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Preprint
Multi-platform discovery of haplotype-resolved structural variation in human genomes
BiorXiv.org
13 Jun 2018
PMID: 30992455
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies.
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- Title
- Multi-platform discovery of haplotype-resolved structural variation in human genomes
- Creators
- Mark J P Chaisson - University of Southern CaliforniaAshley D Sanders - European Molecular Biology Laboratory, Genome Biology Unit, 69117, Heidelberg, GermanyXuefang Zhao - Center for Genomic Medicine, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, 02114, USAAnkit Malhotra - The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USADavid Porubsky - Center for Bioinformatics, Saarland University and the Max Planck Institute for Informatics, 66123, Saarbrücken, GermanyTobias Rausch - European Molecular Biology Laboratory, Genome Biology Unit, 69117, Heidelberg, GermanyEugene J Gardner - Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USAOscar L Rodriguez - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USALi Guo - Xi'an Jiaotong UniversityRyan L Collins - Harvard UniversityXian Fan - Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USAJia Wen - Department of Bioinformatics and Genomics, College of Computing and Informatics, The University of North Carolina at Charlotte, Charlotte, NC, 28223, USARobert E Handsaker - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USASusan Fairley - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United KingdomZev N Kronenberg - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USAXiangmeng Kong - Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT, 06520, USAFereydoun Hormozdiari - UC Davis Genome Center, University of California, Davis, Davis, CA, 95616, USADillon Lee - USTAR Center for Genetic Discovery and Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, 84112, USAAaron M Wenger - Pacific Biosciences, Menlo Park, CA, 94025, USAAlex R Hastie - BioNano Genomics (United States)Danny Antaki - Beyster Center for Genomics of Psychiatric Diseases, Department of Psychiatry University of California San Diego, La Jolla, CA, 92093, USAThomas Anantharaman - BioNano Genomics (United States)Peter A Audano - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USAHarrison Brand - Massachusetts General HospitalStuart Cantsilieris - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USAHan Cao - BioNano Genomics (United States)Eliza Cerveira - The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USAChong Chen - Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USAXintong Chen - Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USAChen-Shan Chin - Pacific Biosciences, Menlo Park, CA, 94025, USAZechen Chong - Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USANelson T Chuang - Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USAChristine C Lambert - Pacific Biosciences, Menlo Park, CA, 94025, USADeanna M Church - National Center for Biotechnology InformationLaura Clarke - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United KingdomAndrew Farrell - USTAR Center for Genetic Discovery and Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, 84112, USAJoey Flores - Illumina Clinical Services Laboratory, Illumina, Inc., 5200 Illumina Way, San Diego, CA, 92122, USATimur Galeev - Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT, 06520, USADavid U Gorkin - Ludwig Institute for Cancer Research, La Jolla, CA, 92093, USAMadhusudan Gujral - Beyster Center for Genomics of Psychiatric Diseases, Department of Psychiatry University of California San Diego, La Jolla, CA, 92093, USAVictor Guryev - European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, AV, NL-9713, The NetherlandsWilliam Haynes Heaton - 10X Genomics, Pleasanton, CA, 94566, USAJonas Korlach - Pacific Biosciences, Menlo Park, CA, 94025, USASushant Kumar - Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT, 06520, USAJee Young Kwon - Department of Graduate Studies - Life Sciences, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, South KoreaErnest T Lam - University of California, San FranciscoJong Eun Lee - DNA Link (South Korea)Joyce Lee - BioNano Genomics (United States)Wan-Ping Lee - Jackson LaboratorySau Peng Lee - TreeCode Sdn Bhd, Bandar Botanic, 41200, Klang, MalaysiaShantao Li - Yale UniversityPatrick Marks - 10X Genomics, Pleasanton, CA, 94566, USAKarine Viaud-Martinez - Illumina Clinical Services Laboratory, Illumina, Inc., 5200 Illumina Way, San Diego, CA, 92122, USASascha Meiers - European Molecular Biology Laboratory, Genome Biology Unit, 69117, Heidelberg, GermanyKatherine M Munson - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USAFabio C P Navarro - Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT, 06520, USABradley J Nelson - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USAConor Nodzak - Department of Bioinformatics and Genomics, College of Computing and Informatics, The University of North Carolina at Charlotte, Charlotte, NC, 28223, USAAmina Noor - Beyster Center for Genomics of Psychiatric Diseases, Department of Psychiatry University of California San Diego, La Jolla, CA, 92093, USASofia Kyriazopoulou-Panagiotopoulou - 10X Genomics, Pleasanton, CA, 94566, USAAndy W C Pang - BioNano Genomics (United States)Yunjiang Qiu - Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, 92093, USAGabriel Rosanio - Beyster Center for Genomics of Psychiatric Diseases, Department of Psychiatry University of California San Diego, La Jolla, CA, 92093, USAMallory Ryan - The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USAAdrian Stütz - European Molecular Biology Laboratory, Genome Biology Unit, 69117, Heidelberg, GermanyDiana C J Spierings - European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, AV, NL-9713, The NetherlandsAlistair Ward - USTAR Center for Genetic Discovery and Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, 84112, USAAnneMarie E Welch - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USAMing Xiao - Drexel University, School of Biomedical Engineering, Science, and Health SystemsWei Xu - 10X Genomics (United States)Chengsheng Zhang - The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USAQihui Zhu - The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USAXiangqun Zheng-Bradley - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United KingdomErnesto Lowy - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United KingdomSergei Yakneen - European Molecular Biology Laboratory, Genome Biology Unit, 69117, Heidelberg, GermanySteven McCarroll - Broad InstituteGoo Jun - Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77225, USALi Ding - Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MI, 63108, USAChong Lek Koh - High Impact Research, University of Malaya, 50603, Kuala Lumpur, MalaysiaBing Ren - University of California San DiegoPaul Flicek - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United KingdomKen Chen - Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USAMark B Gerstein - Department of Statistics and Data Science, Yale University, 266 Whitney Avenue, New Haven, CT, 06520, USAPui-Yan Kwok - University of California, San FranciscoPeter M Lansdorp - University of British ColumbiaGabor T Marth - USTAR Center for Genetic Discovery and Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, 84112, USAJonathan Sebat - Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USAXinghua Shi - Department of Bioinformatics and Genomics, College of Computing and Informatics, The University of North Carolina at Charlotte, Charlotte, NC, 28223, USAAli Bashir - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USAKai Ye - The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, ChinaScott E Devine - Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USAMichael E Talkowski - Broad InstituteRyan E Mills - Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USATobias Marschall - Center for Bioinformatics, Saarland University and the Max Planck Institute for Informatics, 66123, Saarbrücken, GermanyJan O Korbel - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom. jan.korbel@embl.deEvan E Eichler - Howard Hughes Medical InstituteCharles Lee - Brigham and Women's Hospital
- Publication Details
- BiorXiv.org
- Publisher
- American Physical Society (APS)
- Grant note
- Wellcome Trust R15 HG009565 / NHGRI NIH HHS R01 HG005946 / NHGRI NIH HHS R21 AI117407 / NIAID NIH HHS R01 HG010169 / NHGRI NIH HHS R01 HG002898 / NHGRI NIH HHS P30 CA016672 / NCI NIH HHS R01 HG007068 / NHGRI NIH HHS S10 OD021644 / NIH HHS U01 HG006513 / NHGRI NIH HHS R01 HG002385 / NHGRI NIH HHS R01 CA166661 / NCI NIH HHS U41 HG007497 / NHGRI NIH HHS R25 HG007153 / NHGRI NIH HHS R56 MH115957 / NIMH NIH HHS U24 HG007497 / NHGRI NIH HHS R01 MH115957 / NIMH NIH HHS R03 HD098552 / NICHD NIH HHS T32 DK067872 / NIDDK NIH HHS T32 GM008666 / NIGMS NIH HHS R01 HG008628 / NHGRI NIH HHS P30 CA034196 / NCI NIH HHS T32 HG002295 / NHGRI NIH HHS R01 CA172652 / NCI NIH HHS R01 HD081256 / NICHD NIH HHS F31 HG009223 / NHGRI NIH HHS
- Resource Type
- Preprint
- Language
- English
- Academic Unit
- Microbiology and Immunology; School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000464654700023
- Scopus ID
- 2-s2.0-85060084825
- Other Identifier
- 991021866608804721
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- Industry collaboration
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- Web of Science research areas
- Genetics & Heredity