Marcella, Freimer, Nelson B., Ophoff, Roel A., Fromer, Menachem, Stahl, Eli A., Frustaci, Alessandra, Gershon, Elliot S., Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Giusti-Rodríguez, Paola, Szatkiewicz, Jin P., Godard, Stephanie, González Peñas, Javier, Gopal, Srihari, Savitz, Adam, Li, Qingqin S., Green, Michael F., Nuechterlein, Keith H., Sugar, Catherine A., Greenwood, Tiffany A., Light, Gregory A., Swerdlow, Neal R., Braff, David, Guillin, Olivier, Campion, Dominique, Gülöksüz, Sinan, Luykx, Jurjen J., Rutten, Bart P. F., van Winkel, Ruud, Gutiérrez, Blanca, Hahn, Eric, Hakonarson, Hakon, Pellegrino, Renata, Pantelis, Christos, Hayward, Caroline, Henskens, Frans A., Kelly, Brian J., Herms, Stefan, Hoffmann, Per, Ikeda, Masashi, Iwata, Nakao, Iyegbe, Conrad, van Os, Jim, Joa, Inge, Julià, Antonio, Marsal, Sara, Kam-Thong, Tony, Rautanen, Anna, Kamatani, Yoichiro, Karachanak-Yankova, Sena, Toncheva, Draga, Keller, Matthew C., Khrunin, Andrey, Limborska, Svetlana, Slominsky, Petr, Kim, Sung-Wan, Klovins, Janis, Nikitina-Zake, Liene, Kondratiev, Nikolay, Golimbet, Vera, Kubo, Michiaki, Kučinskas, Vaidutis, Kučinskiene, Zita Ausrele, Kusumawardhani, Agung, Kuzelova-Ptackova, Hana, Landi, Stefano, Lazzeroni, Laura C., Levinson, Douglas F., Petryshen, Tracey L., Lehrer, Douglas S., Lerer, Bernard, Li, Miaoxin, Lieberman, Jeffrey, Stroup, T. Scott, Liu, Chih-Min, Hwu, Hai-Gwo, Lönnqvist, Jouko, Loughland, Carmel M., Lubinski, Jan, Bakker, Steven, Kahn, René, Macek, Milan, Mackinnon, Andrew, Maher, Brion S., Maier, Wolfgang, Atbaşoğlu, Eşref Cem, Mallet, Jacques, Marder, Stephen R., Martorell, Lourdes, Muntané, Gerard, Vilella, Elisabet, Meier, Sandra, Schulze, Thomas G., McCarley, Robert W., McDonald, Colm, Donohoe, Gary, Morris, Derek W., Periyasamy, Sathish, Mowry, Bryan J., Medeiros, Helena, Sobell, Janet L., Melegh, Bela, Metspalu, Andres, Milani, Lili, Esko, Tõnu, Michie, Patricia T., Milanova, Vihra, Molden, Espen, Molina, Esther, Morley, Christopher P., Murphy, Kieran C., Myin-Germeys, Inez, Nenadić, Igor, Nestadt, Gerald, Pulver, Ann E., O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Freedman, Robert, Paunio, Tiina, Perkins, Diana O., Pfuhlmann, Bruno, Benner, Christian, Pirinen, Matti, Palotie, Aarno, Porteous, David, Powell, John, Quested, Digby, Radant, Allen D., Tsuang, Debby W., Rapaport, Mark H., Roe, Cheryl, Liu, Chunyu, Roffman, Joshua L., Roth, Julian, Gawlik, Micha, Saker-Delye, Safaa, Salomaa, Veikko, Suvisaari, Jaana, Shi, Jianxin, Sigurdsson, Engilbert, Sim, Kang, So, Hon-Cheong, Stain, Helen J., Stögmann, Elisabeth, Zimprich, Fritz, Stone, William S., Straub, Richard E., Hyde, Thomas, Jaffe, Andrew, Weinberger, Daniel R., Strengman, Eric, Svrakic, Dragan M., Cloninger, C. Robert, Ta, Thi Minh Tam, Takahashi, Atsushi, Terao, Chikashi, Thibaut, Florence, Tosato, Sarah, Tura, Gian Battista, Üçok, Alp, Vaaler, Arne, Veijola, Juha, Waddington, John, Waterreus, Anna, Morgan, Vera A., Jablensky, Assen V., Weiser, Mark, Wu, Jing Qin, Xu, Zhida, Yolken, Robert, Zai, Clement C., Kennedy, James L., Zhu, Feng, Saka, Meram C., Ayub, Muhammad, Black, Donald W., Buccola, Nancy G., Byerley, William F., Chen, Wei J., Crespo-Facorro, Benedicto, Galletly, Cherrie, Gennarelli, Massimo, Müller-Myhsok, Bertram, Neil, Amanda L., Pato, Michele T., Pato, Carlos N., Wang, Shi-Heng, Xu, Shuhua, Adolfsson, Rolf, Bramon, Elvira, Cervilla, Jorge A., Cichon, Sven, Corvin, Aiden, Gill, Michael, Curtis, David, Domenici, Enrico, Gareeva, Anna, Khusnutdinova, Elza, Glatt, Stephen J., Hong, Kyung Sue, Knowles, James A., Lee, Jimmy, Liu, Jianjun, Malhotra, Dheeraj, Menezes, Paulo R., Nimgaonkar, Vishwajit, Paciga, Sara A., Rivera, Margarita, Schwab, Sibylle G., Serretti, Alessandro, Sham, Pak C., Clair, David St, Tsuang, Ming T., Vawter, Marquis P., Werge, Thomas, Wildenauer, Dieter B., Yu, Xin, Yue, Weihua, Verhage, Matthijs, Sahasrabudhe, Dnyanada, Toonen, Ruud F., Posthuma, Danielle, Dai, Nan, Wenwen, Qin, Wildenauer, D. B., Agiananda, Feranindhya, Amir, Nurmiati, Antoni, Ronald, Arsianti, Tiana, Asmarahadi, Asmarahadi, Diatri, H., Djatmiko, Prianto, Irmansyah, Irmansyah, Khalimah, Siti, Kusumadewi, Irmia, Kusumaningrum, Profitasari, Lukman, Petrin R., Nasrun, Martina W., Safyuni, N. S., Prasetyawan, Prasetyawan, Semen, G., Siste, Kristiana, Tobing, Heriani, Widiasih, Natalia, Wiguna, Tjhin, Wulandari, D., Evalina, None, Hananto, A. J., Ismoyo, Joni H., Marini, T. M., Henuhili, Supiyani, Reza, Muhammad, Yusnadewi, Suzy, Abyzov, Alexej, Akbarian, Schahram, van Bakel, Harm, Breen, Michael, Charney, Alex, Dracheva, Stella, Girdhar, Kiran, Hoffman, Gabriel, Jiang, Yan, Pinto, Dalila, Purcell, Shaun, Roussos, Panagiotis, Wiseman, Jennifer, Ashley-Koch, Allison, Crawford, Gregory, Reddy, Tim, Brown, Miguel, Grennan, Kay, Carlyle, Becky, Emani, Prashant, Galeev, Timur, Gerstein, Mark, Gu, Mengting, Guerra, Brittney, Gursoy, Gamze, Kitchen, Robert, Lee, Donghoon, Li, Mingfeng, Liu, Shuang, Navarro, Fabio, Pan, Xinghua, Pochareddy, Sirisha, Rozowsky, Joel, Sestan, Nenad, Sethi, Anurag, Shi, Xu, Szekely, Anna, Wang, Daifeng, Warrell, Jonathan, Weissman, Sherman, Wu, Feinan, Xu, Xuming, Coetzee, Gerard, Farnham, Peggy, Lay, Fides, Rhie, Suhn, Witt, Heather, Wood, Shannon, Yao, Lijing, Gandal, Mike, Polioudakis, Damon, Swarup, Vivek, Won, Hyejung, Giase, Gina, Jiang, Shan, Kefi, Amira, Shieh, Annie, Goes, Fernando, Zandi, Peter, Kim, Yunjung, Mattei, Eugenio, Purcaro, Michael, Pratt, Henry, Peters, Mette A., Sanders, Stephan, Weng, Zhiping, White, Kevin, Arranz, Maria J., Lewis, Cathryn, Lin, Kuang, Walshe, Muriel, Bender, Stephan, Weisbrod, Matthias, Hall, Jeremy, Lawrie, Stephen, Linszen, Don H., Achsel, Tilmann, Bagni, Claudia, Andres-Alonso, Maria, Kreutz, Michael R., Bayés, Àlex, Biederer, Thomas, Brose, Nils, Chua, John Jia En, Coba, Marcelo P., Cornelisse, L. Niels, van Weering, Jan R. T., de Jong, Arthur P. H., MacGillavry, Harold D., de Juan-Sanz, Jaime, Dieterich, Daniela C., Pielot, Rainer, Smalla, Karl-Heinz, Gundelfinger, Eckart D., Goldschmidt, Hana L., Huganir, Richard L., Hoogenraad, Casper, Imig, Cordelia, Jahn, Reinhard, Jung, Hwajin, Kim, Eunjoon, Kaeser, Pascal S., Lipstein, Noa, Malenka, Robert, McPherson, Peter S., O’Connor, Vincent, Ryan, Timothy A., Sala, Carlo, Verpelli, Chiara, Smit, August B., Südhof, Thomas C., Thomas, Paul D., Medical Research Council (UK), National Natural Science Foundation of China, Royal Society (UK), Chinese Academy of Sciences, Shanghai Science and Technology Committee, Research Council of Norway, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Comunidad de Madrid, Fundación Alicia Koplowitz, Fundación Alonso Lozano, Mental Health Research UK, Wellcome Trust, Brain and Behavior Research Foundation, NIHR Biomedical Research Centre (UK), University College London, Generalitat Valenciana, Internal medicine, Human genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, RS: MHeNs - R3 - Neuroscience, MUMC+: MA Psychiatrie (3), MUMC+: MA Med Staf Spec Psychiatrie (9), MUMC+: Hersen en Zenuw Centrum (3), Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Benyamin, Beben, O'Donovan, Michael C, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Molecular and Cellular Neurobiology, Functional Genomics, and Complex Trait Genetics

Subjects
Genetics of the nervous system, Schizophrenia/genetics, VARIANTS, PROFILE, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, DISEASE, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, Alleles, Genomics, Genome-Wide Association Study, Schizophrenia, Polymorphism, RISK, ARCHITECTURE, Science & Technology, Multidisciplinary, MUTATIONS, Genetic Predisposition to Disease/genetics, Settore BIO/13, Single Nucleotide, ASSOCIATION, Polymorphism, Single Nucleotide/genetics, STATISTICS, Multidisciplinary Sciences, INDIVIDUALS, Science & Technology - Other Topics, Diseases of the nervous system, ddc:500, Single Nucleotide/genetics, INTEGRATION
Abstract

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., The work at Cardiff University was additionally supported by Medical Research Council Centre grant no. MR/L010305/1 and program grant no. G0800509. S. Xu also gratefully acknowledges the support of the National Natural Science Foundation of China (NSFC) grants (31525014, 91731303, 31771388, 31961130380 and 32041008), the UK Royal Society-Newton Advanced Fellowship (NAF\R1\191094), the Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) and the Strategic Priority Research Program (XDB38000000) of the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). O. A. Andreassen was supported by the Research Council of Norway (283798, 262656, 248980, 273291, 248828, 248778, 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, EU H2020 no. 847776. B. Melegh was supported in part by the National Scientific Research Program (NKFIH) K 138669. S. V. Faraone is supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreements 667302 and 728018 and NIMH grants 5R01MH101519 and U01 MH109536-01. S. I. Belangero was supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo), grant numbers: 2010/08968-6; 2014/07280-1 2011/50740-5 (including R. A. Bressan). The Singapore team (J. Lee, J. Liu, K. Sim, S. A. Chong and M. Subramanian) acknowledges the National Medical Research Council Translational and Clinical Research Flagship Programme (grant no.: NMRC/TCR/003/2008). M. Macek was supported by LM2018132, CZ.02.1.01/0.0/0.0/18_046/0015515 and IP6003 –VZFNM00064203. C. Arango has been funded by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF Funds from the European Commission, ‘A way of making Europe’, CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement no 115916, project PRISM; and grant agreement no. 777394, project AIMS-2-TRIALS), Fundación Familia Alonso and Fundación Alicia Koplowitz. E. Bramon acknowledges support from the National Institute of Health Research UK (grant NIHR200756); Mental Health Research UK John Grace QC Scholarship 2018; an ESRC collaborative award 2020; BMA Margaret Temple Fellowship 2016; Medical Research Council New Investigator Award (G0901310); MRC Centenary Award (G1100583); MRC project grant G1100583; National Institute of Health Research UK post-doctoral fellowship (PDA/02/06/016); NARSAD Young Investigator awards 2005 and 2008; Wellcome Trust Research Training Fellowship; Wellcome Trust Case Control Consortium awards (085475/B/08/Z, 085475/Z/08/Z); European Commission Horizon 2020 (747429); NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King’s College London; and NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London (UCLH BRC - Mental Health Theme). D. Molto is funded by the European Regional Development Fund (ERDF)–Valencian Community 2014–2020, Spain. E. G. Atkinson was supported by the NIMH K01MH121659.

