New Results
Germline determinants of the somatic mutation landscape in 2,642 cancer genomes
View ORCID ProfileSebastian M Waszak, Grace Tiao, Bin Zhu, Tobias Rausch, Francesc Muyas, Bernardo Rodríguez-Martín, Raquel Rabionet, Sergei Yakneen, Georgia Escaramis, Yilong Li, Natalie Saini, Steven A Roberts, German M Demidov, Esa Pitkänen, Olivier Delaneau, Jose Maria Heredia-Genestar, Joachim Weischenfeldt, Suyash S Shringarpure, Jieming Chen, Hidewaki Nakagawa, Ludmil B Alexandrov, Oliver Drechsel, L Jonathan Dursi, Ayellet V Segre, Erik Garrison, Serap Erkek, Nina Habermann, Lara Urban, Ekta Khurana, Andy Cafferkey, Shuto Hayashi, Seiya Imoto, Lauri A Aaltonen, Eva G Alvarez, Adrian Baez-Ortega, Matthew Bailey, Mattia Bosio, Alicia L Bruzos, Ivo Buchhalter, Carlos D. Bustamante, Claudia Calabrese, Anthony DiBiase, Mark Gerstein, Aliaksei Z Holik, Xing Hua, Kuan-lin Huang, Ivica Letunic, Leszek J Klimczak, Roelof Koster, Sushant Kumar, Mike McLellan, Jay Mashl, Lisa Mirabello, Steven Newhouse, Aparna Prasad, Gunnar Rätsch, Matthias Schlesner, Roland Schwarz, Pramod Sharma, Tal Shmaya, Nikos Sidiropoulos, Lei Song, Hana Susak, Tomas Tanskanen, Marta Tojo, David C Wedge, Mark Wright, Ying Wu, Kai Ye, Venkata D Yellapantula, Jorge Zamora, Atul J Butte, Gad Getz, Jared Simpson, Li Ding, Tomas Marques-Bonet, Arcadi Navarro, Alvis Brazma, Peter Campbell, Stephen J Chanock, Nilanjan Chatterjee, Oliver Stegle, Reiner Siebert, Stephan Ossowski, Olivier Harismendy, Dmitry A Gordenin, Jose MC Tubio, Francisco M De La Vega, Douglas F Easton, Xavier Estivill, Jan O Korbel, on behalf of the PCAWG Germline Working group%, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
doi: https://doi.org/10.1101/208330
Sebastian M Waszak
1European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Grace Tiao
2The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02124, USA.
Bin Zhu
3Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Tobias Rausch
1European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Francesc Muyas
4Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
5Universitat Pompeu Fabra, Barcelona, Spain.
Bernardo Rodríguez-Martín
6Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.
7Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
Raquel Rabionet
4Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
Sergei Yakneen
1European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Georgia Escaramis
4Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
8CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
Yilong Li
9Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Natalie Saini
10Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, NC, USA.
Steven A Roberts
11School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
German M Demidov
4Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
5Universitat Pompeu Fabra, Barcelona, Spain.
Esa Pitkänen
1European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Olivier Delaneau
12Swiss Institute of Bioinformatics, University of Geneva, 1 Michel Servet, Geneva CH1211, Switzerland.
13Department of Genetic Medicine and Development, University of Geneva, 1 Michel Servet, Geneva CH1211, Switzerland.
14Institute of Genetics and Genomics in Geneva, University of Geneva, 1 Michel Servet, Geneva CH1211, Switzerland.
Jose Maria Heredia-Genestar
15Institute of Evolutionary Biology (UPF-CSIC), Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, Doctor Aiguader 88, Barcelona, 08003, Spain.
Joachim Weischenfeldt
1European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
16Biotech Research &Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory, Rigshospitalet, Denmark.
Suyash S Shringarpure
17Annai Systems, 1700 Aviara Parkway 130063, Carlsbad, CA 92013, USA.
Jieming Chen
18Institute for Computational Health Sciences and Department of Pediatrics, University of California, San Francisco, California 94143, USA.
Hidewaki Nakagawa
19RIKEN Center for Integrative Medical Sciences, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Ludmil B Alexandrov
20Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
Oliver Drechsel
4Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
5Universitat Pompeu Fabra, Barcelona, Spain.
L Jonathan Dursi
21Ontario Institute for Cancer Research, 661 University Ave, Suite 510, Toronto, ON M5G 0A3, Canada.
Ayellet V Segre
2The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02124, USA.
Erik Garrison
9Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Serap Erkek
1European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Nina Habermann
1European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Lara Urban
22European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
Ekta Khurana
23Sandra and Edward Meyer Cancer Center, Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA.
Andy Cafferkey
22European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
Shuto Hayashi
24Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Seiya Imoto
25Health Intelligence Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Lauri A Aaltonen
26Department of Medical and Clinical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Finland.
Eva G Alvarez
6Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.
7Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
Adrian Baez-Ortega
27Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK.
Matthew Bailey
33Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, 06520, USA.
