Mako: A Graph-Based Pattern Growth Approach to Detect Complex Structural Variants
Genomics Proteomics & Bioinformatics, vol. 20, pp. 205–218
Abstract
Complex structural variants (CSVs) are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants. However, detecting the compounded mutational signals of CSVs is challenging through a commonly used model-match strategy. As a result, there has been limited progress for CSV discovery compared with simple structural variants. Here, we systematically analyzed the multi-breakpoint connection feature of CSVs, and proposed Mako, utilizing a bottom-up guided model-free strategy, to detect CSVs from paired-end short-read sequencing. Specifically, we implemented a graph-based pattern growth approach, where the graph depicts potential breakpoint connections, and pattern growth enables CSV detection without pre-defined models. Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms. Notably, validation rates of CSVs on real data based on experimental and computational validations as well as manual inspections are around 70%, where the medians of experimental and computational breakpoint shift are 13 bp and 26 bp, respectively. Moreover, the Mako CSV subgraph effectively characterized the breakpoint connections of a CSV event and uncovered a total of 15 CSV types, including two novel types of adjacent segment swap and tandem dispersed duplication. Further analysis of these CSVs also revealed the impact of sequence homology on the formation of CSVs. Mako is publicly available at https://github.com/xjtu-omics/Mako.
Authors 50
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Jiadong Lin Aachen Leiden Institute of Advanced Computer Science Faculty of Science, Leiden University
Leiden University · First Affiliated Hospital of Xi'an Jiaotong University · Xi'an Jiaotong University
Affiliation as printed
Genome Institute, the First Affiliated Hospital of Xi’an Jiaotong University , Xi’an, 710061 , China
Leiden Institute of Advanced Computer Science, Faculty of Science, Leiden University , Leiden, 2311EZ , Netherland
MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University , Xi’an, 710049 , China
School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University , Xi’an, 710049 , China
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Affiliation as printed
MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University , Xi’an, 710049 , China
School of Computer Science and Technology, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University , Xi’an, 710049 , China
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Walter A. Kosters Aachen Leiden Institute of Advanced Computer Science Faculty of Science, Leiden University
Affiliation as printed
Leiden Institute of Advanced Computer Science, Faculty of Science, Leiden University , Leiden, 2311EZ , Netherland
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Affiliation as printed
School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University , Xi’an, 710049 , China
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Affiliation as printed
School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University , Xi’an, 710049 , China
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Affiliation as printed
School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University , Xi’an, 710049 , China
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The Jackson Laboratory for Genomic Medicine
Affiliation as printed
The Jackson Laboratory for Genomic Medicine , Farmington, CT, 06032 , USA
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The Jackson Laboratory for Genomic Medicine
Affiliation as printed
The Jackson Laboratory for Genomic Medicine , Farmington, CT, 06032 , USA
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Affiliation as printed
MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University , Xi’an, 710049 , China
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Affiliation as printed
Program in Computational Biology and Bioinformatics, Yale University , New Haven, CT, 06520 , USA
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European Molecular Biology Laboratory · European Molecular Biology Laboratory
Affiliation as printed
European Molecular Biology Laboratory (EMBL), Genome Biology Unit , D-69117 Heidelberg , Germany
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Affiliation as printed
New York Genome Center , New York, NY, 10013 , USA
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Harvard University · Massachusetts General Hospital
Affiliation as printed
Center for Genomic Medicine, Massachusetts General Hospital, Department of Neurology, Harvard Medical School , Boston, MA, 02114 , USA
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Affiliation as printed
Department of Computational Medicine & Bioinformatics, University of Michigan , Ann Arbor, MI, 48109 , USA
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European Molecular Biology Laboratory · European Molecular Biology Laboratory
Affiliation as printed
European Molecular Biology Laboratory (EMBL), Genome Biology Unit , D-69117 Heidelberg , Germany
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Heinrich Heine University Düsseldorf
Affiliation as printed
Heinrich Heine University, Medical Faculty, Institute for Medical Biometry and Bioinformatics , D-40225 Düsseldorf , Germany
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Heinrich Heine University Düsseldorf
Affiliation as printed
Heinrich Heine University, Medical Faculty, Institute for Medical Biometry and Bioinformatics , D-40225 Düsseldorf , Germany