Published
2022
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18. Genetic mechanisms of critical illness in COVID-19

Author

Pairo-Castineira, Erola, Clohisey, Sara, Klaric, Lucija, Bretherick, Andrew D, Rawlik, Konrad, Pasko, Dorota, Walker, Susan, Parkinson, Nick, Fourman, Max Head, Russell, Clark D, Furniss, James, Richmond, Anne, Gountouna, Elvina, Wrobel, Nicola, Harrison, David, Wang, Bo, Yang, Wu, Meynert, Alison, Griffiths, Fiona, Oosthuyzen, Wilna, Kousathanas, Athanasios, Moutsianas, Loukas, Yang, Zhijian, Zhai, Ranran, Zheng, Chenqing, Grimes, Graeme, Beale, Rupert, Millar, Jonathan, Shih, Barbara, Keating, Sean, Zechner, Marie, Haley, Chris, Porteous, David J, Hayward, Caroline, Yang, Jian, Knight, Julian, Summers, Charlotte, Shankar-Hari, Manu, Klenerman, Paul, Turtle, Lance, Antonia, Ho, Moore, Shona C, Hinds, Charles, Horby, Peter, Nichol, Alistair, Maslove, David, Ling, Lowell, Mcauley, Danny, Montgomery, Hugh, Walsh, Timothy, Pereira, Alexandre C, Renieri, Johnny, Millar, Alistair, Nichol, Tim, Walsh, Manu, Shankar-Hari, Chris, Ponting, Jen, Meikle, Paul, Finernan, Ellie, Mcmaster, Andy, Law, J Kenneth Baillie, Trevor, Paterson, Tony, Wackett, Ruth, Armstrong, Richard, Clark, Audrey, Coutts, Lorna, Donnelly, Tammy, Gilchrist, Katarzyna, Hafezi, Louise, Macgillivray, Alan, Maclean, Sarah, Mccafferty, Kirstie, Morrice, Jane, Weaver, Ceilia, Boz, Ailsa, Golightly, Mari, Ward, Hanning, Mal, Helen, Szoor-McElhinney, Adam, Brown, Ross, Hendry, Andrew, Stenhouse, Louise, Cullum, Dawn, Law, Sarah, Law, Rachel, Law, Maaike, Swets, Nicky, Day, Filip, Taneski, Esther, Duncan, Nicholas, Parkinson, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthope, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Shankar-Hari, M, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, O Jones, T, Whitton, C, Marotti, M, Arbane, G, Bonner, S, Hugill, K, Reid, J, Welters, I, Waugh, V, Williams, K, Shaw, D, J Fernandez Roman, M Lopez Martinez, Johnson, E, Waite, A, Johnston, B, Hamilton, D, Mulla, S, Mcphail, M, Smith, J, K Baillie, J, Barclay, L, Hope, D, Mcculloch, C, Mcquillan, L, Clark, S, Singleton, J, Priestley, K, Rea, N, Callaghan, M, Campbell, R, Andrew, G, Marshall, L, Mckechnie, S, Hutton, P, Bashyal, A, Davidson, N, Summers, C, Polgarova, P, Stroud, K, Pathan, N, Elston, K, Agrawal, S, Battle, C, Newey, L, Rees, T, Harford, R, Brinkworth, E, Williams, M, Murphy, C, White, I, Croft, M, Bandla, N, Gellamucho, M, Tomlinson, J, Turner, H, Davies, M, Quinn, A, Hussain, I, Thompson, C, Parker, H, Bradley, R, Griffiths, R, Scriven, J, Nilsson, A, Bates, M, Dasgin, J, Gill, J, Puxty, A, Cathcart, S, Salutous, D, Turner, L, Duffy, K, Puxty, K, Joseph, A, Herdman-Grant, R, Simms, R, Swain, A, Naranjo, A, Crowe, R, Sollesta, K, Loveridge, A, Baptista, D, Morino, E, Davey, M, Golden, D, Jones, J, J Moreno Cuesta, Haldeos, A, Bakthavatsalam, D, Vincent, R, Elhassan, M, Xavier, K, Ganesan, A, Purohit, D, Abdelrazik, M, Morgan, J, Akeroyd, L, Bano, S, Lawton, T, Warren, D, Bromley, M, Sellick, K, Gurr, L, Wilkinson, B, Nagarajan, V, Szedlak, P, Cupitt, J, Stoddard, E, Benham, L, Preston, S, Laha, S, Slawson, N, Bradshaw, Z, Brown, J, Caswell, M, Melling, S, Bamford, P, Faulkner, M, Cawley, K, Jeffrey, H, London, E, Sainsbury, H, Nagra, I, Nasir, F, Dunmore, C, Jones, R, Abraheem, A, Al-Moasseb, M, Girach, R, Padden, G, Egan, J, Brantwood, C, Alexander, P, Bradley-Potts, J, Allen, S, Felton, T, Manna, S, Farnell-Ward, S, Leaver, S, Queiroz, J, Maccacari, E, Dawson, D, C Castro Delgado, R Pepermans Saluzzio, Ezeobu, O, Ding, L, Sicat, C, Kanu, R, Durrant, G, Texeira, J, Harrison, A, Samakomva, T, Willis, H, Hopkins, B, Thrasyvoulou, L, Jackson, M, Zaki, A, Tibke, C, Bennett, S, Woodyatt, W, Kent, A, Goodwin, E, Brandwood, C, Clark, R, Smith, L, Rooney, K, Thomson, N, 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Konrad [0000-0002-0010-370X], Walker, Susan [0000-0002-5016-6426], Fourman, Max Head [0000-0001-7381-2278], Russell, Clark D [0000-0002-9873-8243], Gountouna, Elvina [0000-0001-7870-2780], Wang, Bo [0000-0002-1580-797X], Wu, Yang [0000-0002-0128-7280], Kousathanas, Athanasios [0000-0001-6265-6521], Moutsianas, Loukas [0000-0001-5453-345X], Zhai, Ranran [0000-0002-5834-9120], Beale, Rupert [0000-0002-6705-8560], Keating, Sean [0000-0001-8552-5604], Haley, Chris [0000-0002-9811-0210], Porteous, David J [0000-0003-1249-6106], Hayward, Caroline [0000-0002-9405-9550], Yang, Jian [0000-0003-2001-2474], Knight, Julian [0000-0002-0377-5536], Summers, Charlotte [0000-0002-7269-2873], Shankar-Hari, Manu [0000-0002-5338-2538], Turtle, Lance [0000-0002-0778-1693], Moore, Shona C [0000-0001-8610-2806], Hinds, Charles [0000-0001-5094-8324], McAuley, Danny [0000-0002-3283-1947], Montgomery, Hugh [0000-0001-8797-5019], Renieri, Alessandra [0000-0002-0846-9220], Shen, Xia [0000-0003-4390-1979], 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J., Ye, C., Weldon, C. H., Filshtein-Sonmez, T., Coker, D., Symons, A., Esparza-Gordillo, J., Aslibekyan, S., Auton, A., Krieger, J. E., Marques, E., Jannes, C. E., Mari, F., Daga, S., Baldassarri, M., Benetti, E., Furini, S., Fallerini, C., Fava, F., Valentino, F., Doddato, G., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Pinto, A. M., Frullanti, E., Mencarelli, M. A., Rizzo, C. L., Montagnani, F., Di Sarno, L., Tommasi, A., Palmieri, M., Emiliozzi, A., Fabbiani, M., Rossetti, B., Zanelli, G., Bargagli, E., Bergantini, L., D'Alessandro, M., Cameli, P., Bennet, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Spertilli, C., Feri, M., Donati, A., Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Spagnesi, M., Piacentini, P., Bandini, M., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Ognibene, A., Vaghi, M., D'Arminio Monforte, A., Merlini, E., Mondelli, M. U., Mantovani, S., Ludovisi, S., Girardis, M., Venturelli, S., Sita, M., Cossarizza, A., Antinori, A., Vergori, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Gatti, F., Parisi, S. G., Castelli, F., Quiros-Roldan, M. E., Magro, P., Zanella, I., Della Monica, M., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Merla, G., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, M., Masucci, L., Valente, S., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Baratti, S., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Bosio, G., Martinelli, E., Mancarella, S., Tavecchia, L., Crotti, L., Picchiotti, N., Gori, M., Gabbi, C., Sanarico, M., Ceri, S., Pinoli, P., Raimondi, F., Biscarini, F., Stella, A., Shen, X., Ponting, C. P., Fawkes, A., Tenesa, A., Caulfield, M., Scott, R., Rowan, K., Murphy, L., Openshaw, P. J. M., Semple, M. G., Vitart, V., and Wilson, J. F.

Subjects
0301 basic medicine, Male, CCR2, Chromosomes, Human, Pair 21, Genome-wide association study, Receptor, Interferon alpha-beta, Disease, Bioinformatics, Genome-wide association studies, 23andMe Investigators, Interferon alpha-beta, 0302 clinical medicine, Receptors, 2',5'-Oligoadenylate Synthetase, Pair 12, genetics, Lung, BRACOVID Investigators, Multidisciplinary, GenOMICC Investigators, Tyrosine kinase 2, 030220 oncology & carcinogenesis, Multigene Family, Medical genetics, Female, Dipeptidyl-Peptidases and Tripeptidyl-Peptidase, 5'-Oligoadenylate Synthetase, Human, Receptor, medicine.medical_specialty, Critical Care, Receptors, CCR2, General Science & Technology, Critical Illness, Chromosomes, 03 medical and health sciences, Intensive care, Mendelian randomization, Immunogenetics, medicine, Humans, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Gen-COVID Investigators, Inflammation, TYK2 Kinase, Chromosomes, Human, Pair 12, Pair 19, SARS-CoV-2, business.industry, Drug Repositioning, COVID-19, United Kingdom, COVID-19 Human Genetics Initiative, 030104 developmental biology, Viral infection, Chromosomes, Human, Pair 19, Genome-Wide Association Study, Pharmacogenomics, ISARICC Investigators, Pair 21, 2', business
Abstract

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079,P=1.65×10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1,OAS2andOAS3); on chromosome 19p13.2 (rs74956615,P=2.3×10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069,P=3.98× 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757,P=4.99×10−8) in the interferon receptor geneIFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression ofIFNAR2, or high expression ofTYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptorCCR2is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.