Mattia Bosio
4Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
5Universitat Pompeu Fabra, Barcelona, Spain.
Alicia L Bruzos
6Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.
7Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
Ivo Buchhalter
28Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Carlos D. Bustamante
29Departments of Genetics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
Claudia Calabrese
22European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
Anthony DiBiase
30Cray Inc. 901 Fifth Avenue, Seattle, WA 98164, USA.
Mark Gerstein
31Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA.
32Department of Computer Science, Yale University, New Haven, CT, 06520, USA.
33Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, 06520, USA.
Aliaksei Z Holik
4Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
5Universitat Pompeu Fabra, Barcelona, Spain.
Xing Hua
3Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Kuan-lin Huang
34The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Ivica Letunic
35Biobyte solutions GmbH, Bothestrasse 142, 69126 Heidelberg, Germany.
Leszek J Klimczak
36Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.
Roelof Koster
3Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Sushant Kumar
31Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA.
Mike McLellan
34The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Jay Mashl
34The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Lisa Mirabello
3Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Steven Newhouse
22European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
Aparna Prasad
4Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
5Universitat Pompeu Fabra, Barcelona, Spain.
Gunnar Rätsch
37Department of Computer Science, Swiss Federal Institute of Technology in Zurich, 8092, Switzerland.
Matthias Schlesner
28Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Roland Schwarz
38Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
Pramod Sharma
30Cray Inc. 901 Fifth Avenue, Seattle, WA 98164, USA.
Tal Shmaya
17Annai Systems, 1700 Aviara Parkway 130063, Carlsbad, CA 92013, USA.
Nikos Sidiropoulos
16Biotech Research &Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory, Rigshospitalet, Denmark.
Lei Song
3Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Hana Susak
4Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
5Universitat Pompeu Fabra, Barcelona, Spain.
Tomas Tanskanen
26Department of Medical and Clinical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Finland.
Marta Tojo
6Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.
7Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
David C Wedge
39Oxford Big Data Institute and Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, Oxford, UK.
Mark Wright
29Departments of Genetics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
Ying Wu
17Annai Systems, 1700 Aviara Parkway 130063, Carlsbad, CA 92013, USA.
Kai Ye
40McDonnell Genome Institute, Washington University, St. Louis, Missouri 63108, USA.
41Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri 63108, USA.
Venkata D Yellapantula
40McDonnell Genome Institute, Washington University, St. Louis, Missouri 63108, USA.
41Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri 63108, USA.
Jorge Zamora
6Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.
7Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
Atul J Butte
18Institute for Computational Health Sciences and Department of Pediatrics, University of California, San Francisco, California 94143, USA.
Gad Getz
2The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02124, USA.
42Harvard Medical School, Boston, Massachusetts 02115, USA.
Jared Simpson
43Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
Li Ding
34The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Tomas Marques-Bonet
15Institute of Evolutionary Biology (UPF-CSIC), Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, Doctor Aiguader 88, Barcelona, 08003, Spain.
Arcadi Navarro
15Institute of Evolutionary Biology (UPF-CSIC), Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, Doctor Aiguader 88, Barcelona, 08003, Spain.
Alvis Brazma
22European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
Peter Campbell
44Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
Stephen J Chanock
3Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Nilanjan Chatterjee
45Department of Biostatistics, Bloomberg School of Public Health and Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Oliver Stegle
1European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Reiner Siebert
46Institute of Human Genetics, University of Ulm, Ulm, Germany.
Stephan Ossowski
4Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
5Universitat Pompeu Fabra, Barcelona, Spain.
47Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Olivier Harismendy
48Moores Cancer Center, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Dmitry A Gordenin
10Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, NC, USA.
Jose MC Tubio
6Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.
7Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
Francisco M De La Vega
17Annai Systems, 1700 Aviara Parkway 130063, Carlsbad, CA 92013, USA.
29Departments of Genetics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
Douglas F Easton
49Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Xavier Estivill
4Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
Jan O Korbel
1European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
22European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
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Abstract
Cancers develop through somatic mutagenesis, however germline genetic variation can markedly contribute to tumorigenesis via diverse mechanisms. We discovered and phased 88 million germline single nucleotide variants, short insertions/deletions, and large structural variants in whole genomes from 2,642 cancer patients, and employed this genomic resource to study genetic determinants of somatic mutagenesis across 39 cancer types. Our analyses implicate damaging germline variants in a variety of cancer predisposition and DNA damage response genes with specific somatic mutation patterns. Mutations in the MBD4 DNA glycosylase gene showed association with elevated C>T mutagenesis at CpG dinucleotides, a ubiquitous mutational process acting across tissues. Analysis of somatic structural variation exposed complex rearrangement patterns, involving cycles of templated insertions and tandem duplications, in BRCA1-deficient tumours. Genome-wide association analysis implicated common genetic variation at the APOBEC3 gene cluster with reduced basal levels of somatic mutagenesis attributable to APOBEC cytidine deaminases across cancer types. We further inferred over a hundred polymorphic L1/LINE elements with somatic retrotransposition activity in cancer. Our study highlights the major impact of rare and common germline variants on mutational landscapes in cancer.
