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High-Resolution Imaging of Human Viruses in Liquid Droplets

Advanced materials (Deerfield Beach, Fla.) 2021年第37期33卷 e2103221页

作者： G M Jonaid William J Dearnaley Michael A Casasanta Liam Kaylor Samantha Berry Madeline J Dukes Michael S Spilman Jennifer L Gray Deborah F Kelly Bioinformatics and Genomics Graduate Program Huck Institutes of the Life Sciences Pennsylvania State University University Park PA 16802 USA. Department of Biomedical Engineering Pennsylvania State University University Park PA 16802 USA. Materials Research Institute Pennsylvania State University University Park PA 16802 USA. Center for Structural Oncology Pennsylvania State University University Park PA 16802 USA. Molecular Cellular and Integrative Biosciences Graduate Program Huck Institutes of the Life Sciences Pennsylvania State University University Park PA 16802 USA. Protochips Inc. Morrisville NC 27560 USA. Direct Electron LP. San Diego CA 92128 USA.

Liquid-phase electron microscopy (LP-EM) is an exciting new area in the materials imaging field, providing unprecedented views of molecular processes. Time-resolved insights from LP-EM studies are a strong complement to the remarkable results achievable with other high-resolution techniques. Here, the opportunities to expand LP-EM technology beyond 2D temporal assessments and into the 3D regime are described. The results show new structures and dynamic insights of human viruses contained in minute volumes of liquid while acquired in a rapid timeframe. To develop this strategy, adeno-associated virus (AAV) is used as a model system. AAV is a well-known gene therapy vehicle with current applications involving drug delivery and vaccine development for COVID-19. Improving the understanding of the physical properties of biological entities in a liquid state, as maintained in the human body, has broad societal implications for human health and disease.

关键词： COVID-19 SARS-CoV-2 adeno-associated virus direct electron detector liquid-phase electron microscopy silicon nitride

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Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants

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Science (New York, N.Y.) 2025年第6734期387卷 eadp4753页

作者： Liu, Hongbo Abedini, Amin Ha, Eunji Ma, Ziyuan Sheng, Xin Dumoulin, Bernhard Qiu, Chengxiang Aranyi, Tamas Li, Shen Dittrich, Nicole Chen, Hua-Chang Tao, Ran Tarng, Der-Cherng Hsieh, Feng-Jen Chen, Shih-Ann Yang, Shun-Fa Lee, Mei-Yueh Kwok, Pui-Yan Wu, Jer-Yuarn Chen, Chien-Hsiun Khan, Atlas Limdi, Nita A. Wei, Wei-Qi Walunas, Theresa L. Karlson, Elizabeth W. Kenny, Eimear E. Luo, Yuan Kottyan, Leah Connolly, John J. Jarvik, Gail P. Weng, Chunhua Shang, Ning Cole, Joanne B. Mercader, Josep M. Mandla, Ravi Majarian, Timothy D. Florez, Jose C. Haas, Mary E. Lotta, Luca A. Drivas, Theodore G. Vy, Ha My T Nadkarni, Girish N. Wiley, Laura K. Wilson, Melissa P. Gignoux, Christopher R. Rasheed, Humaira Thomas, Laurent F. Åsvold, Bjørn Olav Brumpton, Ben M. Hallan, Stein I. Hveem, Kristian Zheng, Jie Hellwege, Jacklyn N. Zawistowski, Matthew Zöllner, Sebastian Franceschini, Nora Hu, Hailong Zhou, Jianfu Kiryluk, Krzysztof Ritchie, Marylyn D. Palmer, Matthew Edwards, Todd L. Voight, Benjamin F. Hung, Adriana M. Susztak, Katalin Department of Medicine Renal Electrolyte and Hypertension Division University of Pennsylvania Philadelphia PA United States Institute of Diabetes Obesity and Metabolism University of Pennsylvania Philadelphia PA United States Department of Genetics University of Pennsylvania Philadelphia PA United States Penn-CHOP Kidney Innovation Center University of Pennsylvania Philadelphia PA United States Liangzhu Laboratory Zhejiang University 1369 West Wenyi Road Hangzhou Zhejiang China Department of Nephrology Children' Hospital Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang China Institute of Molecular Life Sciences HUN-REN Research Center for Natural Sciences Budapest Hungary Department of Molecular Biology Semmelweis University Budapest Hungary Department of Medicine Federal University of São Paulo São Paulo Brazil Department of Biostatistics Vanderbilt University Medical Center Nashville TN United States Vanderbilt Genetics Institute Vanderbilt University Medical Center Nashville TN United States Institute of Clinical Medicine School of Medicine National Yang Ming Chiao Tung University ROC Taipei Taiwan Division of Nephrology Department of Medicine Taipei Veterans General Hospital ROC Taipei Taiwan Institute of Biomedical Sciences Academia Sinica ROC Taipei Taiwan Cardiovascular Center Taichung Veterans General Hospital Taichung Taiwan ROC National Chung Hsing University Taichung Taiwan ROC Heart Rhythm Center Division of Cardiology Department of Medicine Taipei Veterans General Hospital ROC Taipei Taiwan Department of Internal Medicine College of Medicine National Yang Ming Chiao Tung University ROC Taipei Taiwan Institute of Medicine Chung Shan Medical University Taichung Taiwan ROC Department of Medical Research Chung Shan Medical University Hospital Taichung Taiwan ROC Division of Endocrinology and Metabolism Department of Internal Medicine Kaohsiung Medical Universit

Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. In this study, we conducted a multiancestry genome-wide association study in 2.2 million individuals and identified 1026 (97 previously unknown) independent loci. Ancestry-specific analysis indicated an attenuation of newly identified signals on common variants in European ancestry populations and the power of population diversity for further discoveries. We defined genotype effects on allele-specific gene expression and regulatory circuitries in more than 700 human kidneys and 237,000 cells. We found 1363 coding variants disrupting 782 genes, with 601 genes also targeted by regulatory variants and convergence in 161 genes. Integrating 32 types of genetic information, we present the "Kidney Disease Genetic Scorecard" for prioritizing potentially causal genes, cell types, and druggable targets for kidney disease.

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Characterization of primary Sjögren's syndrome in the Taiwan Han population through a genome-wide association study and polygenic risk score analysis

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Clinical Immunology 2024年 269卷 110381-110381页

作者： Liu, Ting-Yuan Lin, Min-Rou Lu, Hsing-Fang Chen, Yu-Chia Lin, Hui-Ju Chou, Wan-Hsuan Wei, Chun-Yu Palupi, Poppy Diah Liao, Chi-Chou Chang, Yen-Ting Chang, Wei-Chiao Tsai, Fuu-Jen Department of Medical Research China Medical University Hospital China Medical University Taichung 40447 Taiwan Department of Clinical Pharmacy School of Pharmacy Taipei Medical University Taipei 110 Taiwan Department of Ophthalmology Eye Center China Medical University Hospital Taichung 40447 Taiwan Master Program in Clinical Genomics and Proteomics School of Pharmacy Taipei Medical University Taipei 110 Taiwan Core Laboratory of Neoantigen Analysis for Personalized Cancer Vaccine Office of R&D Taipei Medical University Taipei 110 Taiwan Integrative Research Center in Critical Care Wanfang Hospital Taipei Medical University Taipei 116 Taiwan Department of Pharmacy Wan Fang Hospital Taipei Medical University Taipei 110 Taiwan Department of Pharmacology National Defense Medical Center Taipei 110 Taiwan Department of Medical Research China Medical University Hospital Taichung 40402 Taiwan School of Chinese Medicine China Medical University Taichung 40402 Taiwan Division of Pediatric Medical Genetics Children's Hospital of China Medical University Taichung 40447 Taiwan Department of Biotechnology and Bioinformatics Asia University Taichung 41354 Taiwan

Background: Sjögren's syndrome (SS) is an autoimmune disorder that primarily affects the exocrine glands, leading to dryness of mucous membranes and systemic manifestations. This study aimed to identify genetic markers associated with primary SS (pSS) in the Taiwan Han population through a hospital-based genome-wide association study (GWAS) and polygenic risk score (PRS) analysis, addressing the lack of genetic research. Results: This study included 11,390 patients diagnosed with pSS and 113,900 controls. GWAS identified one known locus and eight novel loci. Known HLA alleles, including HLA-DRB1*15:01 and HLA-DQA1*03:01, were successfully replicated in a consistent effect direction. PRS analysis revealed that several autoimmune diseases share similar genetic backgrounds with pSS, including rheumatoid arthritis and systemic lupus erythematosus. Conclusion: This study represents the largest cohort to date on the genetics of pSS in the Taiwan Han population. Our findings provide valuable insights into the pathogenesis of pSS and emphasize the comorbidities associated with it as an autoimmune disease. © 2024