Published
2020
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19. CLSTN3β enforces adipocyte multilocularity to facilitate lipid utilization

Author

Qian, Kevin, primary, Tol, Marcus J., additional, Wu, Jin, additional, Uchiyama, Lauren F., additional, Xiao, Xu, additional, Cui, Liujuan, additional, Bedard, Alexander H., additional, Weston, Thomas A., additional, Rajendran, Pradeep S., additional, Vergnes, Laurent, additional, Shimanaka, Yuta, additional, Yin, Yesheng, additional, Jami-Alahmadi, Yasaman, additional, Cohn, Whitaker, additional, Bajar, Bryce T., additional, Lin, Chia-Ho, additional, Jin, Benita, additional, DeNardo, Laura A., additional, Black, Douglas L., additional, Whitelegge, Julian P., additional, Wohlschlegel, James A., additional, Reue, Karen, additional, Shivkumar, Kalyanam, additional, Chen, Feng-Jung, additional, Young, Stephen G., additional, Li, Peng, additional, and Tontonoz, Peter, additional

Published
2022
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20. Using DNA sequencing data to quantify T cell fraction and therapy response

Author

Javier Herrero, Gary Middleton, Charles Swanton, John Edwards, Ricky Thakrar, David Pearce, Domenic Marrone, Mickael Escudero, Christian Ottensmeier, Francisco Gimeno Valiente, Jonas Demeulemeester, James Black, Kevin Litchfield, Claire Wilson, Neal Navani, Helen Lowe, JAMES READING, Nicholas McGranahan, Diana Johnson, Hugo Aerts, Benny Chain, Miljana Tanic, and Robert Hynds

Subjects
Multidisciplinary, Tumor-infiltrating lymphocytes, Somatic cell, T-cell receptor excision circles, medicine.medical_treatment, T cell, Ipilimumab, Immunotherapy, Biology, medicine.anatomical_structure, Immune system, medicine, Cancer research, Exome, medicine.drug
Abstract

The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy1,2. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-α gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31–32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes. A robust, cost-effective technique based on whole-exome sequencing data can be used to characterize immune infiltrates, relate the extent of these infiltrates to somatic changes in tumours, and enables prediction of tumour responses to immune checkpoint inhibition therapy.

Published
2021
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21. A core viral protein binds host nucleosomes to sequester immune danger signals

Author

Avgousti, Daphne C., Herrmann, Christin, Kulej, Katarzyna, Pancholi, Neha J., Sekulic, Nikolina, Petrescu, Joana, Molden, Rosalynn C., Blumenthal, Daniel, Paris, Andrew J., Reyes, Emigdio D., Ostapchuk, Philomena, Hearing, Patrick, Seeholzer, Steven H., Worthen, G. Scott, Black, Ben E., Garcia, Benjamin A., and Weitzman, Matthew D.

Subjects
Protein binding -- Observations, Immune response -- Observations, Host-virus relationships -- Observations, Viral proteins -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Viral proteins mimic host protein structure and function to redirect cellular processes and subvert innate defenses (1). Small basic proteins compact and regulate both viral and cellular DNA genomes. Nucleosomes are the repeating units of cellular chromatin and play an important part in innate immune responses (2). Viral-encoded core basic proteins compact viral genomes, but their impact on host chromatin structure and function remains unexplored. Adenoviruses encode a highly basic protein called protein VII that resembles cellular histones (3). Although protein VII binds viral DNA and is incorporated with viral genomes into virus particles (4,5), it is unknown whether protein VII affects cellular chromatin. Here we show that protein VII alters cellular chromatin, leading us to hypothesize that this has an impact on antiviral responses during adenovirus infection in human cells. We find that protein VII forms complexes with nucleosomes and limits DNA accessibility. We identified post-translational modifications on protein VII that are responsible for chromatin localization. Furthermore, proteomic analysis demonstrated that protein VII is sufficient to alter the protein composition of host chromatin. We found that protein VII is necessary and sufficient for retention in the chromatin of members of the high-mobility-group protein B family (HMGB1, HMGB2 and HMGB3). HMGB1 is actively released in response to inflammatory stimuli and functions as a danger signal to activate immune responses (6,7). We showed that protein VII can directly bind HMGB1 in vitro and further demonstrated that protein VII expression in mouse lungs is sufficient to decrease inflammation-induced HMGB1 content and neutrophil recruitment in the bronchoalveolar lavage fluid. Together, our in vitro and in vivo results show that protein VII sequesters HMGB1 and can prevent its release. This study uncovers a viral strategy in which nucleosome binding is exploited to control extracellular immune signalling., As viruses commandeer cellular functions to promote viral production, they induce numerous cellular changes. Manipulation of host chromatin is important for viral takeover of cellular functions (1,8-11). Although there are [...]

Published
2016

23. Biodiversity impacts of the 2019–2020 Australian megafires

Author

Driscoll, Don A., Macdonald, Kristina J., Gibson, Rebecca K., Doherty, Tim S., Nimmo, Dale G., Nolan, Rachael H., Ritchie, Euan G., Williamson, Grant J., Heard, Geoffrey W., Tasker, Elizabeth M., Bilney, Rohan, Porch, Nick, Collett, Rachael A., Crates, Ross A., Hewitt, Alison C., Pendall, Elise, Boer, Matthias M., Gates, Jody, Boulton, Rebecca L., Mclean, Christopher M., Groffen, Heidi, Maisey, Alex C., Beranek, Chad T., Ryan, Shelby A., Callen, Alex, Hamer, Andrew J., Stauber, Andrew, Daly, Garry J., Gould, John, Klop-Toker, Kaya L., Mahony, Michael J., Kelly, Oliver W., Wallace, Samantha L., Stock, Sarah E., Weston, Christopher J., Volkova, Liubov, Black, Dennis, Gibb, Heloise, Grubb, Joshua J., McGeoch, Melodie A., Murphy, Nick P., Lee, Joshua S., Dickman, Chris R., Neldner, Victor J., Ngugi, Michael R., Miritis, Vivianna, Köhler, Frank, Perri, Marc, Denham, Andrew J., Mackenzie, Berin D. E., Reid, Chris A. M., Rayment, Julia T., Arriaga-Jiménez, Alfonsina, Hewins, Michael W., Hicks, Andrew, Melbourne, Brett A., Davies, Kendi F., Bitters, Matthew E., Linley, Grant D., Greenville, Aaron C., Webb, Jonathan K., Roberts, Bridget, Letnic, Mike, Price, Owen F., Walker, Zac C., Murray, Brad R., Verhoeven, Elise M., Thomsen, Alexandria M., Keith, David, Lemmon, Jedda S., Ooi, Mark K. J., Allen, Vanessa L., Decker, Orsi T., Green, Peter T., Moussalli, Adnan, Foon, Junn K., Bryant, David B., Walker, Ken L., Bruce, Matthew J., Madani, George, Tscharke, Jeremy L., Wagner, Benjamin, Nitschke, Craig R., Gosper, Carl R., Yates, Colin J., Dillon, Rebecca, Barrett, Sarah, Spencer, Emma E., Wardle, Glenda M., Newsome, Thomas M., Pulsford, Stephanie A., Singh, Anu, Roff, Adam, Marsh, Karen J., Mcdonald, Kye, Howell, Lachlan G., Lane, Murraya R., Cristescu, Romane H., Witt, Ryan R., Cook, Emma J., Grant, Felicity, Law, Bradley S., Seddon, Julian, Berris, Karleah K., Shofner, Ryan M., Barth, Mike, Welz, Torran, Foster, Alison, Hancock, David, Beitzel, Matthew, Tan, Laura X. L., Waddell, Nathan A., Fallow, Pamela M., Schweickle, Laura, Le Breton, Tom D., Dunne, Craig, Green, Mikayla, Gilpin, Amy-Marie, Cook, James M., Power, Sally A., Hogendoorn, Katja, Brawata, Renee, Jolly, Chris J., Tozer, Mark, Reiter, Noushka, and Phillips, Ryan D.

Abstract

With large wildfires becoming more frequent1,2, we must rapidly learn how megafires impact biodiversity to prioritize mitigation and improve policy. A key challenge is to discover how interactions among fire-regime components, drought and land tenure shape wildfire impacts. The globally unprecedented3,42019–2020 Australian megafires burnt more than 10 million hectares5, prompting major investment in biodiversity monitoring. Collated data include responses of more than 2,000 taxa, providing an unparalleled opportunity to quantify how megafires affect biodiversity. We reveal that the largest effects on plants and animals were in areas with frequent or recent past fires and within extensively burnt areas. Areas burnt at high severity, outside protected areas or under extreme drought also had larger effects. The effects included declines and increases after fire, with the largest responses in rainforests and by mammals. Our results implicate species interactions, dispersal and extent of in situ survival as mechanisms underlying fire responses. Building wildfire resilience into these ecosystems depends on reducing fire recurrence, including with rapid wildfire suppression in areas frequently burnt. Defending wet ecosystems, expanding protected areas and considering localized drought could also contribute. While these countermeasures can help mitigate the impacts of more frequent megafires, reversing anthropogenic climate change remains the urgent broad-scale solution.

Published
2024
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24. A protein assembly mediates Xist localization and gene silencing

Author

Chun-Kan Chen, Douglas L. Black, Anthony Chau, Yolanda Markaki, Andrey Damianov, Sika Zheng, Shan Sabri, Mitchell Guttman, Bernadett Papp, Constantinos Chronis, Amy Pandya-Jones, Jacques Serizay, Xiao-Jun Wang, Walter R. Mancia Leon, Tsotne Chitiashvili, Robin McKee, Heinrich Leonhardt, and Kathrin Plath

Subjects
Male, General Science & Technology, 1.1 Normal biological development and functioning, In situ hybridization, Heterogeneous-Nuclear Ribonucleoproteins, Fluorescence, Article, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Nuclear Matrix-Associated Proteins, Underpinning research, X Chromosome Inactivation, Transcription (biology), Gene expression, Genetics, Animals, Humans, Gene silencing, Gene Silencing, In Situ Hybridization, Fluorescence, In Situ Hybridization, CELF1 Protein, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Chemistry, RNA-Binding Proteins, A protein, RNA, Cell biology, DNA-Binding Proteins, Cell culture, RNA, Long Noncoding, Female, Long Noncoding, XIST, Generic health relevance, 030217 neurology & neurosurgery, Polypyrimidine Tract-Binding Protein
Abstract

Nuclear compartments have diverse roles in regulating gene expression, yet the molecular forces and components that drive compartment formation remain largely unclear1. The long non-coding RNA Xist establishes an intra-chromosomal compartment by localizing at a high concentration in a territory spatially close to its transcription locus2 and binding diverse proteins3-5 to achieve X-chromosome inactivation (XCI)6,7. The XCI process therefore serves as a paradigm for understanding how RNA-mediated recruitment of various proteins induces a functional compartment. The properties of the inactive X (Xi)-compartment are known to change over time, because after initial Xist spreading and transcriptional shutoff a state is reached in which gene silencing remains stable even if Xist is turned off8. Here we show that the Xist RNA-binding proteins PTBP19, MATR310, TDP-4311 and CELF112 assemble on the multivalent E-repeat element of Xist7 and, via self-aggregation and heterotypic protein-protein interactions, form a condensate1 in the Xi. This condensate is required for gene silencing and for the anchoring of Xist to the Xi territory, and can be sustained in the absence of Xist. Notably, these E-repeat-binding proteins become essential coincident with transition to the Xist-independent XCI phase8, indicating that the condensate seeded by the E-repeat underlies the developmental switch from Xist-dependence to Xist-independence. Taken together, our data show that Xist forms the Xi compartment by seeding a heteromeric condensate that consists of ubiquitous RNA-binding proteins, revealing an unanticipated mechanism for heritable gene silencing.

