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GRIDSS2: harnessing the power of phasing and single breakends in somatic structural variant detection

View ORCID ProfileDaniel L. Cameron, Jonathan Baber, Charles Shale, Jose Espejo Valle-Inclan, Nicolle Besselink, View ORCID ProfileEdwin Cuppen, View ORCID ProfilePeter Priestley, View ORCID ProfileAnthony T. Papenfuss
doi: https://doi.org/10.1101/2020.07.09.196527
Daniel L. Cameron
1Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
2Hartwig Medical Foundation Australia, Sydney, Australia
5Department of Medical Biology, University of Melbourne, Australia
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  • For correspondence: papenfuss@wehi.edu.au cameron.d@wehi.edu.au
Jonathan Baber
2Hartwig Medical Foundation Australia, Sydney, Australia
3Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
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Charles Shale
2Hartwig Medical Foundation Australia, Sydney, Australia
3Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
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Jose Espejo Valle-Inclan
4Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands
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Nicolle Besselink
4Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands
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Edwin Cuppen
3Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
4Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands
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Peter Priestley
2Hartwig Medical Foundation Australia, Sydney, Australia
3Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
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Anthony T. Papenfuss
1Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
5Department of Medical Biology, University of Melbourne, Australia
6Peter MacCallum Cancer Centre, Melbourne, Australia
7Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia
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  • ORCID record for Anthony T. Papenfuss
  • For correspondence: papenfuss@wehi.edu.au cameron.d@wehi.edu.au
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Abstract

Here we present GRIDSS2, a general purpose structural variant caller optimised for tumour/normal somatic calling. Using cell line, patient sample validation and cohort-level comparisons, we show GRIDSS2 outperforms recent state-of-the-art tools. We demonstrate GRIDSS2 retains high sensitivity and precision even for small events by identifying a small (32-100bp) duplication signature strongly associated with colorectal cancer using 3,782 metastatic cancers that have been deeply sequenced by the Hartwig Medical Foundation. Essential to the high precision achieved by GRIDSS2 is the novel reporting of single breakend variants: structural variants in which only one side can be unambiguously determined. We show that the inclusion of single breakends reduces the false negative rate from 10.4% to 3.4%. Demonstrating the power single breakend calling has in genomic regions traditionally considered inaccessible to short read callers, we find that 47% of somatic centromeric breaks are repaired to non-centromeric sequence, with chromosome 1 exhibiting a unique centromeric rearrangement signature. Finally, we show that somatic structural variants are highly clustered with GRIDSS2 able to phase 16% of somatic structural variants in the Hartwig cohort from short read sequencing alone.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://github.com/PapenfussLab/gridss

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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GRIDSS2: harnessing the power of phasing and single breakends in somatic structural variant detection
Daniel L. Cameron, Jonathan Baber, Charles Shale, Jose Espejo Valle-Inclan, Nicolle Besselink, Edwin Cuppen, Peter Priestley, Anthony T. Papenfuss
bioRxiv 2020.07.09.196527; doi: https://doi.org/10.1101/2020.07.09.196527
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GRIDSS2: harnessing the power of phasing and single breakends in somatic structural variant detection
Daniel L. Cameron, Jonathan Baber, Charles Shale, Jose Espejo Valle-Inclan, Nicolle Besselink, Edwin Cuppen, Peter Priestley, Anthony T. Papenfuss
bioRxiv 2020.07.09.196527; doi: https://doi.org/10.1101/2020.07.09.196527

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