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Affiliation as printed
Department of Genome Sciences, University of Washington School of Medicine , Seattle, WA, 98195-5065 , USA
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European Molecular Biology Laboratory · European Molecular Biology Laboratory
Affiliation as printed
European Molecular Biology Laboratory (EMBL), Genome Biology Unit , D-69117 Heidelberg , Germany
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University of Washington · Heinrich Heine University Düsseldorf
Affiliation as printed
Heinrich Heine University, Medical Faculty, Institute for Medical Biometry and Bioinformatics , D-40225 Düsseldorf , Germany
Department of Genome Sciences, University of Washington
School of Medicine, Seattle, WA 98195, USA
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University of Maryland, Baltimore · German Cancer Research Center · European Molecular Biology Laboratory · European Molecular Biology Laboratory · Xi'an Jiaotong University
Affiliation as printed
Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ) , D-69120 Heidelberg , Germany
European Molecular Biology Laboratory (EMBL), Genome Biology Unit , D-69117 Heidelberg , Germany
Division of Computational Genomics and Systems Genetics,
Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA
MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an 710049, China
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University of Washington · First Affiliated Hospital of Xi'an Jiaotong University
Affiliation as printed
Department of Genome Sciences, University of Washington School of Medicine , Seattle, WA, 98195-5065 , USA
Precision Medicine Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
School of Medicine, Seattle, WA 98195, USA
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The Jackson Laboratory for Genomic Medicine · Heinrich Heine University Düsseldorf
Affiliation as printed
Heinrich Heine University ,Medical Faculty, Institute for Medical Biometry and Bioinformatics , D-40225 Düsseldorf , Germany
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
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University of Michigan · Xi'an Jiaotong University
Affiliation as printed
Department of Computational Medicine & Bioinformatics, University of Michigan , Ann Arbor, MI, 48109 , USA
School of Computer Science and Technology, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an 710049, China
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Heinrich Heine University Düsseldorf
Affiliation as printed
Heinrich Heine University, Medical Faculty, Institute for Medical Biometry and Bioinformatics , D-40225 Düsseldorf , Germany
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University of Washington · The Jackson Laboratory for Genomic Medicine
Affiliation as printed
The Jackson Laboratory for Genomic Medicine , Farmington, CT, 06030 , USA
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98119, USA
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA
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Xuefang Zhao Aachen Leiden Institute of Advanced Computer Science Faculty of Science, Leiden University
Leiden University · Harvard University · Massachusetts General Hospital
Affiliation as printed
Center for Genomic Medicine, Massachusetts General Hospital, Department of Neurology, Harvard Medical School , Boston, MA, 02114 , USA
Leiden Institute of Advanced Computer Science, Faculty of Science, Leiden University, Leiden 2311EZ, Netherland
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University of Washington · First Affiliated Hospital of Xi'an Jiaotong University
Affiliation as printed
Department of Genome Sciences, University of Washington School of Medicine , Seattle, WA, 98195-5065 , USA
Precision Medicine Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
School of Medicine, Seattle, WA 98195, USA
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Howard Hughes Medical Institute · University of Washington · BioNano Genomics (United States)
Affiliation as printed
Bionano Genomics , San Diego, CA, 92121 , USA
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA
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Yale University · Xi'an Jiaotong University
Affiliation as printed
Program in Computational Biology and Bioinformatics, Yale University , New Haven, CT, 06520 , USA
School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an 710049, China
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European Molecular Biology Laboratory · European Molecular Biology Laboratory
Affiliation as printed
European Molecular Biology Laboratory (EMBL), Genome Biology Unit , D-69117 Heidelberg , Germany
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University of Alabama at Birmingham · The Jackson Laboratory for Genomic Medicine
Affiliation as printed
Department of Genetics and Informatics Institute, School of Medicine, University of Alabama at Birmingham , Birmingham, AL, 35294 , USA
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
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University of Alabama at Birmingham · Xi'an Jiaotong University
Affiliation as printed
Department of Genetics and Informatics Institute, School of Medicine, University of Alabama at Birmingham , Birmingham, AL, 35294 , USA
The School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
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University of Washington · First Affiliated Hospital of Xi'an Jiaotong University
Affiliation as printed