关键词： Gene polymorphism Genome-wide association study (GWAS) Human leukocyte antigen (HLA) Phenome-wide association study (PheWAS) Polygenic risk score (PRS) Sjögren's syndrome

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The Genome Sequence of Taurine Cattle: A Window to Ruminant Biology and Evolution

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SCIENCE 2009年第5926期324卷 522-528页

作者： Elsik, Christine G. Tellam, Ross L. Worley, Kim C. Gibbs, Richard A. Abatepaulo, Antonio R. R. Abbey, Colette A. Adelson, David L. Aerts, Jan Ahola, Virpi Alexander, Lee Alioto, Tyler Almeida, Iassudara G. Amadio, Ariel F. Anatriello, Elen Antonarakis, Stylianos E. Anzola, Juan M. Astashyn, Alex Bahadue, Suria M. Baldwin, Cynthia L. Barris, Wes Baxter, Rebecca Bell, Stephanie Nicole Bennett, Anna K. Bennett, Gary L. Biase, Fernando H. Boldt, Clayton R. Bradley, Daniel G. Brinkman, Fiona S. L. Brinkmeyer-Langford, Candice L. Brown, Wendy C. Brownstein, Michael J. Buhay, Christian Caetano, Alexandre R. Camara, Francisco Carroll, Jeffrey A. Carvalho, Wanessa A. Casey, Theresa Cervelatti, Elaine P. Chack, Joseph Chacko, Elsa Chandrabose, Mimi M. Chapin, Jennifer E. Chapple, Charles E. Chen, Hsiu-Chuan Chen, Lin Cheng, Ye Cheng, Ze Childers, Christopher P. Chitko-McKown, Carol G. Chiu, Readman Choi, Jungwoo Chrast, Jacqueline Colley, Adam J. Connelley, Tomothy Cree, Andy Curry, Stacey Dalrymple, Brian Diep Dao, Marvin Davis, Clay de Oliveira, Carlo J. F. de Miranda Santos, Isabel K. F. de Campos, Tatiana A. Deobald, Heather Devinoy, Eve Dickins, C. Michael Yan, Ding Dinh, Huyen H. De Donato, Marcos Donohue, Kaitlin E. Donthu, Ravikiran Dovc, Peter Dugan-Rocha, Shannon Durbin, K. James Eberlein, Annett Edgar, Robert C. Egan, Amy Eggen, Andre Eichler, Evan E. Elhaik, Eran Ellis, Shirley A. Elnitski, Laura Ermolaeva, Olga Eyras, Eduardo Fitzsimmons, Carolyn J. Fowler, Gerald R. Franzin, Alessandra M. Fritz, Krista Gabisi, Ramatu Ayiesha Garcia, Gustavo R. Garcia, Jose Fernando Genini, Sem Gerlach, Daniel German, J. Bruce Gilbert, James G. R. Gill, Clare A. Gladney, Cody J. Glass, Elizabeth J. Goodell, Jason Grant, Jason R. Graur, Dan Greaser, Marion L. Green, Jonathan A. Green, Ronnie D. Guan, Leluo Guigo, Roderic Hadsell, Darryl L. Hagen, Darren E. Hakimov, Hatam A. Halgren, Rob Hamernik, Debora L. Hamilton, Cerissa Harhay, Gregory P. Harrow, Jennifer L. Hart, Elizabeth A. Hastings, Nicola Havlak, Paul Henrichsen, Charl Georgetown Univ Dept Biol 406 Reiss37th & O St NW Washington DC 20057 USA CSIRO Livestock Ind St Lucia Qld 4067 Australia Baylor Coll Med Dept Mol & Human Genet Human Genome Sequencing Ctr Houston TX 77030 USA Washington Univ Sch Med Genome Ctr St Louis MO 63108 USA Texas A&M Univ Dept Anim Sci College Stn TX 77843 USA Univ Adelaide Sch Mol Biomed & Sci Sch Agr Food & Wine Adelaide SA 5005 Australia Univ Washington Dept Genome Sci Seattle WA 98195 USA Howard Hughes Med Inst Seattle WA 98195 USA Natl Human Genome Res Inst Natl Inst Hlth Rockville MD 20878 USA Univ Pompeu Fabra Ctr Genomic Regulation Grp Recerca Informatica Biomed Inst Municipal Invest Med E-08003 Barcelona Spain USDA Cooperative State Res Educ & Extension Serv Washington DC 20250 USA USDA Agr Res Serv Natl Program Staff Beltsville MD 20705 USA Univ Illinois Urban Champaign Dept Anim Sci Urbana IL 61801 USA Univ Illinois Urban Champaign Inst Genomic Biol Urbana IL 61801 USA Simon Fraser Univ Dept Mol Biol Biochem Burnaby BC V5A 1S6 Canada Univ Sydney Fac Vet Sci Sydney NSW 2006 Australia Univ Lausanne Ctr Integrative Genomics CH-1015 Lausanne Switzerland Baylor Coll Med Dept Pediat Nutr USDA Agr Res Serv Childrens Nutr Res Ctr Houston TX 77030 USA Texas A&M Univ Dept Vet Integrative Biosci College Stn TX 77843 USA Univ Geneva Med Sch Dept Genetic Med & Dev CH-1211 Geneva Switzerland Swiss Inst Bioinformatics CH-1211 Geneva Switzerland Imperial Coll S Kensington Campus Div Mol Biosci London SW7 2AZ England Texas A&M Univ Dept Vet Pathobiol College Stn TX 77843 USA Natl Inst Hlth Natl Lib Med Natl Ctr Biotech Information Bethesda MD 20892 USA Wellcome Trust Sanger Inst Hinxton Informatics Dept Cambridge CB10 1HH England Univ London Royal Holloway Egham Dept Comp Sci Surrey TW20 0EX England Univ Houston Dept Biol & Biochem Houston TX 77204 USA Johns Hopkins Univ Sch Med McKusick Nathans Inst Genetic Med Baltimore MD 21205 USA 45 Monterey Dr Tiburon CA 94