Published
2020

25. Plasma proteomic associations with genetics and health in the UK Biobank

Author

Sun, Benjamin B., Chiou, Joshua, Traylor, Matthew, Benner, Christian, Hsu, Yi-Hsiang, Richardson, Tom G., Surendran, Praveen, Mahajan, Anubha, Robins, Chloe, Vasquez-Grinnell, Steven G., Hou, Liping, Kvikstad, Erika M., Burren, Oliver S., Davitte, Jonathan, Ferber, Kyle L., Gillies, Christopher E., Hedman, Åsa K., Hu, Sile, Lin, Tinchi, Mikkilineni, Rajesh, Pendergrass, Rion K., Pickering, Corran, Prins, Bram, Baird, Denis, Chen, Chia-Yen, Ward, Lucas D., Deaton, Aimee M., Welsh, Samantha, Willis, Carissa M., Lehner, Nick, Arnold, Matthias, Wörheide, Maria A., Suhre, Karsten, Kastenmüller, Gabi, Sethi, Anurag, Cule, Madeleine, Raj, Anil, Burkitt-Gray, Lucy, Melamud, Eugene, Black, Mary Helen, Fauman, Eric B., Howson, Joanna M. M., Kang, Hyun Min, McCarthy, Mark I., Nioi, Paul, Petrovski, Slavé, Scott, Robert A., Smith, Erin N., Szalma, Sándor, Waterworth, Dawn M., Mitnaul, Lyndon J., Szustakowski, Joseph D., Gibson, Bradford W., Miller, Melissa R., and Whelan, Christopher D.

Abstract

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into transpQTLs across multiple biological domains, highlight genetic influences on ligand–receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABOblood group and FUT2secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public–private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.

Published
2023
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26. Act now before Ukraine war plunges millions into malnutrition

Author

Osendarp, Saskia, primary, Verburg, Gerda, additional, Bhutta, Zulfiqar, additional, Black, Robert E., additional, de Pee, Saskia, additional, Fabrizio, Cecilia, additional, Headey, Derek, additional, Heidkamp, Rebecca, additional, Laborde, David, additional, and Ruel, Marie T., additional

Published
2022
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27. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity

Author

Wahl, Simone, Drong, Alexander, Lehne, Benjamin, Loh, Marie, Scott, William R., Kunze, Sonja, Tsai, Pei-Chien, Ried, Janina S., Zhang, Weihua, Yang, Youwen, Tan, Sili, Fiorito, Giovanni, Franke, Lude, Guarrera, Simonetta, Kasela, Silva, Kriebel, Jennifer, Richmond, Rebecca C., Adamo, Marco, Afzal, Uzma, Ala-Korpela, Mika, Albetti, Benedetta, Ammerpohl, Ole, Apperley, Jane F., Beekman, Marian, Bertazzi, Pier Alberto, Black, Lucas S., Blancher, Christine, Bonder, Marc-Jan, Brosch, Mario, Carstensen-Kirberg, Maren, de Craen, Anton J. M., de Lusignan, Simon, Dehghan, Abbas, Elkalaawy, Mohamed, Fischer, Krista, Franco, Oscar H., Gaunt, Tom R., Hampe, Jochen, Hashemi, Majid, Isaacs, Aaron, Jenkinson, Andrew, Jha, Sujeet, Kato, Norihiro, Krogh, Vittorio, Laffan, Michael, Meisinger, Christa, Meitinger, Thomas, Mok, Zuan Yu, Motta, Valeria, Ng, Hong Kiat, Nikolakopoulou, Zacharoula, Nteliopoulos, Georgios, Panico, Salvatore, Pervjakova, Natalia, Prokisch, Holger, Rathmann, Wolfgang, Roden, Michael, Rota, Federica, Rozario, Michelle Ann, Sandling, Johanna K., Schafmayer, Clemens, Schramm, Katharina, Siebert, Reiner, Slagboom, Eline P., Soininen, Pasi, Stolk, Lisette, Strauch, Konstantin, Tai, E-Shyong, Tarantini, Letizia, Thorand, Barbara, Tigchelaar, Ettje F., Tumino, Rosario, Uitterlinden, Andre G., van Duijn, Cornelia, van Meurs, Joyce B. J., Vineis, Paolo, Wickremasinghe, Ananda Rajitha, Wijmenga, Cisca, Yang, Tsun-Po, Yuan, Wei, Zhernakova, Alexandra, Batterham, Rachel L., Smith, George Davey, Deloukas, Panos, Heijmans, Bastiaan T., Herder, Christian, Hofman, Albert, Lindgren, Cecilia M., Milani, Lili, van der Harst, Pim, Peters, Annette, Illig, Thomas, Relton, Caroline L., Waldenberger, Melanie, Jürvelin, Marjo-Riitta, Bollati, Valentina, Soong, Richie, Spector, Tim D., Scott, James, McCarthy, Mark I., Elliott, Paul, Bell, Jordana T., Matullo, Giuseppe, Gieger, Christian, Kooner, Jaspal S., Grallert, Harald, and Chambers, John C.

Published
2017
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28. The evolution of lung cancer and impact of subclonal selection in TRACERx.

Author

Frankell, Alexander M., Dietzen, Michelle, Al Bakir, Maise, Lim, Emilia L., Karasaki, Takahiro, Ward, Sophia, Veeriah, Selvaraju, Colliver, Emma, Huebner, Ariana, Bunkum, Abigail, Hill, Mark S., Grigoriadis, Kristiana, Moore, David A., Black, James R. M., Liu, Wing Kin, Thol, Kerstin, Pich, Oriol, Watkins, Thomas B. K., Naceur-Lombardelli, Cristina, and Cook, Daniel E.

Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome. [ABSTRACT FROM AUTHOR]

Published
2023
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29. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.

Author

Abbosh, Christopher, Frankell, Alexander M., Harrison, Thomas, Kisistok, Judit, Garnett, Aaron, Johnson, Laura, Veeriah, Selvaraju, Moreau, Mike, Chesh, Adrian, Chaunzwa, Tafadzwa L., Weiss, Jakob, Schroeder, Morgan R., Ward, Sophia, Grigoriadis, Kristiana, Shahpurwalla, Aamir, Litchfield, Kevin, Puttick, Clare, Biswas, Dhruva, Karasaki, Takahiro, and Black, James R. M.

Abstract

Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer. [ABSTRACT FROM AUTHOR]

Published
2023
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30. Antibodies against endogenous retroviruses promote lung cancer immunotherapy.

Author

Ng, Kevin W., Boumelha, Jesse, Enfield, Katey S. S., Almagro, Jorge, Cha, Hongui, Pich, Oriol, Karasaki, Takahiro, Moore, David A., Salgado, Roberto, Sivakumar, Monica, Young, George, Molina-Arcas, Miriam, de Carné Trécesson, Sophie, Anastasiou, Panayiotis, Fendler, Annika, Au, Lewis, Shepherd, Scott T. C., Martínez-Ruiz, Carlos, Puttick, Clare, and Black, James R. M.

Abstract

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy. [ABSTRACT FROM AUTHOR]

Published
2023
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31. Genomic–transcriptomic evolution in lung cancer and metastasis.

Author

Martínez-Ruiz, Carlos, Black, James R. M., Puttick, Clare, Hill, Mark S., Demeulemeester, Jonas, Larose Cadieux, Elizabeth, Thol, Kerstin, Jones, Thomas P., Veeriah, Selvaraju, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Prymas, Paulina, Rowan, Andrew, Ward, Sophia, Cubitt, Laura, Athanasopoulou, Foteini, Pich, Oriol, Karasaki, Takahiro, Moore, David A., and Salgado, Roberto

Abstract

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.Computational and machine-learning approaches that integrate genomic and transcriptomic variation from paired primary and metastatic non-small cell lung cancer samples from the TRACERx cohort reveal the role of transcriptional events in tumour evolution. [ABSTRACT FROM AUTHOR]

Published
2023
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33. The human body at cellular resolution: the NIH Human Biomolecular Atlas Program

Author

William J. Greenleaf, Sarah A. Teichmann, Margaret Vella, Ajay Pillai, Aviv Regev, Ananda L. Roy, Kristin E. Burnum-Johnson, Cole Trapnell, Yiing Lin, Marda Jorgensen, Gloria S. Pryhuber, Leslie Gaffney, Ken S. Lau, Kimberly Robasky, Jeffrey M. Spraggins, Chuck McCallum, Stavros Michailidis, Randy Heiland, Orit Rozenblatt-Rosen, Allyson Ricarte, Xin bSun, Kevin J. Otto, Amir Bahmani, Zorina S. Galis, James S. Hagood, Monica Nagendran, Gökcen Eraslan, Robin M. Scibek, Jocelyn Y. Kishi, Jay Mulye, Maria Keays, Griffin M. Weber, Caltech-UW Tmc, Charles Ansong, Nicholas A. Nystrom, Vishal G. Venkataraaman, Vladimir Yu. Kiselev, Ucsd Tmc, Ellen M. Quardokus, Tushar bDesai, Bruce Herr, Engagement Component, James E. Anderson, Shin Lin, Lisel Record, Peter V. Kharchenko, Robert F. dMurphy, Stanford-WashU Tmc, Yu Wang, Jian Ma, Sergio Maffioletti, Sarah Black, Matthew Ruffalo, Salvatore Sechi, John C. Marioni, Ziv Bar-Joseph, Richard M. Caprioli, Stanford Ttd, Garry P. Nolan, Marishka Brown, Elizabeth L. Wilder, Maigan A. Brusko, Peter Chou, Tommaso Biancalani, Christian Martijn Schuerch, Julia Laskin, Richard Conroy, Jonathan C. Silverstein, Paula M. Mabee, Dena Procaccini, Pehr B. Harbury, Michael Snyder, Pothur Srinivas, Jennifer Rood, Dana Jackson, Sanjay Jain, Katy Börner, Visualization HuBMAP Integration, William E. Shirey, Sinem K. Saka, James P. Sluka, Agnes B. Fogo, Isabel Goldaracena, Sushma A. Akoju, Raymond C. Harris, Rahul Satija, Sylvia K. Plevritis, Tim Stuart, Shila Ghazanfar, Peng Yin, Harvard Ttd, Aaron M. Horning, Ed Esplin, Amanda Posgai, Michael J. Clare-Salzler, Raf Van de Plas, Aaron Pawlyk, Guo-Cheng Yuan, Benedict aten, DongHye Ye, Hayan Lee, Eyal Fisher, Jay Shendure, Long Cai, Danielle cGutierrez, Carl Kingsford, Ruben Dries, Sara Ahadi, Paul D. Piehowski, Bernd bBodenmiller, Purdue Ttd, Stephanie A. Nevins, Philip D. Blood, Andrew Butler, W. Christopher Lenhardt, Ying Zhu, Alexander J. Ropelewski, Harry S. Nick, Nathan Heath Patterson, Elizabeth K. Neumann, Anna Hupalowska, Samuel H. Friedman, Clive hWasserfall, Qian Zhu, Mark P. deCaestecker, Leonard E. Cross, Mark A. Atkinson, Paul Macklin, Todd M. Brusko, Eeshit Dhaval Vaishnav, Nils Gehlenborg, and Kun Zhang

Subjects
Male, Models, Anatomic, Aging, Biomedical Research, media_common.quotation_subject, International Cooperation, Art history, Technology development, Molecular resolution, 03 medical and health sciences, 0302 clinical medicine, Atlases as Topic, Computational platforms and environments, Research community, Common fund, Humans, Molecular Biology, 030304 developmental biology, media_common, 0303 health sciences, Shared vision, Multidisciplinary, Spatial mapping, Art, Genomics, United States, 3. Good health, Cellular resolution, National Institutes of Health (U.S.), Health, Organ Specificity, Perspective, Female, Single-Cell Analysis, 030217 neurology & neurosurgery
Abstract

Transformative technologies are enabling the construction of three-dimensional maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible three-dimensional molecular and cellular atlas of the human body, in health and under various disease conditions., HuBMAP supports technology development, data acquisition, and spatial analyses to generate comprehensive molecular and cellular three-dimensional tissue maps.

