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Nat Methods. 2015 Aug;12(8):780-6. doi: 10.1038/nmeth.3454. Epub 2015 Jun 29.

Assembly and diploid architecture of an individual human genome via single-molecule technologies.

Author information

1
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
BioNano Genomics, San Diego, California, USA.
3
Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
4
The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA.
5
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, USA.
6
Pacific Biosciences, Menlo Park, California, USA.
7
1] Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany. [2] European Bioinformatics Institute, European Molecular Biology Laboratory, Hinxton, UK.
8
1] Laboratory of Neuro-Oncology, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, New York, New York, USA.
9
1] The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. [2] The Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
10
Institute for Human Genetics, University of California-San Francisco, San Francisco, California, USA.
11
1] The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA. [2] Department of Medicine, Division of Hematology/Oncology, Weill Cornell Medical College, New York, New York, USA. [3] The Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.

Abstract

We present the first comprehensive analysis of a diploid human genome that combines single-molecule sequencing with single-molecule genome maps. Our hybrid assembly markedly improves upon the contiguity observed from traditional shotgun sequencing approaches, with scaffold N50 values approaching 30 Mb, and we identified complex structural variants (SVs) missed by other high-throughput approaches. Furthermore, by combining Illumina short-read data with long reads, we phased both single-nucleotide variants and SVs, generating haplotypes with over 99% consistency with previous trio-based studies. Our work shows that it is now possible to integrate single-molecule and high-throughput sequence data to generate de novo assembled genomes that approach reference quality.

PMID:
26121404
PMCID:
PMC4646949
DOI:
10.1038/nmeth.3454
[Indexed for MEDLINE]
Free PMC Article
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