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Nature. 2015 Jan 29;517(7536):608-11. doi: 10.1038/nature13907. Epub 2014 Nov 10.

Resolving the complexity of the human genome using single-molecule sequencing.

Author information

1
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
2
1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
3
Dipartimento di Biologia, Università degli Studi di Bari 'Aldo Moro', Bari 70125, Italy.
4
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
5
Pacific Biosciences of California, Inc., Menlo Park, California 94025, USA.

Abstract

The human genome is arguably the most complete mammalian reference assembly, yet more than 160 euchromatic gaps remain and aspects of its structural variation remain poorly understood ten years after its completion. To identify missing sequence and genetic variation, here we sequence and analyse a haploid human genome (CHM1) using single-molecule, real-time DNA sequencing. We close or extend 55% of the remaining interstitial gaps in the human GRCh37 reference genome--78% of which carried long runs of degenerate short tandem repeats, often several kilobases in length, embedded within (G+C)-rich genomic regions. We resolve the complete sequence of 26,079 euchromatic structural variants at the base-pair level, including inversions, complex insertions and long tracts of tandem repeats. Most have not been previously reported, with the greatest increases in sensitivity occurring for events less than 5 kilobases in size. Compared to the human reference, we find a significant insertional bias (3:1) in regions corresponding to complex insertions and long short tandem repeats. Our results suggest a greater complexity of the human genome in the form of variation of longer and more complex repetitive DNA that can now be largely resolved with the application of this longer-read sequencing technology.

PMID:
25383537
PMCID:
PMC4317254
DOI:
10.1038/nature13907
[Indexed for MEDLINE]
Free PMC Article

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