Published
2019

34. Noncoding deletions reveal a gene that is critical for intestinal function

Author

Wouter de Laat, Yiwen Zhu, Iris Barshack, Corina Hartman, Devin Coleman-Derr, Christopher N. Mayhew, Robert Kleta, E.K. Ruzzo, Diane E. Dickel, Brian L. Black, James M. Wells, Ralston M. Barnes, E.S. Vos, Ifat Bar-Joseph, Matthew F. Kuhar, Yair Anikster, Horia Stanescu, Roni Milgrom, Pavlo Tatarskyy, David Goldstein, Amy Pitstick, Haike Reznik-Wolf, Marco Osterwalder, Axel Visel, Mehmet Tekman, Denise M. Imai, Raanan Shamir, Ben Pode-Shakked, Len A. Pennacchio, Danit Oz-Levi, Kelly Lammerts van Bueren, Rivka Shapiro, Iros Barozzi, Yujun Han, Dina Marek-Yagel, Tsviya Olender, Anna Alkelai, Veena Afzal, Elon Pras, Batia Weiss, Alexander Nord, Michael Schvimer, Doron Lancet, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Male, animal diseases, Intestines/physiology, Transgenic, Transcriptome, Mice, 0302 clinical medicine, Genes, Reporter, Pair 16/genetics, Sequence Deletion/genetics, 2.1 Biological and endogenous factors, Developmental, Transgenes, Aetiology, Sequence Deletion, Mice, Knockout, Genetics, Regulation of gene expression, 0303 health sciences, Multidisciplinary, Gene Expression Regulation, Developmental, virus diseases, Transcriptome/genetics, Phenotype, Pedigree, 3. Good health, Intestines, Enhancer Elements, Genetic, Regulatory sequence, Genetic Loci/genetics, Female, Chromosomes, Human, Pair 16/genetics, Human, Biotechnology, Diarrhea, Transcriptional Activation, Genetically modified mouse, Enhancer Elements, Transgenes/genetics, General Science & Technology, Knockout, Transgene, Mice, Transgenic, Biology, Chromosomes, 03 medical and health sciences, Oral and Gastrointestinal, Genetic, Animals, Humans, Reporter, Gene, Genetic/genetics, 030304 developmental biology, Pair 16, Animal, Enhancer Elements, Genetic/genetics, Human Genome, Diarrhea/congenital, Disease Models, Animal, Open reading frame, Gene Expression Regulation, Genes, Genetic Loci, Disease Models, Digestive Diseases, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery
Abstract

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.

Published
2019
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35. Noncoding Deletions Expose a Novel Gene Critical for Intestinal Function

Author

Oz-Levi, Danit, Olender, Tsviya, Bar-Joseph, Ifat, Zhu, Yiwen, Marek-Yagel, Dina, Barozzi, Iros, Osterwalder, Marco, Alkelai, Anna, Ruzzo, Elizabeth K., Han, Yujun, Vos, Erica S. M., Reznik-Wolf, Haike, Hartman, Corina, Shamir, Raanan, Weiss, Batia, Shapiro, Rivka, Pode-Shakked, Ben, Tatarskyy, Pavlo, Milgrom, Roni, Schvimer, Michael, Barshack, Iris, Imai, Denise M., Coleman-Derr, Devin, Dickel, Diane E., Nord, Alex S., Afzal, Veena, van Bueren, Kelly Lammerts, Barnes, Ralston M., Black, Brian L., Mayhew, Christopher N., Kuhar, Matthew F., Pitstick, Amy, Tekman, Mehmet, Stanescu, Horia C., Wells, James M., Kleta, Robert, de Laat, Wouter, Goldstein, David B., Pras, Elon, Visel, Axel, Lancet, Doron, Anikster, Yair, and Pennacchio, Len A.

Subjects
Diarrhea, Male, Mice, Knockout, Transcriptional Activation, Gene Expression Regulation, Developmental, Mice, Transgenic, Article, Pedigree, Intestines, Disease Models, Animal, Mice, Enhancer Elements, Genetic, Phenotype, Genes, Genes, Reporter, Genetic Loci, Animals, Humans, Female, Transgenes, Transcriptome, Chromosomes, Human, Pair 16, Sequence Deletion
Abstract

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants

Published
2019

36. Fatty acid transport protein 2 reprograms neutrophils in cancer

Author

Brian Nam, Zach Schug, Fang Wang, Vladimir A. Tyurin, Maureen E. Murphy, Alessandra De Leo, Maria Blasi, Paul N. Black, Cindy Lin, Subhasree Basu, Michael J. Guarino, Valerian E. Kagan, Charles Mulligan, Robert H. Vonderheide, Yulia Nefedova, Dmitry I. Gabrilovich, Paul M. Lieberman, Filippo Veglia, Laxminarasimha Donthireddy, Concetta C. DiRusso, Gregory A. Masters, Tsun Ki Jerrick To, Andrew V. Kossenkov, Emanuela Ricciotti, and Neil Hockstein

Subjects
0301 basic medicine, Multidisciplinary, biology, Chemistry, Cancer, medicine.disease, 3. Good health, Transport protein, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Immune system, Downregulation and upregulation, 030220 oncology & carcinogenesis, medicine, biology.protein, Cancer research, Arachidonic acid, Prostaglandin E2, Transcription factor, STAT5, medicine.drug
Abstract

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that are crucial for the regulation of immune responses in cancer. These cells contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite recent advances in the understanding of PMN-MDSC biology, the mechanisms responsible for the pathological activation of neutrophils are not well defined, and this limits the selective targeting of these cells. Here we report that mouse and human PMN-MDSCs exclusively upregulate fatty acid transport protein 2 (FATP2). Overexpression of FATP2 in PMN-MDSCs was controlled by granulocyte-macrophage colony-stimulating factor, through the activation of the STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSCs. The main mechanism of FATP2-mediated suppressive activity involved the uptake of arachidonic acid and the synthesis of prostaglandin E2. The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSCs and substantially delayed tumour progression. In combination with checkpoint inhibitors, FATP2 inhibition blocked tumour progression in mice. Thus, FATP2 mediates the acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer therapy.

Published
2019
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37. Fatty acid transporter 2 reprograms neutrophils in cancer

Author

Veglia, Filippo, Tyurin, Vladimir A., Blasi, Maria, De Leo, Alessandra, Kossenkov, Andrew, Donthireddy, Laxminarasimha, Jerrick, To Tsun Ki, Schug, Zach, Basu, Subhasree, Wang, Fang, Ricciotti, Emanuela, DiRusso, Concetta, Murphy, Maureen E., Vonderheide, Robert H., Lieberman, Paul M., Mulligan, Charles, Nam, Brian, Hockstein, Neil, Masters, Gregory, Guarino, Michael, Lin, Cindy, Nefedova, Yulia, Black, Paul, Kagan, Valerian E., and Gabrilovich, Dmitry

Subjects
Neutrophils, Neoplasms, Fatty Acids, Humans, Fatty Acid Transport Proteins, Article
Abstract

Summary Polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) are pathologically activated neutrophils that are critically important for the regulation of immune responses in cancer. They contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite the recent advances in understanding of the PMN-MDSC biology, the mechanisms responsible for pathological activation of neutrophils are not well defined, which limits selective targeting of these cells. Here, we report that mouse and human PMN-MDSC exclusively up-regulate fatty acid transporter protein 2 (FATP2). Over-expression of FATP2 in PMN-MDSC was controlled by GM-CSF, through the activation of STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSC. The main mechanism of FATP2 mediated suppressive activity involved uptake of arachidonic acid (AA) and synthesis of prostaglandin E2 (PGE2). The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSC and substantially delayed tumor progression. In combination with check-point inhibitors it blocked tumor progression in mice. Thus, FATP2 mediates acquisition of immune suppressive activity by PMN-MDSC and represents a new target to selectively inhibit the functions of PMN-MDSC and improve the effect of cancer therapy.

Published
2019

38. Hepatocytes direct the formation of a pro-metastatic niche in the liver

Author

Dong Xin, Ailing Ji, Austin L. Chien, Meredith L. Stone, Kathleen Graham, Maria C. de Beer, Ramesh K. Ramanathan, Jae W. Lee, Mitesh J. Borad, Taylor A. Black, Krishna S. Majmundar, Mark H. O'Hara, Devora Delman, Stephanie S. Yee, Stacy K. Thomas, Mingming Gao, Joey H. Li, Abraham Shaked, Paige M. Porrett, Dexi Liu, Xia Hua, Erica L. Carpenter, Whitney L. Gladney, Gregory L. Beatty, Frederick C. de Beer, Charu Aggarwal, Chad A. Komar, Jeffrey C. Thompson, and Nancy R. Webb

Subjects
Male, STAT3 Transcription Factor, 0301 basic medicine, Cell, medicine.disease_cause, Article, Metastasis, Mice, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Tumor Microenvironment, medicine, Animals, Neoplasm Metastasis, Interleukin 6, STAT3, Serum Amyloid A Protein, Tumor microenvironment, Multidisciplinary, biology, Interleukin-6, Liver Neoplasms, Serum amyloid A1, medicine.disease, 3. Good health, Pancreatic Neoplasms, 030104 developmental biology, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hepatocytes, biology.protein, Cancer research, Female, Colorectal Neoplasms, Carcinogenesis, Carcinoma, Pancreatic Ductal
Abstract

The liver is the most common site of metastatic disease1. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a 'pro-metastatic' niche that supports the spread of tumour cells to the liver2,3. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6-STAT3-SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.