To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.

关键词： Alternative Splicing Animals Animals, Domestic Biological Evolution Cattle Evolution, Molecular Evolution, Molecular Female Genetic Variation Genome Humans Male MicroRNAs/genetics MicroRNAs/genetics Molecular Sequence Data Proteins/genetics Sequence Analysis, DNA Species Specificity Synteny

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Author Correction: A B-ARR-mediated cytokinin transcriptional network directs hormone cross-regulation and shoot development

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Nature communications 2018年第1期9卷 2075页

作者： Mingtang Xie Hongyu Chen Ling Huang Ryan C O'Neil Maxim N Shokhirev Joseph R Ecker Plant Biology Laboratory and Genomic Analysis Laboratory The Salk Institute for Biological Studies La Jolla CA 92037 USA. Howard Hughes Medical Institute The Salk Institute for Biological Studies La Jolla CA 92037 USA. Department of Computer Science Dartmouth College Hanover NH 03755 USA. The Razavi Newman Integrative Genomics and Bioinformatics Core Facility The Salk Institute for Biological Studies La Jolla CA 92037 USA. Bioinformatics Program University of California at San Diego La Jolla CA 92093 USA. Plant Biology Laboratory and Genomic Analysis Laboratory The Salk Institute for Biological Studies La Jolla CA 92037 USA. ecker@salk.edu. Howard Hughes Medical Institute The Salk Institute for Biological Studies La Jolla CA 92037 USA. ecker@salk.edu.

The original version of this Article contained an error in Fig. 3. Panel b was inadvertently duplicated and the correct panel c was originally omitted. This error has been corrected in both the PDF and HTML versions o...

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Author Correction: Single-cell multi-ome regression models identify functional and disease-associated enhancers and enable chromatin potential analysis

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Nature genetics 2024年第6期56卷 1319页

作者： Sneha Mitra Rohan Malik Wilfred Wong Afsana Rahman Alexander J Hartemink Yuri Pritykin Kushal K Dey Christina S Leslie Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York City NY USA. Rye Country Day School Rye NY USA. Tri-Institutional Training Program in Computational Biology and Medicine New York City NY USA. Hunter College City University of New York New York City NY USA. Department of Computer Science Duke University Durham NC USA. Program in Computational Biology and Bioinformatics Duke University Durham NC USA. Center for Genomic and Computational Biology Duke University Durham NC USA. Department of Computer Science Princeton University Princeton NJ USA. Lewis-Sigler Institute for Integrative Genomics Princeton University Princeton NJ USA. Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York City NY USA. deyk@***. Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York City NY USA. lesliec@***.