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-NC-ND 4.0 International license.
Posted November 01, 2017.
Germline determinants of the somatic mutation landscape in 2,642 cancer genomes
Sebastian M Waszak, Grace Tiao, Bin Zhu, Tobias Rausch, Francesc Muyas, Bernardo Rodríguez-Martín, Raquel Rabionet, Sergei Yakneen, Georgia Escaramis, Yilong Li, Natalie Saini, Steven A Roberts, German M Demidov, Esa Pitkänen, Olivier Delaneau, Jose Maria Heredia-Genestar, Joachim Weischenfeldt, Suyash S Shringarpure, Jieming Chen, Hidewaki Nakagawa, Ludmil B Alexandrov, Oliver Drechsel, L Jonathan Dursi, Ayellet V Segre, Erik Garrison, Serap Erkek, Nina Habermann, Lara Urban, Ekta Khurana, Andy Cafferkey, Shuto Hayashi, Seiya Imoto, Lauri A Aaltonen, Eva G Alvarez, Adrian Baez-Ortega, Matthew Bailey, Mattia Bosio, Alicia L Bruzos, Ivo Buchhalter, Carlos D. Bustamante, Claudia Calabrese, Anthony DiBiase, Mark Gerstein, Aliaksei Z Holik, Xing Hua, Kuan-lin Huang, Ivica Letunic, Leszek J Klimczak, Roelof Koster, Sushant Kumar, Mike McLellan, Jay Mashl, Lisa Mirabello, Steven Newhouse, Aparna Prasad, Gunnar Rätsch, Matthias Schlesner, Roland Schwarz, Pramod Sharma, Tal Shmaya, Nikos Sidiropoulos, Lei Song, Hana Susak, Tomas Tanskanen, Marta Tojo, David C Wedge, Mark Wright, Ying Wu, Kai Ye, Venkata D Yellapantula, Jorge Zamora, Atul J Butte, Gad Getz, Jared Simpson, Li Ding, Tomas Marques-Bonet, Arcadi Navarro, Alvis Brazma, Peter Campbell, Stephen J Chanock, Nilanjan Chatterjee, Oliver Stegle, Reiner Siebert, Stephan Ossowski, Olivier Harismendy, Dmitry A Gordenin, Jose MC Tubio, Francisco M De La Vega, Douglas F Easton, Xavier Estivill, Jan O Korbel, on behalf of the PCAWG Germline Working group%, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 208330; doi: https://doi.org/10.1101/208330
Germline determinants of the somatic mutation landscape in 2,642 cancer genomes
Sebastian M Waszak, Grace Tiao, Bin Zhu, Tobias Rausch, Francesc Muyas, Bernardo Rodríguez-Martín, Raquel Rabionet, Sergei Yakneen, Georgia Escaramis, Yilong Li, Natalie Saini, Steven A Roberts, German M Demidov, Esa Pitkänen, Olivier Delaneau, Jose Maria Heredia-Genestar, Joachim Weischenfeldt, Suyash S Shringarpure, Jieming Chen, Hidewaki Nakagawa, Ludmil B Alexandrov, Oliver Drechsel, L Jonathan Dursi, Ayellet V Segre, Erik Garrison, Serap Erkek, Nina Habermann, Lara Urban, Ekta Khurana, Andy Cafferkey, Shuto Hayashi, Seiya Imoto, Lauri A Aaltonen, Eva G Alvarez, Adrian Baez-Ortega, Matthew Bailey, Mattia Bosio, Alicia L Bruzos, Ivo Buchhalter, Carlos D. Bustamante, Claudia Calabrese, Anthony DiBiase, Mark Gerstein, Aliaksei Z Holik, Xing Hua, Kuan-lin Huang, Ivica Letunic, Leszek J Klimczak, Roelof Koster, Sushant Kumar, Mike McLellan, Jay Mashl, Lisa Mirabello, Steven Newhouse, Aparna Prasad, Gunnar Rätsch, Matthias Schlesner, Roland Schwarz, Pramod Sharma, Tal Shmaya, Nikos Sidiropoulos, Lei Song, Hana Susak, Tomas Tanskanen, Marta Tojo, David C Wedge, Mark Wright, Ying Wu, Kai Ye, Venkata D Yellapantula, Jorge Zamora, Atul J Butte, Gad Getz, Jared Simpson, Li Ding, Tomas Marques-Bonet, Arcadi Navarro, Alvis Brazma, Peter Campbell, Stephen J Chanock, Nilanjan Chatterjee, Oliver Stegle, Reiner Siebert, Stephan Ossowski, Olivier Harismendy, Dmitry A Gordenin, Jose MC Tubio, Francisco M De La Vega, Douglas F Easton, Xavier Estivill, Jan O Korbel, on behalf of the PCAWG Germline Working group%, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 208330; doi: https://doi.org/10.1101/208330
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