Published
2019

40. Comprehensive genomic characterization of head and neck squamous cell carcinomas

Author

Lawrence, Michael S., Sougnez, Carrie, Lichtenstein, Lee, Cibulskis, Kristian, Lander, Eric, Gabriel, Stacey B., Getz, Gad, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, Bowlby, Reanne, Brooks, Denise, Butterfield, Yaron S. N., Carlsen, Rebecca, Cheng, Dean, Chu, Andy, Dhalla, Noreen, Guin, Ranabir, Holt, Robert A., Jones, Steven J. M., Lee, Darlene, Li, Haiyan I., Marra, Marco A., Mayo, Michael, Moore, Richard A., Mungall, Andrew J., Robertson, Gordon A., Schein, Jacqueline E., Sipahimalani, Payal, Tam, Angela, Thiessen, Nina, Wong, Tina, Protopopov, Alexei, Santoso, Netty, Lee, Semin, Parfenov, Michael, Zhang, Jianhua, Mahadeshwar, Harshad S., Tang, Jiabin, Ren, Xiaojia, Seth, Sahil, Haseley, Psalm, Zeng, Dong, Yang, Lixing, Xu, Andrew W., Song, Xingzhi, Pantazi, Angeliki, Bristow, Christopher A., Hadjipanayis, Angela, Seidman, Jonathan, Chin, Lynda, Park, Peter J., Kucherlapati, Raju, Akbani, Rehan, Casasent, Tod, Liu, Wenbin, Lu, Yiling, Mills, Gordon, Motter, Thomas, Weinstein, John, Diao, Lixia, Wang, Jing, Fan, You Hong, Liu, Jinze, Wang, Kai, Auman, Todd J., Balu, Saianand, Bodenheimer, Thomas, Buda, Elizabeth, Hayes, Neil D., Hoadley, Katherine A., Hoyle, Alan P., Jefferys, Stuart R., Jones, Corbin D., Kimes, Patrick K., Liu, Yufeng, Meng, Shaowu, Mieczkowski, Piotr A., Mose, Lisle E., Parker, Joel S., Perou, Charles M., Prins, Jan F., Roach, Jeffrey, Shi, Yan, Simons, Janae V., Singh, Darshan, Soloway, Matthew G., Tan, Donghui, Veluvolu, Umadevi, Walter, Vonn, Waring, Scot, Wilkerson, Matthew D., Wu, Junyuan, Zhao, Ni, Cherniack, Andrew D., Hammerman, Peter S., Tward, Aaron D., Pedamallu, Chandra Sekhar, Saksena, Gordon, Jung, Joonil, Ojesina, Akinyemi I., Carter, Scott L., Zack, Travis I., Schumacher, Steven E., Beroukhim, Rameen, Freeman, Samuel S., Meyerson, Matthew, Cho, Juok, Noble, Michael S., DiCara, Daniel, Zhang, Hailei, Heiman, David I., Gehlenborg, Nils, Voet, Doug, Lin, Pei, Frazer, Scott, Stojanov, Petar, Liu, Yingchun, Zou, Lihua, Kim, Jaegil, Muzny, Donna, Doddapaneni, HarshaVardhan, Kovar, Christie, Reid, Jeff, Morton, Donna, Han, Yi, Hale, Walker, Chao, Hsu, Chang, Kyle, Drummond, Jennifer A., Gibbs, Richard A., Kakkar, Nipun, Wheeler, David, Xi, Liu, Ciriello, Giovanni, Ladanyi, Marc, Lee, William, Ramirez, Ricardo, Sander, Chris, Shen, Ronglai, Sinha, Rileen, Weinhold, Nils, Taylor, Barry S., Aksoy, Arman B., Dresdner, Gideon, Gao, Jianjiong, Gross, Benjamin, Jacobsen, Anders, Reva, Boris, Schultz, Nikolaus, Sumer, Onur S., Sun, Yichao, Chan, Timothy A., Morris, Luc G., Stuart, Joshua, Benz, Stephen, Ng, Sam, Benz, Christopher, Yau, Christina, Baylin, Stephen B., Cope, Leslie, Danilova, Ludmila, Herman, James G., Bootwalla, Moiz, Maglinte, Dennis T., Laird, Peter W., Triche, Timothy, Jr, Weisenberger, Daniel J., Van Den Berg, David J., Agrawal, Nishant, Bishop, Justin, Boutros, Paul C., Bruce, Jeff P., Byers, Lauren Averett, Califano, Joseph, Carey, Thomas E., Chen, Zhong, Cheng, Hui, Chiosea, Simion I., Cohen, Ezra, Diergaarde, Brenda, Egloff, Ann Marie, El-Naggar, Adel K., Ferris, Robert L., Frederick, Mitchell J., Grandis, Jennifer R., Guo, Yan, Haddad, Robert I., Harris, Thomas, Hui, Angela B. Y., Lee, Jack J., Lippman, Scott M., Liu, Fei-Fei, McHugh, Jonathan B., Myers, Jeff, Ng, Patrick Kwok Shing, Perez-Ordonez, Bayardo, Pickering, Curtis R., Prystowsky, Michael, Romkes, Marjorie, Saleh, Anthony D., Sartor, Maureen A., Seethala, Raja, Seiwert, Tanguy Y., Si, Han, Van Waes, Carter, Waggott, Daryl M., Wiznerowicz, Maciej, Yarbrough, Wendell G., Zhang, Jiexin, Zuo, Zhixiang, Burnett, Ken, Crain, Daniel, Gardner, Johanna, Lau, Kevin, Mallery, David, Morris, Scott, Paulauskis, Joseph, Penny, Robert, Shelton, Candace, Shelton, Troy, Sherman, Mark, Yena, Peggy, Black, Aaron D., Bowen, Jay, Frick, Jessica, Gastier-Foster, Julie M., Harper, Hollie A., Leraas, Kristen, Lichtenberg, Tara M., Ramirez, Nilsa C., Wise, Lisa, Zmuda, Erik, Baboud, Julien, Jensen, Mark A., Kahn, Ari B., Pihl, Todd D., Pot, David A., Srinivasan, Deepak, Walton, Jessica S., Wan, Yunhu, Burton, Robert A., Davidsen, Tanja, Demchok, John A., Eley, Greg, Ferguson, Martin L., Shaw, Kenna Mills R., Ozenberger, Bradley A., Sheth, Margi, Sofia, Heidi J., Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean Claude, Saller, Charles, Tarvin, Katherine, Chen, Chu, Bollag, Roni, Weinberger, Paul, Golusiński, Wojciech, Golusiński, Paweł, Ibbs, Matthew, Korski, Konstanty, Mackiewicz, Andrzej, Suchorska, Wiktoria, Szybiak, Bartosz, Curley, Erin, Beard, Christina, Mitchell, Colleen, Sandusky, George, Ahn, Julie, Khan, Zubair, Irish, Jonathan, Waldron, John, William, William N., Jr, Egea, Sophie, Gomez-Fernandez, Carmen, Herbert, Lynn, Bradford, Carol R., Chepeha, Douglas B., Haddad, Andrea S., Jones, Tamara R., Komarck, Christine M., Malakh, Mayya, Moyer, Jeffrey S., Nguyen, Ariane, Peterson, Lisa A., Prince, Mark E., Rozek, Laura S., Taylor, Evan G., Walline, Heather M., Wolf, Gregory T., Boice, Lori, Chera, Bhishamjit S., Funkhouser, William K., Gulley, Margaret L., Hackman, Trevor G., Hayward, Michele C., Huang, Mei, Rathmell, Kimryn W., Salazar, Ashley H., Shockley, William W., Shores, Carol G., Thorne, Leigh, Weissler, Mark C., Wrenn, Sylvia, Zanation, Adam M., Brown, Brandee T., and Pham, Michelle

Published
2015
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41. The structure of [(CENP-A-H4).sub.2] reveals physical features that mark centromeres

Author

Sekulic, Nikolina, Bassett, Emily A., Rogers, Danielle J., and Black, Ben E.

Subjects
Centromeres -- Properties -- Physiological aspects, Proteins -- Structure, Gene expression -- Physiological aspects, Chromatin -- Properties -- Physiological aspects, Histones -- Properties -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Centromeres are specified epigenetically, and the histone H3 variant CENP-A is assembled into the chromatin of all active centromeres (1). Divergence from H3 raises the possibility that CENP-A generates unique chromatin features to mark physically centromere location. Here we report the crystal structure of a subnucleosomal heterotetramer, human [(CENP-A-H4).sub.2], that reveals three distinguishing properties encoded by the residues that comprise the CENP-A targeting domain (CATD; ref. 2): (1) a CENP-A-CENP-A interface that is substantially rotated relative to the H3-H3 interface; (2) a protruding loop L1 of the opposite charge as that on H3; and (3) strong hydrophobic contacts that rigidify the CENP-A-H4 interface. Residues involved in the CENP-A-CENP-A rotation are required for efficient incorporation into centromeric chromatin, indicating specificity for an unconventional nucleosome shape. DNA topological analysis indicates that CENP-A-containing nucleosomes are octameric with conventional left-handed DNA wrapping, in contrast to other recent proposals (3-6). Our results indicate that CENP-A marks centromere location by restructuring the nucleosome from within its folded histone core., Several experiments have identified functionally important portions of CENP-A, whereas others have supported proposals of its assembly onto DNA in atypical histone arrangements. Early attention was given to the amino-terminal [...]

Published
2010
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42. Comprehensive molecular characterization of gastric adenocarcinoma

Author

Bass, Adam J., Thorsson, Vesteinn, Shmulevich, Ilya, Reynolds, Sheila M., Miller, Michael, Bernard, Brady, Hinoue, Toshinori, Laird, Peter W., Curtis, Christina, Shen, Hui, Weisenberger, Daniel J., Schultz, Nikolaus, Shen, Ronglai, Weinhold, Nils, Kelsen, David P., Bowlby, Reanne, Chu, Andy, Kasaian, Katayoon, Mungall, Andrew J., Robertson, Gordon A., Sipahimalani, Payal, Cherniack, Andrew, Getz, Gad, Liu, Yingchun, Noble, Michael S., Pedamallu, Chandra, Sougnez, Carrie, Akbani, Rehan, Lee, Ju-Seog, Liu, Wenbin, Mills, Gordon B., Yang, Da, Zhang, Wei, Pantazi, Angeliki, Gulley, Margaret, Piazuelo, Blanca M., Schneider, Barbara G., Kim, Jihun, Boussioutas, Alex, Sheth, Margi, Demchok, John A., Rabkin, Charles S., Willis, Joseph E., Ng, Sam, Garman, Katherine, Beer, David G., Pennathur, Arjun, Raphael, Benjamin J., Wu, Hsin-Ta, Odze, Robert, Kim, Hark K., Bowen, Jay, Leraas, Kristen M., Lichtenberg, Tara M., Weaver, Stephanie, McLellan, Michael, Wiznerowicz, Maciej, Sakai, Ryo, Lawrence, Michael S., Cibulskis, Kristian, Lichtenstein, Lee, Fisher, Sheila, Gabriel, Stacey B., Lander, Eric S., Ding, Li, Niu, Beifang, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, Brooks, Denise, Butterfield, Yaron S. N., Carlsen, Rebecca, Chu, Justin, Chuah, Eric, Chun, Hye-Jung E., Clarke, Amanda, Dhalla, Noreen, Guin, Ranabir, Holt, Robert A., Jones, Steven J. M., Lee, Darlene, Li, Haiyan A., Lim, Emilia, Ma, Yussanne, Marra, Marco A., Mayo, Michael, Moore, Richard A., Mungall, Karen L., Nip, Ka Ming, Schein, Jacqueline E., Tam, Angela, Thiessen, Nina, Beroukhim, Rameen, Carter, Scott L., Cherniack, Andrew D., Cho, Juok, DiCara, Daniel, Frazer, Scott, Gehlenborg, Nils, Heiman, David I., Jung, Joonil, Kim, Jaegil, Lin, Pei, Meyerson, Matthew, Ojesina, Akinyemi I., Pedamallu, Chandra Sekhar, Saksena, Gordon, Schumacher, Steven E., Stojanov, Petar, Tabak, Barbara, Voet, Doug, Rosenberg, Mara, Zack, Travis I., Zhang, Hailei, Zou, Lihua, Protopopov, Alexei, Santoso, Netty, Parfenov, Michael, Lee, Semin, Zhang, Jianhua, Mahadeshwar, Harshad S., Tang, Jiabin, Ren, Xiaojia, Seth, Sahil, Yang, Lixing, Xu, Andrew W., Song, Xingzhi, Xi, Ruibin, Bristow, Christopher A., Hadjipanayis, Angela, Seidman, Jonathan, Chin, Lynda, Park, Peter J., Kucherlapati, Raju, Ling, Shiyun, Rao, Arvind, Weinstein, John N., Kim, Sang-Bae, Lu, Yiling, Mills, Gordon, Bootwalla, Moiz S., Lai, Phillip H., Triche, Timothy, Jr, Van Den Berg, David J., Baylin, Stephen B., Herman, James G., Murray, Bradley A., Askoy, Arman B., Ciriello, Giovanni, Dresdner, Gideon, Gao, Jianjiong, Gross, Benjamin, Jacobsen, Anders, Lee, William, Ramirez, Ricardo, Sander, Chris, Senbabaoglu, Yasin, Sinha, Rileen, Sumer, Onur S., Sun, Yichao, Thorsson, Vésteinn, Iype, Lisa, Kramer, Roger W., Kreisberg, Richard, Rovira, Hector, Tasman, Natalie, Haussler, David, Stuart, Josh M., Verhaak, Roeland G. W., Leiserson, Mark D. M., Taylor, Barry S., Black, Aaron D., Carney, Julie Ann, Gastier-Foster, Julie M., Helsel, Carmen, McAllister, Cynthia, Ramirez, Nilsa C., Tabler, Teresa R., Wise, Lisa, Zmuda, Erik, Penny, Robert, Crain, Daniel, Gardner, Johanna, Lau, Kevin, Curely, Erin, Mallery, David, Morris, Scott, Paulauskis, Joseph, Shelton, Troy, Shelton, Candace, Sherman, Mark, Benz, Christopher, Lee, Jae-Hyuk, Fedosenko, Konstantin, Manikhas, Georgy, Potapova, Olga, Voronina, Olga, Belyaev, Dmitry, Dolzhansky, Oleg, Rathmell, Kimryn W., Brzezinski, Jakub, Ibbs, Matthew, Korski, Konstanty, Kycler, Witold, Łaźniak, Radoslaw, Leporowska, Ewa, Mackiewicz, Andrzej, Murawa, Dawid, Murawa, Pawel, Spychała, Arkadiusz, Suchorska, Wiktoria M., Tatka, Honorata, Teresiak, Marek, Abdel-Misih, Raafat, Bennett, Joseph, Brown, Jennifer, Iacocca, Mary, Rabeno, Brenda, Kwon, Sun-Young, Kemkes, Ariane, Curley, Erin, Alexopoulou, Iakovina, Engel, Jay, Bartlett, John, Albert, Monique, Park, Do-Youn, Dhir, Rajiv, Luketich, James, Landreneau, Rodney, Janjigian, Yelena Y., Cho, Eunjung, Ladanyi, Marc, Tang, Laura, McCall, Shannon J., Park, Young S., Cheong, Jae-Ho, Ajani, Jaffer, Camargo, Constanza M., Alonso, Shelley, Ayala, Brenda, Jensen, Mark A., Pihl, Todd, Raman, Rohini, Walton, Jessica, Wan, Yunhu, Eley, Greg, Mills Shaw, Kenna R., Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean Claude, Davidsen, Tanja, Hutter, Carolyn M., Sofia, Heidi J., Burton, Robert, Chudamani, Sudha, and Liu, Jia

