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Mapping and phasing of structural variation in patient genomes using nanopore sequencing

Author

Listed:
  • Mircea Cretu Stancu

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

  • Markus J. Roosmalen

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

  • Ivo Renkens

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

  • Marleen M. Nieboer

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

  • Sjors Middelkamp

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

  • Joep Ligt

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

  • Giulia Pregno

    (Department of Clinical and Biological Sciences, University of Torino)

  • Daniela Giachino

    (Department of Clinical and Biological Sciences, University of Torino)

  • Giorgia Mandrile

    (Department of Clinical and Biological Sciences, University of Torino)

  • Jose Espejo Valle-Inclan

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

  • Jerome Korzelius

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

  • Ewart Bruijn

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

  • Edwin Cuppen

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

  • Michael E. Talkowski

    (Massachusetts General Hospital
    Harvard Medical School
    The Broad Institute of M.I.T. and Harvard)

  • Tobias Marschall

    (Center for Bioinformatics, Saarland University
    Max Planck Institute for Informatics)

  • Jeroen Ridder

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

  • Wigard P. Kloosterman

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University)

Abstract

Despite improvements in genomics technology, the detection of structural variants (SVs) from short-read sequencing still poses challenges, particularly for complex variation. Here we analyse the genomes of two patients with congenital abnormalities using the MinION nanopore sequencer and a novel computational pipeline—NanoSV. We demonstrate that nanopore long reads are superior to short reads with regard to detection of de novo chromothripsis rearrangements. The long reads also enable efficient phasing of genetic variations, which we leveraged to determine the parental origin of all de novo chromothripsis breakpoints and to resolve the structure of these complex rearrangements. Additionally, genome-wide surveillance of inherited SVs reveals novel variants, missed in short-read data sets, a large proportion of which are retrotransposon insertions. We provide a first exploration of patient genome sequencing with a nanopore sequencer and demonstrate the value of long-read sequencing in mapping and phasing of SVs for both clinical and research applications.

Suggested Citation

  • Mircea Cretu Stancu & Markus J. Roosmalen & Ivo Renkens & Marleen M. Nieboer & Sjors Middelkamp & Joep Ligt & Giulia Pregno & Daniela Giachino & Giorgia Mandrile & Jose Espejo Valle-Inclan & Jerome Ko, 2017. "Mapping and phasing of structural variation in patient genomes using nanopore sequencing," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01343-4
    DOI: 10.1038/s41467-017-01343-4
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    Cited by:

    1. Yichen Henry Liu & Can Luo & Staunton G. Golding & Jacob B. Ioffe & Xin Maizie Zhou, 2024. "Tradeoffs in alignment and assembly-based methods for structural variant detection with long-read sequencing data," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Zhikun Wu & Zehang Jiang & Tong Li & Chuanbo Xie & Liansheng Zhao & Jiaqi Yang & Shuai Ouyang & Yizhi Liu & Tao Li & Zhi Xie, 2021. "Structural variants in the Chinese population and their impact on phenotypes, diseases and population adaptation," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    3. Yoshitaka Sakamoto & Shuhei Miyake & Miho Oka & Akinori Kanai & Yosuke Kawai & Satoi Nagasawa & Yuichi Shiraishi & Katsushi Tokunaga & Takashi Kohno & Masahide Seki & Yutaka Suzuki & Ayako Suzuki, 2022. "Phasing analysis of lung cancer genomes using a long read sequencer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Heyang Cui & Yong Zhou & Fang Wang & Caixia Cheng & Weimin Zhang & Ruifang Sun & Ling Zhang & Yanghui Bi & Min Guo & Yan Zhou & Xinhui Wang & Jiaxin Ren & Ruibing Bai & Ning Ding & Chen Cheng & Longlo, 2022. "Characterization of somatic structural variations in 528 Chinese individuals with Esophageal squamous cell carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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