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Author Correction: A B-ARR-mediated cytokinin transcriptional network directs hormone cross-regulation and shoot development

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Nature communications 2023年第1期14卷 5988页

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Author Correction: Mapping disease regulatory circuits at cell-type resolution from single-cell multiomics data

Nature computational science

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Nature computational science 2023年第9期3卷 805页

作者： Xi Chen Yuan Wang Antonio Cappuccio Wan-Sze Cheng Frederique Ruf Zamojski Venugopalan D Nair Clare M Miller Aliza B Rubenstein German Nudelman Alicja Tadych Chandra L Theesfeld Alexandria Vornholt Mary-Catherine George Felicia Ruffin Michael Dagher Daniel G Chawla Alessandra Soares-Schanoski Rachel R Spurbeck Lishomwa C Ndhlovu Robert Sebra Steven H Kleinstein Andrew G Letizia Irene Ramos Vance G Fowler Christopher W Woods Elena Zaslavsky Olga G Troyanskaya Stuart C Sealfon Center for Computational Biology Flatiron Institute New York NY USA. Lewis-Sigler Institute of Integrative Genomics Princeton University Princeton NJ USA. Department of Computer Science Princeton University Princeton NJ USA. Department of Neurology Icahn School of Medicine at Mount Sinai New York NY USA. Division of Infectious Diseases Department of Medicine Duke University School of Medicine Durham NC USA. Program in Computational Biology and Bioinformatics Yale University New Haven CT USA. Battelle Memorial Institute Columbus OH USA. Division of Infectious Diseases Department of Medicine Weill Cornell Medicine New York NY USA. Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY USA. Department of Pathology and Department of Immunobiology Yale School of Medicine New Haven CT USA. Naval Medical Research Center Silver Spring MD USA. Precision Immunology Institute Icahn School of Medicine at Mount Sinai New York NY USA. Department of Neurology Icahn School of Medicine at Mount Sinai New York NY USA. elena.zaslavsky@mssm.edu. Center for Computational Biology Flatiron Institute New York NY USA. ogt@genomics.princeton.edu. Lewis-Sigler Institute of Integrative Genomics Princeton University Princeton NJ USA. ogt@genomics.princeton.edu. Department of Computer Science Princeton University Princeton NJ USA. ogt@genomics.princeton.edu. Department of Neurology Icahn School of Medicine at Mount Sinai New York NY USA. stuart.sealfon@mssm.edu.

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Proceedings of the 16th Annual UT-KBRIN bioinformatics Summit 2016: bioinformatics

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BMC bioinformatics 2017年第9期18卷 1-9页

作者： Eric C. Rouchka Juw Won Park Julia H. Chariker David A. Tieri Shreedharkumar Rajurkar Vikas Singh Nishchal K. Verma Yan Cui Mark Farman Bradford Condon Jolanta Jaromczyk Neil Moore Jerzy Jaromczyk Daniel Harris Patrick Calie Eun Kyong Shin Robert L. Davis Arash Shaban-Nejad Joshua M. Mitchell Hunter N. B. Moseley Robert M. Flight Qing Jun Wang Richard M. Higashi Teresa W-M Fan Andrew N. Lane Liangqun Lu Bernie J Daigle Jr. Xi Chen Andrey Smelter Jerzy W. Jaromczyk Bailey K. Phan Nathaniel J. Serpico Ethan G. Toney Li Chen Caroline E. Melton Jennifer R. Mandel Bernie J. Daigle Jr. Hao Chen Kazi I. Zaman Ramin Homayouni Patrick J. Trainor Andrew P. DeFilippis Samantha M. Carlisle Shesh N. Rai Department of Computer Engineering and Computer Science University of Louisville Duthie Center for Engineering Louisville KY 40292 USA Kentucky Biomedical Research Infrastructure (KBRIN) Bioinformatics Core 522 East Gray Street Louisville KY 40292 USA Department of Psychological and Brain Sciences University of Louisville Louisville KY 40292 USA Department of Anatomical Sciences and Neurobiology University of Louisville Louisville KY 40292 USA Department of Electrical Engineering IIT Kanpur India Department of Microbiology Immunology and Biochemistry University of Tennessee Health Science Center Memphis TN 38103 USA Center for Integrative and Translational Genomics University of Tennessee Health Science Center Memphis TN 38103 USA Department of Plant Pathology University of Kentucky Lexington KY 40546 USA UK Healthcare Genomics University of Kentucky Lexington KY 40536 USA Department of Entomology & Plant Pathology University of Tennessee Knoxville TN 37996 USA Department of Forestry University of Kentucky Lexington KY 40506 USA Department of Computer Science University of Kentucky Lexington KY 40506 USA Department of Computer Science University of Kentucky Lexington KY 40508 USA Department of Biological Sciences Eastern Kentucky University Richmond KY 40475 USA University of Tennessee Health Science Center – Oak-Ridge National Lab (UTHSC-ORNL) Center for Biomedical Informatics Department of Pediatrics Memphis TN 38103 USA Department of Molecular & Cellular Biochemistry University of Kentucky Lexington KY 40536 USA Markey Cancer Center University of Kentucky Lexington KY 40536 USA Center for Environmental and Systems Biochemistry University of Kentucky Lexington KY 40536 USA Institute for Biomedical Informatics University of Kentucky Lexington KY 40536 USA Department of Molecular and Cellular Biochemistry University of Kentucky Lexington KY 40536 USA Department of Statistics University of Kentucky Louisville KY