Published
2014
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43. Comprehensive molecular characterization of urothelial bladder carcinoma

Author

Weinstein, John N., Akbani, Rehan, Broom, Bradley M., Wang, Wenyi, Verhaak, Roeland G. W., McConkey, David, Lerner, Seth, Morgan, Margaret, Creighton, Chad J., Smith, Carolyn, Kwiatkowski, David J., Cherniack, Andrew D., Kim, Jaegil, Pedamallu, Chandra Sekhar, Noble, Michael S., Al-Ahmadie, Hikmat A., Reuter, Victor E., Rosenberg, Jonathan E., Bajorin, Dean F., Bochner, Bernard H., Solit, David B., Koppie, Theresa, Robinson, Brian, Gordenin, Dmitry A., Fargo, David, Klimczak, Leszek J., Roberts, Steven A., Au, Jessie, Laird, Peter W., Hinoue, Toshinori, Schultz, Nikolaus, Ramirez, Ricardo, Hansel, Donna, Hoadley, Katherine A., Kim, William Y., Damrauer, Jeffrey S., Baylin, Stephen B., Mungall, Andrew J., Robertson, Gordon A., Chu., Andy, Sougnez, Carrie, Cibulskis, Kristian, Lichtenstein, Lee, Sivachenko, Andrey, Stewart, Chip, Lawrence, Michael S., Getz, Gad, Lander, Eric, Gabriel., Stacey B., Donehower, Lawrence, Carter, Scott L., Saksena, Gordon, Schumacher, Steven E., Freeman, Samuel S., Jung, Joonil, Bhatt, Ami S., Pugh, Trevor, Beroukhim, Rameen, Gabriel, Stacey B., Meyerson, Matthew, Chu, Andy, Ally, Adrian, Balasundaram, Miruna, Butterfield, Yaron S. N., Dhalla, Noreen, Hirst, Carrie, Holt, Robert A., Jones, Steven J. M., Lee, Darlene, Li, Haiyan I., Marra, Marco A., Mayo, Michael, Moore, Richard A., Schein, Jacqueline E., Sipahimalani, Payal, Tam, Angela, Thiessen, Nina, Wong, Tina, Wye, Natasja, Bowlby, Reanne, Chuah, Eric, Guin, Ranabir, Shen, Hui, Bootwalla, Moiz S., Jr, Timothy Triche, Lai, Phillip H., Van Den Berg, David J., Weisenberger, Daniel J., Balu, Saianand, Bodenheimer, Tom, Damrauer Alan P. Hoyle, Jeffrey S., Jefferys, Stuart R., Meng, Shaowu, Mose, Lisle E., Simons, Janae V., Soloway, Mathew G., Wu, Junyuan, Parker, Joel S., Hayes, Neil D., Roach, Jeffrey, Buda, Elizabeth, Jones, Corbin D., Mieczkowski, Piotr A., Tan, Donghui, Veluvolu, Umadevi, Waring, Scot, Auman, Todd J., Perou, Charles M., Wilkerson, Matthew D., Santoso, Netty, Parfenov, Michael, Ren, Xiaojia, Pantazi, Angeliki, Hadjipanayis, Angela, Seidman, Jonathan, Kucherlapati, Raju, Lee, Semin, Yang, Lixing, Park, Peter J., Xu, Andrew Wei, Protopopov, Alexei, Zhang, Jianhua, Bristow, Christopher, Mahadeshwar, Harshad S., Seth, Sahil, Song, Xingzhi, Tang, Jiabin, Zeng, Dong, Chin, Lynda, Guo, Charles, Casasent, Tod D., Liu, Wenbin, Ju, Zhenlin, Motter, Thomas, Peng, Bo, Ryan, Michael, Su, Xiaoping, Yang, Ji-Yeon, Lorenzi, Philip L., Yao, Hui, Zhang, Nianxiang, Zhang, Jiexin, Mills, Gordon B., Cho, Juok, DiCara, Daniel, Frazer, Scott, Gehlenborg, Nils, Heiman, David I., Lin, Pei, Liu, Yingchun, Stojanov, Petar, Voet, Doug, Zhang, Hailei, Zou, Lihua, Bernard, Brady, Kreisberg, Dick, Reynolds, Sheila, Rovira, Hector, Shmulevich, Ilya, Gao, Jianjiong, Jacobsen, Anders, Aksoy, Arman B., Antipin, Yevgeniy, Ciriello, Giovanni, Dresdner, Gideon, Gross, Benjamin, Lee, William, Reva, Boris, Shen, Ronglai, Sinha, Rileen, Sumer, Onur S., Weinhold, Nils, Ladanyi, Marc, Sander, Chris, Benz, Christopher, Carlin, Daniel, Haussler, David, Ng, Sam, Paull, Evan O., Stuart, Joshua, Zhu, Jing, Liu, Yuexin, Zhang, Wei, Taylor, Barry S., Lichtenberg, Tara M., Zmuda, Erik, Barr, Thomas, Black, Aaron D., George, Myra, Hanf, Benjamin, Helsel, Carmen, McAllister, Cynthia, Ramirez, Nilsa C., Tabler, Teresa R., Weaver, Stephanie, Wise, Lisa, Bowen, Jay, Gastier-Foster, Julie M., Jian, Weiguo, Tello, Sebrina, Ittman, Michael, Castro, Patricia, McClenden, Whitney D., Gibbs, Richard, Saller, Charles, Tarvin, Katherine, DiPiero, Jennifer M., Owens, Jennifer, Bollag, Roni, Li, Qiang, Weinberger, Paul, Czerwinski, Christine, Huelsenbeck-Dill, Lori, Iacocca, Mary, Petrelli, Nicholas, Rabeno, Brenda, Swanson, Pat, Shelton, Troy, Curley, Erin, Gardner, Johanna, Mallery, David, Penny, Robert, Van Bang, Nguyen, Thi Hanh, Phan, Kohl, Bernard, Van Le, Xuan, Duc Phu, Bui, Thorp, Richard, Tien, Nguyen Viet, Vinh, Le Quang, Sandusky, George, Burks, Eric, Christ, Kimberly, Gee, Jason, Holway, Antonia, Moinzadeh, Alireza, Sorcini, Andrea, Sullivan, Travis, Garcia-Grossman, Ilana R., Regazzi, Ashley M., Boice, Lori, Rathmell, Wendy Kimryn, Thorne, Leigh, Bastacky, Sheldon, Davies, Benjamin, Dhir, Rajiv, Gingrich, Jeffrey, Hrebinko, Ronald, Maranchie, Jodi, Nelson, Joel, Parwani, Anil, Bshara, Wiam, Gaudioso, Carmelo, Morrison, Carl, Alexopoulou, Vina, Bartlett, John, Engel, Jay, Kodeeswaran, Sugy, Antic, Tatjana, O’Donnell, Peter H., Smith, Norm D., Steinberg, Gary D., Egea, Sophie, Gomez-Fernandez, Carmen, Herbert, Lynn, Jorda, Merce, Soloway, Mark, Beaver, Allison, Carter, Suzie, Kapur, Payal, Lewis, Cheryl, Lotan, Yair, Bondaruk, Jolanta, Czerniak, Bogdan, Skinner, Eila, Aldape, Kenneth, Jensen, Mark A., Kahn, Ari B., Pihl, Todd D., Pot, David A., Srinivasan, Deepak, Wan, Yunhu, Ferguson, Martin L., Zenklusen, Jean Claude, Davidsen, Tanja, Demchok, John A., Mills Shaw, Kenna R., Sheth, Margi, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Hutter, Carolyn, Ozenberger, Bradley A., Sofia, Heidi J., and Eley, Greg

Published
2014
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44. Lung adenocarcinoma promotion by air pollutants

Author

Hill, William, Lim, Emilia L., Weeden, Clare E., Lee, Claudia, Augustine, Marcellus, Chen, Kezhong, Kuan, Feng-Che, Marongiu, Fabio, Evans, Edward J., Moore, David A., Rodrigues, Felipe S., Pich, Oriol, Bakker, Bjorn, Cha, Hongui, Myers, Renelle, van Maldegem, Febe, Boumelha, Jesse, Veeriah, Selvaraju, Rowan, Andrew, Naceur-Lombardelli, Cristina, Karasaki, Takahiro, Sivakumar, Monica, De, Swapnanil, Caswell, Deborah R., Nagano, Ai, Black, James R. M., Martínez-Ruiz, Carlos, Ryu, Min Hyung, Huff, Ryan D., Li, Shijia, Favé, Marie-Julie, Magness, Alastair, Suárez-Bonnet, Alejandro, Priestnall, Simon L., Lüchtenborg, Margreet, Lavelle, Katrina, Pethick, Joanna, Hardy, Steven, McRonald, Fiona E., Lin, Meng-Hung, Troccoli, Clara I., Ghosh, Moumita, Miller, York E., Merrick, Daniel T., Keith, Robert L., Al Bakir, Maise, Bailey, Chris, Hill, Mark S., Saal, Lao H., Chen, Yilun, George, Anthony M., Abbosh, Christopher, Kanu, Nnennaya, Lee, Se-Hoon, McGranahan, Nicholas, Berg, Christine D., Sasieni, Peter, Houlston, Richard, Turnbull, Clare, Lam, Stephen, Awadalla, Philip, Grönroos, Eva, Downward, Julian, Jacks, Tyler, Carlsten, Christopher, Malanchi, Ilaria, Hackshaw, Allan, Litchfield, Kevin, DeGregori, James, Jamal-Hanjani, Mariam, and Swanton, Charles

Abstract

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFRand KRASdriver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for  PM2.5air pollutants  and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.

