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Deep Sequencing of 10,000 Human Genomes

View ORCID ProfileAmalio Telenti, Levi C.T. Pierce, William H. Biggs, Julia di Iulio, Emily H.M. Wong, Martin M. Fabani, Ewen F. Kirkness, Ahmed Moustafa, Naisha Shah, Chao Xie, Suzanne C. Brewerton, Nadeem Bulsara, Chad Garner, Gary Metzker, Efren Sandoval, Brad A. Perkins, Franz J. Och, Yaron Turpaz, J. Craig Venter
doi: https://doi.org/10.1101/061663
Amalio Telenti
aHuman Longevity Inc., San Diego, CA USA
bJ. Craig Venter Institute, La Jolla, CA USA
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  • ORCID record for Amalio Telenti
Levi C.T. Pierce
aHuman Longevity Inc., San Diego, CA USA
dHuman Longevity Inc., Mountain View, CA USA
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William H. Biggs
aHuman Longevity Inc., San Diego, CA USA
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Julia di Iulio
aHuman Longevity Inc., San Diego, CA USA
bJ. Craig Venter Institute, La Jolla, CA USA
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Emily H.M. Wong
aHuman Longevity Inc., San Diego, CA USA
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Martin M. Fabani
aHuman Longevity Inc., San Diego, CA USA
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Ewen F. Kirkness
aHuman Longevity Inc., San Diego, CA USA
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Ahmed Moustafa
aHuman Longevity Inc., San Diego, CA USA
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Naisha Shah
aHuman Longevity Inc., San Diego, CA USA
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Chao Xie
cHuman Longevity Singapore Pte. Ltd. Singapore
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Suzanne C. Brewerton
cHuman Longevity Singapore Pte. Ltd. Singapore
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Nadeem Bulsara
aHuman Longevity Inc., San Diego, CA USA
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Chad Garner
aHuman Longevity Inc., San Diego, CA USA
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Gary Metzker
aHuman Longevity Inc., San Diego, CA USA
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Efren Sandoval
aHuman Longevity Inc., San Diego, CA USA
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Brad A. Perkins
aHuman Longevity Inc., San Diego, CA USA
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Franz J. Och
aHuman Longevity Inc., San Diego, CA USA
dHuman Longevity Inc., Mountain View, CA USA
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Yaron Turpaz
aHuman Longevity Inc., San Diego, CA USA
cHuman Longevity Singapore Pte. Ltd. Singapore
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J. Craig Venter
aHuman Longevity Inc., San Diego, CA USA
bJ. Craig Venter Institute, La Jolla, CA USA
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  • For correspondence: jcventer@humanlongevity.com
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Abstract

We report on the sequencing of 10,545 human genomes at 30-40x coverage with an emphasis on quality metrics and novel variant and sequence discovery. We find that 84% of an individual human genome can be sequenced confidently. This high confidence region includes 91.5% of exon sequence and 95.2% of known pathogenic variant positions. We present thedistribution of over 150 million single nucleotide variants in the coding and non-coding genome. Each newly sequenced genome contributes an average of 8,579 novel variants. In addition, each genome carries in average 0.7 Mb of sequence that is not found in the main build of the hg38 reference genome. The density of this catalog of variation allowed us to construct highresolution profiles that define genomic sites that are highly intolerant of genetic variation. These results indicate that the data generated by deep genome sequencing is of the quality necessary for clinical use.

Significance statement Declining sequencing costs and new large-scale initiatives towards personalized medicine are driving a massive expansion in the number of human genomes being sequenced. Therefore, there is an urgent need to define quality standards for clinical use. This includes deep coverage and sequencing accuracy of an individual’s genome, rather than aggregated coverage of data across a cohort or population. Our work represents the largest effort to date in sequencing human genomes at deep coverage with these new standards. This study identifies over 150 million human variants, a majority of them rare and unknown. Moreover, these data identify sites in the genome that are highly intolerant to variation - possibly essential for life or health. We conclude that high coverage genome sequencing provides accurate detail on human variation for discovery and for clinical applications.

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-ND 4.0 International license.
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Posted July 01, 2016.
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Deep Sequencing of 10,000 Human Genomes
Amalio Telenti, Levi C.T. Pierce, William H. Biggs, Julia di Iulio, Emily H.M. Wong, Martin M. Fabani, Ewen F. Kirkness, Ahmed Moustafa, Naisha Shah, Chao Xie, Suzanne C. Brewerton, Nadeem Bulsara, Chad Garner, Gary Metzker, Efren Sandoval, Brad A. Perkins, Franz J. Och, Yaron Turpaz, J. Craig Venter
bioRxiv 061663; doi: https://doi.org/10.1101/061663
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Deep Sequencing of 10,000 Human Genomes
Amalio Telenti, Levi C.T. Pierce, William H. Biggs, Julia di Iulio, Emily H.M. Wong, Martin M. Fabani, Ewen F. Kirkness, Ahmed Moustafa, Naisha Shah, Chao Xie, Suzanne C. Brewerton, Nadeem Bulsara, Chad Garner, Gary Metzker, Efren Sandoval, Brad A. Perkins, Franz J. Och, Yaron Turpaz, J. Craig Venter
bioRxiv 061663; doi: https://doi.org/10.1101/061663

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