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Data integration of bulk and single-cell transcriptomics from cerebral organoids and post-mortem brains to identify cell types and cell type specific driver genes in autism

Research Square

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Research Square 2020年

作者： Lim, Elaine T. Chan, Yingleong Burns, Mannix J. Guo, Xiaoge Erdin, Serkan Tai, Derek J.C. Reichert, Julia M. Chan, Ying Kai Chiang, Jessica J. Meyers, Katharina Zhang, Xiaochang Walsh, Christopher A. Yankner, Bruce A. Raychaudhuri, Soumya Hirschhorn, Joel N. Gusella, James F. Talkowski, Michael E. Church, George M. DZNE Germany Program in Bioinformatics and Integrative Biology Departments of Neurology and Molecular Cell and Cancer Biology University of Massachusetts Medical School WorcesterMA01605 United States Department of Genetics Harvard Medical School BostonMA02115 United States Wyss Institute for Biologically Inspired Engineering Harvard University BostonMA02115 United States Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard CambridgeMA02115 United States Center for Genomic Medicine Massachusetts General Hospital BostonMA02115 United States Department of Neurology Massachusetts General Hospital BostonMA02115 United States Department of Human Genetics The Grossman Institute for Neuroscience Quantitative Biology and Human Behavior The University of Chicago ChicagoIL60637 United States Division of Genetics and Genomics Manton Center for Orphan Disease Research Howard Hughes Medical Institute Boston Children’s Hospital BostonMA02115 United States Departments of Pediatrics and Neurology Harvard Medical School BostonMA02115 United States Divisions of Genetics and Rheumatology Brigham and Women's Hospital Harvard Medical School BostonMA02115 United States Partners Center for Personalized Genetic Medicine BostonMA02115 United States Faculty of Medical and Human Sciences University of Manchester ManchesterM13 9PL United Kingdom Division of Endocrinology Boston Children's Hospital BostonMA02115 United States Center for Basic and Translational Obesity Research Boston Children's Hospital BostonMA02115 United States

Human-derived cerebral organoids demonstrate great promise for identifying cell types and cell type specific molecular processes perturbed by genetic variants associated with neuropsychiatric and neurodevelopmental disorders, which are notoriously challenging to study using animal models. However, considerable challenges remain in achieving robust, scalable and generalizable phenotyping of organoids to discover cell types and cell type specific genes. We perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data from human post-mortem brains and cerebral organoids, for the identification of cell types and cell type specific individual genes. We apply Orgo-Seq for two autism-associated loci: 16p11.2 deletions and 15q11-13 duplications, and identify neuroepithelial cells as critical cell types for 16p11.2 deletions, and discover novel and previously reported cell type specific driver genes. Finally, we validated our results that mutations in the KCTD13 gene in the 16p11.2 locus lead to imbalances in the proportion of neuroepithelial cells, using CRISPR/Cas9-edited mosaic organoids. Our work presents a quantitative technological framework to integrate multiple transcriptomics datasets to identify cell types and cell type specific driver genes associated with complex diseases using cerebral organoids. © 2020, CC BY.

关键词： Genes

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