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Dense and accurate whole-chromosome haplotyping of individual genomes

David Porubsky, Shilpa Garg, Ashley D. Sanders, Jan O. Korbel, Victor Guryev, Peter M. Lansdorp, Tobias Marschall
doi: https://doi.org/10.1101/126136
David Porubsky
1European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
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Shilpa Garg
2Center for Bioinformatics, Saarland University, Saarbrücken, Germany
3Max Planck Institute for Informatics, Saarbrücken, Germany
4Graduate School of Computer Science, Saarland University, Saarbrücken, Germany
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Ashley D. Sanders
5European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
6Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
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Jan O. Korbel
5European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
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Victor Guryev
1European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
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Peter M. Lansdorp
1European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
6Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
7Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
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Tobias Marschall
2Center for Bioinformatics, Saarland University, Saarbrücken, Germany
3Max Planck Institute for Informatics, Saarbrücken, Germany
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  • For correspondence: t.marschall@mpi-inf.mpg.de
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ABSTRACT

The diploid nature of the genome is neglected in many analyses done today, where a genome is perceived as a set of unphased variants with respect to a reference genome. Many important biological phenomena such as compound heterozygosity and epistatic effects between enhancers and target genes, however, can only be studied when haplotype-resolved genomes are available. This lack of haplotype-level analyses can be explained by a dearth of methods to produce dense and accurate chromosome-length haplotypes at reasonable costs. Here we introduce an integrative phasing strategy that combines global, but sparse haplotypes obtained from strand-specific single cell sequencing (Strand-seq) with dense, yet local, haplotype information available through long-read or linked-read sequencing. Our experiments provide comprehensive guidance on favorable combinations of Strand-seq libraries and sequencing coverages to obtain complete and genome-wide haplotypes of a single individual genome (NA12878) at manageable costs. We were able to reliably assign > 95% of alleles to their parental haplotypes using as few as 10 Strand-seq libraries in combination with 10-fold coverage PacBio data or, alternatively, 10X Genomics linked-read sequencing data. We conclude that the combination of Strand-seq with different sequencing technologies represents an attractive solution to chart the unique genetic variation of diploid genomes.

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Posted April 10, 2017.
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Dense and accurate whole-chromosome haplotyping of individual genomes
David Porubsky, Shilpa Garg, Ashley D. Sanders, Jan O. Korbel, Victor Guryev, Peter M. Lansdorp, Tobias Marschall
bioRxiv 126136; doi: https://doi.org/10.1101/126136
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Dense and accurate whole-chromosome haplotyping of individual genomes
David Porubsky, Shilpa Garg, Ashley D. Sanders, Jan O. Korbel, Victor Guryev, Peter M. Lansdorp, Tobias Marschall
bioRxiv 126136; doi: https://doi.org/10.1101/126136

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