Department of Genome Sciences, University of Washington School of Medicine , Seattle, WA, 98195-5065 , USA
Precision Medicine Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
School of Medicine, Seattle, WA 98195, USA
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University of Southern California
Affiliation as printed
Molecular and Computational Biology, University of Southern California , Los Angeles, CA, 90089 , USA
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First Affiliated Hospital of Xi'an Jiaotong University · The Jackson Laboratory for Genomic Medicine · Temple University
Affiliation as printed
Department of Computer & Information Sciences, Temple University , Philadelphia, PA, 19122 , USA
Precision Medicine Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
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Affiliation as printed
Department of Computer & Information Sciences, Temple University , Philadelphia, PA, 19122 , USA
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Affiliation as printed
Pacific Biosystems of California, Inc , Menlo Park, CA, 94025 , USA
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University of Washington · First Affiliated Hospital of Xi'an Jiaotong University
Affiliation as printed
Department of Genome Sciences, University of Washington School of Medicine , Seattle, WA, 98195-5065 , USA
Precision Medicine Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
School of Medicine, Seattle, WA 98195, USA
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European Molecular Biology Laboratory · European Molecular Biology Laboratory · Xi'an Jiaotong University
Affiliation as printed
European Molecular Biology Laboratory (EMBL), Genome Biology Unit , D-69117 Heidelberg , Germany
MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an 710049, China
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Washington University in St. Louis
Affiliation as printed
Washington University , St. Louis, MO, 63108 , USA
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Washington University in St. Louis
Affiliation as printed
Washington University , St. Louis, MO, 63108 , USA
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European Bioinformatics Institute
Affiliation as printed
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus , Hinxton, Cambridge, CB10 1SD , United Kingdom
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Howard Hughes Medical Institute · University of Washington · BioNano Genomics (United States)
Affiliation as printed
Bionano Genomics , San Diego, CA, 92121 , USA
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA
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European Bioinformatics Institute
Affiliation as printed
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus , Hinxton, Cambridge, CB10 1SD , United Kingdom
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First Affiliated Hospital of Xi'an Jiaotong University · The Jackson Laboratory for Genomic Medicine
Affiliation as printed
Precision Medicine Center, the First Affiliated Hospital of Xi’an Jiaotong University , Xi’an, 710061 , China
The Jackson Laboratory for Genomic Medicine , Farmington, CT, 06032 , USA
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University of Washington · First Affiliated Hospital of Xi'an Jiaotong University · The Jackson Laboratory for Genomic Medicine
Affiliation as printed
Precision Medicine Center, the First Affiliated Hospital of Xi’an Jiaotong University , Xi’an, 710061 , China
The Jackson Laboratory for Genomic Medicine , Farmington, CT, 06032 , USA
Department of Genome Sciences, University of Washington
School of Medicine, Seattle, WA 98195, USA
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University of Maryland, Baltimore · German Cancer Research Center · Yale University · Xi'an Jiaotong University
Affiliation as printed
Institute for Genome Sciences, University of Maryland School of Medicine , Baltimore, MD, 21201 , USA
School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University , Xi’an, 710049 , China
Division of Computational Genomics and Systems Genetics,
German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA
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Howard Hughes Medical Institute · University of Washington · BioNano Genomics (United States) · The Jackson Laboratory for Genomic Medicine
Affiliation as printed
Department of Genome Sciences, University of Washington School of Medicine , Seattle, WA, 98119 , USA
Howard Hughes Medical Institute, University of Washington , Seattle, WA, 98195 , USA
Bionano Genomics, San Diego, CA 92121, USA
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA
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Kai Ye corresponding
University of Alabama at Birmingham · Yale University · First Affiliated Hospital of Xi'an Jiaotong University · European Molecular Biology Laboratory · New York Genome Center · UAB Medicine · Xi'an Jiaotong University
Affiliation as printed
Genome Institute, the First Affiliated Hospital of Xi’an Jiaotong University , Xi’an, 710061 , China
MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University , Xi’an, 710049 , China
School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University , Xi’an, 710049 , China
The School of Life Science and Technology, Xi’an Jiaotong University , Xi’an, 710049 , China
Department of Genetics and Informatics Institute, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany
New York Genome Center, New York, NY 10013, USA
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA
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