Published
2023
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45. Reptilian heart development and the molecular basis of cardiac chamber evolution

Author

Koshiba-Takeuchi, Kazuko, Mori, Alessandro D., Kaynak, Bogac L., Cebra-Thomas, Judith, Sukonnik, Tatyana, Georges, Romain O., Latham, Stephany, Beck, Laural, Henkelman, R. Mark, Black, Brian L., Olson, Eric N., Wade, Juli, Takeuchi, Jun K., Nemer, Mona, Gilbert, Scott F., and Bruneau, Benoit G.

Subjects
Reptiles -- Physiological aspects -- Research, Evolutionary biology -- Research -- Physiological aspects, Animal development -- Research -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation, Physiological aspects, Research
Abstract

The emergence of terrestrial life witnessed the need for more sophisticated circulatory systems. This has evolved in birds, mammals and crocodilians into complete septation of the heart into left and [...]

Published
2009

46. Common variants on chromosome 6p22.1 are associated with schizophrenia

Author

Shi, Jianxin, Levinson, Douglas F., Duan, Jubao, Sanders, Alan R., Zheng, Yonglan, Pe'er, Itsik, Dudbridge, Frank, Holmans, Peter A., Whittemore, Alice S., Mowry, Bryan J., Olincy, Ann, Amin, Farooq, Cloninger, C. Robert, Silverman, Jeremy M., Buccola, Nancy G., Byerley, William F., Black, Donald W., Crowe, Raymond R., Oksenberg, Jorge R., Mirel, Daniel B., Kendler, Kenneth S., Freedman, Robert, and Gejman, Pablo V.

Subjects
Schizophrenia -- Genetic aspects -- Diagnosis -- Research, Single nucleotide polymorphisms -- Research -- Health aspects -- Genetic aspects, Disease susceptibility -- Health aspects -- Genetic aspects -- Research -- Diagnosis, Environmental issues, Science and technology, Zoology and wildlife conservation, Diagnosis, Genetic aspects, Research, Health aspects
Abstract

Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%)and complex transmission (1). Recent studies implicate rare, large, high-penetrante copy number variants in some cases (2), but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x [10.sup.-9]). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms., The symptoms and course of schizophrenia are variable, without forming distinct familial subtypes (1). There are positive (delusions and hallucinations), negative (reduced emotions, speech and interest), and disorganized (disrupted syntax [...]

Published
2009

47. Establishment and cryptic transmission of Zika virus in Brazil and the Americas

Author

Faria, N. R., Quick, J., Claro, I.M., Thz, J., de Jesus, J. G., Giovanetti, M., Kraemer, M. U. G., Hill, S. C., Black, A., da Costa, A. C., Franco, L. C., Silva, S. P., Wu, C.-H., Raghwani, J., Cauchemez, S., du Plessis, L., Verotti, M. P., de Oliveira, W. K., Carmo, E. H., Coelho, G. E., Santelli, A. C. F. S., Vinhal, L. C., Henriques, C. M., Simpson, J. T., Loose, M., Andersen, K. G., Grubaugh, N. D., Somasekar, S., Chiu, C. Y., Muoz-Medina, J. E., Gonzalez-Bonilla, C. R., Arias, C. F., Lewis-Ximenez, L. L., Baylis, S. A., Chieppe, A. O., Aguiar, S. F., Fernandes, C. A., Lemos, P. S., Nascimento, B. L. S., Monteiro, H. A. O., Siqueira, I. C., de Queiroz, M. G., de Souza, T. R., Bezerra, J. F., Lemos, M. R., Pereira, G. F., Loudal, D., Moura, L. C., Dhalia, R., Frana, R. F., Magalhes, T., Marques, E. T., Jr, Jaenisch, T., Wallau, G. L., de Lima, M. C., Nascimento, V., de Cerqueira, E. M., de Lima, M. M., Mascarenhas, D. L., Neto, J. P. Moura, Levin, A. S., Tozetto-Mendoza, T. R., Fonseca, S. N., Mendes-Correa, M. C., Milagres, F. P., Segurado, A., Holmes, E. C., Rambaut, A., Bedford, T., Nunes, M. R. T., Sabino, E. C., Alcantara, L. C. J., Loman, N. J., and Pybus, O. G.

Subjects
Disease transmission -- Observations, Zika virus -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): N. R. Faria [1, 2]; J. Quick [3]; I.M. Claro [4]; J. Thz [1]; J. G. de Jesus [5]; M. Giovanetti [5, 6]; M. U. G. Kraemer [1, 7, [...]

Published
2017
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48. The sequence and analysis of duplication-rich human chromosome 16

Author

Martin, Joel, Han, Cliff, Gordon, Laurie A., Terry, Astrid, Prabhakar, Shyam, She, Xinwei, Xie, Gary, Hellsten, Uffe, Chan, Yee Man, Altherr, Michael, Couronne, Olivier, Aerts, Andrea, Bajorek, Eva, Black, Stacey, Blumer, Heather, Branscomb, Elbert, Brown, Nancy C., Bruno, William J., Buckingham, Judith M., Callen, David F., Campbell, Connie S., Campbell, Mary L., Campbell, Evelyn W., Caoile, Chenier, Challacombe, Jean F., Chasteen, Leslie A., Chertkov, Olga, Chi, Han C., Christensen, Mari, Clark, Lynn M., Cohn, Judith D., Denys, Mirian, Detter, John C., Dickson, Mark, Dimitrijevic-Bussod, Mira, Escobar, Julio, Fawcett, Joseph J., Flowers, Dave, Fotopulos, Dea, Glavina, Tijana, Gomez, Maria, Gonzales, Eidelyn, Goodstein, David, Goodwin, Lynne A., Grady, Deborah L., Grigoriev, Igor, Groza, Matthew, Hammon, Nancy, Hawkins, Trevor, Haydu, Lauren, Hildebrand, Carl E., Huang, Wayne, Israni, Sanjay, Jett, Jamie, Jewett, Phillip B., Kadner, Kristen, Kimball, Heather, Kobayashi, Arthur, Krawczyk, Marie-Claude, Leyba, Tina, Longmire, Jonathan L., Lopez, Frederick, Lou, Yunian, Lowry, Steve, Ludeman, Thom, Manohar, Chitra F., Mark, Graham A., McMurray, Kimberly L., Meincke, Linda J., Morgan, Jenna, Moyzis, Robert K., Mundt, Mark O., Munk, A. Christine, Nandkeshwar, Richard D., Pitluck, Sam, Pollard, Martin, Predki, Paul, Parson-Quintana, Beverly, Ramirez, Lucia, Rash, Sam, Retterer, James, Ricke, Darryl O., Robinson, Donna L., Rodriguez, Alex, Salamov, Asaf, Saunders, Elizabeth H., Scott, Duncan, Shough, Timothy, Stallings, Raymond L., Stalvey, Malinda, Sutherland, Robert D., Tapia, Roxanne, Tesmer, Judith G., Thayer, Nina, Thompson, Linda S., Tice, Hope, Torney, David C., Tran-Gyamfi, Mary, Tsai, Ming, Ulanovsky, Levy E., Ustaszewska, Anna, Vo, Nu, Scott White, P., Williams, Albert L., Wills, Patricia L., Wu, Jung-Rung, Wu, Kevin, Yang, Joan, DeJong, Pieter, Bruce, David, Doggett, Norman A., Deaven, Larry, Schmutz, Jeremy, Grimwood, Jane, Richardson, Paul, Rokhsar, Daniel S., Eichler, Evan E., Gilna, Paul, Lucas, Susan M., Myers, Richard M., Rubin, Edward M., and Pennacchio, Len A.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Joel Martin [1]; Cliff Han [2]; Laurie A. Gordon [1]; Astrid Terry [1]; Shyam Prabhakar [4]; Xinwei She [5]; Gary Xie [1, 2]; Uffe Hellsten [1]; Yee Man Chan [...]

Published
2004
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49. The DNA sequence and comparative analysis of human chromosome 5

Author

Schmutz, Jeremy, Martin, Joel, Terry, Astrid, Couronne, Olivier, Grimwood, Jane, Lowry, Steve, Gordon, Laurie A., Scott, Duncan, Xie, Gary, Huang, Wayne, Hellsten, Uffe, Tran-Gyamfi, Mary, She, Xinwei, Prabhakar, Shyam, Aerts, Andrea, Altherr, Michael, Bajorek, Eva, Black, Stacey, Branscomb, Elbert, Caoile, Chenier, Challacombe, Jean F., Man Chan, Yee, Denys, Mirian, Detter, John C., Escobar, Julio, Flowers, Dave, Fotopulos, Dea, Glavina, Tijana, Gomez, Maria, Gonzales, Eidelyn, Goodstein, David, Grigoriev, Igor, Groza, Matthew, Hammon, Nancy, Hawkins, Trevor, Haydu, Lauren, Israni, Sanjay, Jett, Jamie, Kadner, Kristen, Kimball, Heather, Kobayashi, Arthur, Lopez, Frederick, Lou, Yunian, Martinez, Diego, Medina, Catherine, Morgan, Jenna, Nandkeshwar, Richard, Noonan, James P., Pitluck, Sam, Pollard, Martin, Predki, Paul, Priest, James, Ramirez, Lucia, Retterer, James, Rodriguez, Alex, Rogers, Stephanie, Salamov, Asaf, Salazar, Angelica, Thayer, Nina, Tice, Hope, Tsai, Ming, Ustaszewska, Anna, Vo, Nu, Wheeler, Jeremy, Wu, Kevin, Yang, Joan, Dickson, Mark, Cheng, Jan-Fang, Eichler, Evan E., Olsen, Anne, Pennacchio, Len A., Rokhsar, Daniel S., Richardson, Paul, Lucas, Susan M., Myers, Richard M., and Rubin, Edward M.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Jeremy Schmutz (corresponding author) [1]; Joel Martin [2]; Astrid Terry [2]; Olivier Couronne [3]; Jane Grimwood [1]; Steve Lowry [2]; Laurie A. Gordon [2, 4]; Duncan Scott [2]; Gary [...]

Published
2004
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50. Structural determinants for generating centromeric chromatin

Author

Black, Ben E., Foltz, Daniel R., Chakravarthy, Srinivas, Luger, Karolin, Woods, Jr, Virgil L., and Cleveland, Don W.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Ben E. Black [1, 2]; Daniel R. Foltz [1, 2]; Srinivas Chakravarthy [4]; Karolin Luger [4]; Virgil L. Woods, Jr (corresponding author) [3]; Don W. Cleveland (corresponding author) [1, [...]

Published
2004
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