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High coverage whole genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios

Marta Byrska-Bishop, Uday S. Evani, Xuefang Zhao, Anna O. Basile, Haley J. Abel, Allison A. Regier, André Corvelo, Wayne E. Clarke, Rajeeva Musunuri, Kshithija Nagulapalli, Susan Fairley, Alexi Runnels, Lara Winterkorn, Ernesto Lowy-Gallego, The Human Genome Structural Variation Consortium, Paul Flicek, Soren Germer, Harrison Brand, View ORCID ProfileIra M. Hall, Michael E. Talkowski, View ORCID ProfileGiuseppe Narzisi, Michael C. Zody
doi: https://doi.org/10.1101/2021.02.06.430068
Marta Byrska-Bishop
1New York Genome Center, New York, NY, USA
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  • For correspondence: mczody@nygenome.org mbyrska-bishop@nygenome.org
Uday S. Evani
1New York Genome Center, New York, NY, USA
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Xuefang Zhao
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
4Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Anna O. Basile
1New York Genome Center, New York, NY, USA
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Haley J. Abel
5McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
6Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Allison A. Regier
5McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
6Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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André Corvelo
1New York Genome Center, New York, NY, USA
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Wayne E. Clarke
1New York Genome Center, New York, NY, USA
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Rajeeva Musunuri
1New York Genome Center, New York, NY, USA
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Kshithija Nagulapalli
1New York Genome Center, New York, NY, USA
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Susan Fairley
7European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
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Alexi Runnels
1New York Genome Center, New York, NY, USA
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Lara Winterkorn
1New York Genome Center, New York, NY, USA
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Ernesto Lowy-Gallego
7European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
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8List of the HGSVC authors and corresponding affiliations are at the end of the manuscript
Paul Flicek
7European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
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Soren Germer
1New York Genome Center, New York, NY, USA
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Harrison Brand
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
4Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Ira M. Hall
5McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
6Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
10Center for Genomic Health, Yale University School of Medicine, New Haven, CT, USA
11Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
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  • ORCID record for Ira M. Hall
Michael E. Talkowski
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
4Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Giuseppe Narzisi
1New York Genome Center, New York, NY, USA
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  • ORCID record for Giuseppe Narzisi
Michael C. Zody
1New York Genome Center, New York, NY, USA
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  • For correspondence: mczody@nygenome.org mbyrska-bishop@nygenome.org
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ABSTRACT

The 1000 Genomes Project (1kGP), launched in 2008, is the largest fully open resource of whole genome sequencing (WGS) data consented for public distribution of raw sequence data without access or use restrictions. The final (phase 3) 2015 release of 1kGP included 2,504 unrelated samples from 26 populations, representing five continental regions of the world and was based on a combination of technologies including low coverage WGS (mean depth 7.4X), high coverage whole exome sequencing (mean depth 65.7X), and microarray genotyping. Here, we present a new, high coverage WGS resource encompassing the original 2,504 1kGP samples, as well as an additional 698 related samples that result in 602 complete trios in the 1kGP cohort. We sequenced this expanded 1kGP cohort of 3,202 samples to a targeted depth of 30X using Illumina NovaSeq 6000 instruments. We performed SNV/INDEL calling against the GRCh38 reference using GATK’s HaplotypeCaller, and generated a comprehensive set of SVs by integrating multiple analytic methods through a sophisticated machine learning model, upgrading the 1kGP dataset to current state-of-the-art standards. Using this strategy, we defined over 111 million SNVs, 14 million INDELs, and ∼170 thousand SVs across the entire cohort of 3,202 samples with estimated false discovery rate (FDR) of 0.3%, 1.0%, and 1.8%, respectively. By comparison to the low-coverage phase 3 callset, we observed substantial improvements in variant discovery and estimated FDR that were facilitated by high coverage re-sequencing and expansion of the cohort. Specifically, we called 7% more SNVs, 59% more INDELs, and 170% more SVs per genome than the phase 3 callset. Moreover, we leveraged the presence of families in the cohort to achieve superior haplotype phasing accuracy and we demonstrate improvements that the high coverage panel brings especially for INDEL imputation. We make all the data generated as part of this project publicly available and we envision this updated version of the 1kGP callset to become the new de facto public resource for the worldwide scientific community working on genomics and genetics.

Competing Interest Statement

M.C.Z. is a shareholder in Merck & Co and Thermo Fisher Scientific. P.F. is a member of the scientific advisory boards of Fabric Genomics, Inc., and Eagle Genomics, Ltd. J.L. is an employee and shareholder of Bionano Genomics.

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 February 07, 2021.
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High coverage whole genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios
Marta Byrska-Bishop, Uday S. Evani, Xuefang Zhao, Anna O. Basile, Haley J. Abel, Allison A. Regier, André Corvelo, Wayne E. Clarke, Rajeeva Musunuri, Kshithija Nagulapalli, Susan Fairley, Alexi Runnels, Lara Winterkorn, Ernesto Lowy-Gallego, The Human Genome Structural Variation Consortium, Paul Flicek, Soren Germer, Harrison Brand, Ira M. Hall, Michael E. Talkowski, Giuseppe Narzisi, Michael C. Zody
bioRxiv 2021.02.06.430068; doi: https://doi.org/10.1101/2021.02.06.430068
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High coverage whole genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios
Marta Byrska-Bishop, Uday S. Evani, Xuefang Zhao, Anna O. Basile, Haley J. Abel, Allison A. Regier, André Corvelo, Wayne E. Clarke, Rajeeva Musunuri, Kshithija Nagulapalli, Susan Fairley, Alexi Runnels, Lara Winterkorn, Ernesto Lowy-Gallego, The Human Genome Structural Variation Consortium, Paul Flicek, Soren Germer, Harrison Brand, Ira M. Hall, Michael E. Talkowski, Giuseppe Narzisi, Michael C. Zody
bioRxiv 2021.02.06.430068; doi: https://doi.org/10.1101/2021.02.06.430068

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