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

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 Korzelius, Ewart Bruijn, Edwin Cuppen, Michael E. Talkowski, Tobias Marschall, Jeroen Ridder and Wigard P. Kloosterman ()
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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
Tobias Marschall: Center for Bioinformatics, Saarland University
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

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01343-4

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