Mako: a graph-based pattern growth approach to detect complex structural variants

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Complex structural variants (CSVs) are genomic alterations that have more than two breakpoints and are considered as 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. 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 predefined models. Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms. Notably, validation rates of CSV 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 13bp and 26bp, respectively. Moreover, 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 segments swap and tandem dispersed duplication. Further analysis of these CSVs also revealed impact of sequence homology in the formation of CSVs. Mako is publicly available at https://github.com/jiadong324/Mako .

Authors 14

1. 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, 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

   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, 70049 China

2. Xiaofei Yang

   Xi'an Jiaotong University

   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

   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

3. Walter A. Kosters Aachen Leiden Institute of Advanced Computer Science Faculty of Science, Leiden University

   Leiden University

   Affiliation as printed

   Leiden Institute of Advanced Computer Science, Faculty of Science, Leiden University, Leiden, Netherland

4. Tun Xu

   Xi'an Jiaotong University

   Affiliation as printed

   School of Automation Science and Engineering, 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, 70049 China

5. Yanyan Jia

   Xi'an Jiaotong University

   Affiliation as printed

   School of Automation Science and Engineering, 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, 70049 China

6. Songbo Wang

   Xi'an Jiaotong University

   Affiliation as printed

   School of Automation Science and Engineering, 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, 70049 China

7. Qihui Zhu

   The Jackson Laboratory for Genomic Medicine

   Affiliation as printed

   The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032

   The Jackson Laboratory for Genomic Medicine, Farmington, CT 0032

8. Mallory Ryan

   The Jackson Laboratory for Genomic Medicine

   Affiliation as printed

   The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032

   The Jackson Laboratory for Genomic Medicine, Farmington, CT 0032

9. Li Guo

   Xi'an Jiaotong University

   Affiliation as printed

   Consortium authors are enumerated at the end of this document

   MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, 710049 China

   MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an, 710049 China

10. Chengsheng Zhang

    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

    Precision Medicine Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 10061 China

    The Jackson Laboratory for Genomic Medicine, Farmington, CT 0032

11. Charles Lee

    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, 10061 China

    The Jackson Laboratory for Genomic Medicine, Farmington, CT 0032

    Precision Medicine Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 10061 China

12. Scott E. Devine

    University of Maryland, Baltimore · 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, 70049 China

    School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an, 70049 China

13. Evan E. Eichler

    Howard Hughes Medical Institute · University of Washington

    Affiliation as printed

    Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98119-5065, USA

    Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA

14. Kai Ye corresponding

    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

    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, 70049 China

    The School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049 China

    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, 70049 China

    The School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049 China