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Nucleic Acids Res. 2016 Jul 8;44(12):e111. doi: 10.1093/nar/gkw281. Epub 2016 Apr 21.

InPhaDel: integrative shotgun and proximity-ligation sequencing to phase deletions with single nucleotide polymorphisms.

Author information

1
Bioinformatics and Systems Biology Program, University of California, San Diego 9500 Gilman Drive, La Jolla, CA 92093, USA Department of Computer Science and Engineering, University of California, San Diego 9500 Gilman Drive, La Jolla, CA 92093, USA adp002@ucsd.edu.
2
Department of Computer Science and Engineering, University of California, San Diego 9500 Gilman Drive, La Jolla, CA 92093, USA.
3
Bioinformatics and Systems Biology Program, University of California, San Diego 9500 Gilman Drive, La Jolla, CA 92093, USA.
4
Department of Pediatrics, School of Medicine, University of California, San Diego 9500 Gilman Drive, La Jolla, CA 92093, USA.
5
Bioinformatics and Systems Biology Program, University of California, San Diego 9500 Gilman Drive, La Jolla, CA 92093, USA Department of Computer Science and Engineering, University of California, San Diego 9500 Gilman Drive, La Jolla, CA 92093, USA.

Abstract

Phasing of single nucleotide (SNV), and structural variations into chromosome-wide haplotypes in humans has been challenging, and required either trio sequencing or restricting phasing to population-based haplotypes. Selvaraj et al demonstrated single individual SNV phasing is possible with proximity ligated (HiC) sequencing. Here, we demonstrate HiC can phase structural variants into phased scaffolds of SNVs. Since HiC data is noisy, and SV calling is challenging, we applied a range of supervised classification techniques, including Support Vector Machines and Random Forest, to phase deletions. Our approach was demonstrated on deletion calls and phasings on the NA12878 human genome. We used three NA12878 chromosomes and simulated chromosomes to train model parameters. The remaining NA12878 chromosomes withheld from training were used to evaluate phasing accuracy. Random Forest had the highest accuracy and correctly phased 86% of the deletions with allele-specific read evidence. Allele-specific read evidence was found for 76% of the deletions. HiC provides significant read evidence for accurately phasing 33% of the deletions. Also, eight of eight top ranked deletions phased by only HiC were validated using long range polymerase chain reaction and Sanger. Thus, deletions from a single individual can be accurately phased using a combination of shotgun and proximity ligation sequencing. InPhaDel software is available at: http://l337x911.github.io/inphadel/.

PMID:
27105843
PMCID:
PMC4937317
DOI:
10.1093/nar/gkw281
[Indexed for MEDLINE]
Free PMC Article

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