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A fully phased accurate assembly of an individual human genome

View ORCID ProfileDavid Porubsky, View ORCID ProfilePeter Ebert, Peter A. Audano, Mitchell R. Vollger, William T. Harvey, Katherine M. Munson, Melanie Sorensen, Arvis Sulovari, Marina Haukness, Maryam Ghareghani, Human Genome Structural Variation Consortium, Peter M. Lansdorp, Benedict Paten, Scott E. Devine, Ashley D. Sanders, Charles Lee, Mark J.P. Chaisson, Jan O. Korbel, View ORCID ProfileEvan E. Eichler, View ORCID ProfileTobias Marschall
doi: https://doi.org/10.1101/855049
David Porubsky
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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Peter Ebert
2Center for Bioinformatics, Saarland University, Saarland Informatics Campus E2.1, 66123 Saarbrücken, Germany
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Peter A. Audano
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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Mitchell R. Vollger
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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William T. Harvey
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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Katherine M. Munson
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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Melanie Sorensen
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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Arvis Sulovari
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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Marina Haukness
3UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA
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Maryam Ghareghani
2Center for Bioinformatics, Saarland University, Saarland Informatics Campus E2.1, 66123 Saarbrücken, Germany
4Max Planck Institute for Informatics, Saarland Informatics Campus E1.4, Saarbrücken, Germany
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5HGSVC author names are listed in the Supplementary Note
Peter M. Lansdorp
6Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada
7Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
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Benedict Paten
3UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA
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Scott E. Devine
8Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
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Ashley D. Sanders
9European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany
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Charles Lee
10The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
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Mark J.P. Chaisson
11Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
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Jan O. Korbel
9European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany
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Evan E. Eichler
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
12Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
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  • For correspondence: t.marschall@mpi-inf.mpg.de eee@gs.washington.edu
Tobias Marschall
2Center for Bioinformatics, Saarland University, Saarland Informatics Campus E2.1, 66123 Saarbrücken, Germany
4Max Planck Institute for Informatics, Saarland Informatics Campus E1.4, Saarbrücken, Germany
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  • ORCID record for Tobias Marschall
  • For correspondence: t.marschall@mpi-inf.mpg.de eee@gs.washington.edu
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Abstract

The prevailing genome assembly paradigm is to produce consensus sequences that “collapse” parental haplotypes into a consensus sequence. Here, we leverage the chromosome-wide phasing and scaffolding capabilities of single-cell strand sequencing (Strand-seq)1,2 and combine them with high-fidelity (HiFi) long sequencing reads3, in a novel reference-free workflow for diploid de novo genome assembly. Employing this strategy, we produce completely phased de novo genome assemblies separately for each haplotype of a single individual of Puerto Rican origin (HG00733) in the absence of parental data. The assemblies are accurate (QV > 40), highly contiguous (contig N50 > 25 Mbp) with low switch error rates (0.4%) providing fully phased single-nucleotide variants (SNVs), indels, and structural variants (SVs). A comparison of Oxford Nanopore and PacBio phased assemblies identifies 150 regions that are preferential sites of contig breaks irrespective of sequencing technology or phasing algorithms.

Footnotes

  • ↵* These authors should be regarded as joint first authors of the manuscript.

  • ↵† These authors should be regarded as joint senior authors of the manuscript.

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.
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Posted November 26, 2019.
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A fully phased accurate assembly of an individual human genome
David Porubsky, Peter Ebert, Peter A. Audano, Mitchell R. Vollger, William T. Harvey, Katherine M. Munson, Melanie Sorensen, Arvis Sulovari, Marina Haukness, Maryam Ghareghani, Human Genome Structural Variation Consortium, Peter M. Lansdorp, Benedict Paten, Scott E. Devine, Ashley D. Sanders, Charles Lee, Mark J.P. Chaisson, Jan O. Korbel, Evan E. Eichler, Tobias Marschall
bioRxiv 855049; doi: https://doi.org/10.1101/855049
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A fully phased accurate assembly of an individual human genome
David Porubsky, Peter Ebert, Peter A. Audano, Mitchell R. Vollger, William T. Harvey, Katherine M. Munson, Melanie Sorensen, Arvis Sulovari, Marina Haukness, Maryam Ghareghani, Human Genome Structural Variation Consortium, Peter M. Lansdorp, Benedict Paten, Scott E. Devine, Ashley D. Sanders, Charles Lee, Mark J.P. Chaisson, Jan O. Korbel, Evan E. Eichler, Tobias Marschall
bioRxiv 855049; doi: https://doi.org/10.1101/855049

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