Evidence map›Paper›PMID 33789087›Full record

ArticleAmerican journal of human genetics2021

Expectations and blind spots for structural variation detection from long-read assemblies and short-read genome sequencing technologies.

Xuefang Zhao, Ryan L Collins, Wan-Ping Lee, Alexandra M Weber, Yukyung Jun, Qihui Zhu, Ben Weisburd, Yongqing Huang, Peter A Audano, Harold Wang and 14 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
92citing papers in PubMed, 1 pooled it
9.0field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

92 citing papers in PubMed, 1 synthesis or guideline pooled it, 132 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. Article
  4. Review
  5. Article
  6. Article
  7. Article
  8. Article
  9. Article
  10. Structural Variant Imputation in Samoans Using a Population-Specific Reference Panel.medRxiv : the preprint server for health sciences · 2026
    Article
  11. Article
  12. Approaches to Studying Viral Pangenome Variation Graphs.Genomics, proteomics & bioinformatics · 2026
    Review
  13. Article
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. Compound Heterozygous Structural Variants in Cases with Unsolved PRKN-Associated Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2025
    Article
  20. Article

32 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors at 13 institutions in 5 countries.

Xuefang ZhaoCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Disorders, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Ryan L CollinsCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Disorders, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Wan-Ping LeeThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
Alexandra M WeberDepartment of Computational Medicine and Bioinformatics, University of Michigan Medical School, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan Medical School, 1241 East Catherine Street, Ann Arbor, MI 48109, USA.
Yukyung JunThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
Qihui ZhuThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
Ben WeisburdProgram in Medical and Population Genetics and Stanley Center for Psychiatric Disorders, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Yongqing HuangData Sciences Platform, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Peter A AudanoDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Harold WangCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Disorders, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Mark WalkerProgram in Medical and Population Genetics and Stanley Center for Psychiatric Disorders, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Chelsea LowtherCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Disorders, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Jack FuCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Disorders, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Human Genome Structural Variation Consortium
Mark B GersteinYale University Medical School, Computational Biology and Bioinformatics Program, New Haven, CT 06520, USA.
Scott E DevineInstitute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Tobias MarschallInstitute for Medical Biometry and Bioinformatics, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
Jan O KorbelEuropean Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Evan E EichlerDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
Mark J P ChaissonDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA.
Charles LeeThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Department of Graduate Studies - Life Sciences, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, South Korea; Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, Shaanxi, People's Republic of China.
Ryan E MillsDepartment of Computational Medicine and Bioinformatics, University of Michigan Medical School, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan Medical School, 1241 East Catherine Street, Ann Arbor, MI 48109, USA.
Harrison BrandCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Disorders, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Michael E TalkowskiCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Disorders, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA. Electronic address: talkowsk@broadinstitute.org.
Massachusetts Institute of Technology · USBroad Institute · USJackson Laboratory · USMassachusetts General Hospital · USUniversity of Michigan–Ann Arbor · USEuropean Molecular Biology Laboratory · DEFirst Affiliated Hospital of Xi'an Jiaotong University · CNHeinrich Heine University Düsseldorf · DEHoward University · USUniversity of Maryland, Baltimore · USUniversity of Southern California · USUniversity of Washington · USYale University · US

Funding

Center for Common Disease GeneticsUM1HG008895 · NHGRI · BROAD INSTITUTE, INC. · PI DALY, MARK JOSEPH, GABRIEL, STACEY · 2016 to 2020
$111.2M
Shared Resource ManagementP30CA034196 · NCI · JACKSON LABORATORY · PI Anna Karolina Palucka · 1985 to 2026
$61.9M
Identifying and Characterizing the Full Spectrum of Haplotype-resolved Structural Variation in Human GenomesU24HG007497 · NHGRI · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · PI Evan Eichler, Jan Oliver Korbel · 2019 to 2026
$17.2M
University of Michigan Training Program in Genomic ScienceT32HG000040 · NHGRI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Sebastian Zoellner · 1995 to 2026
$16.4M
Training Program in Bioinformatics and Integrative GenomicsT32HG002295 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Peter J Park · 2001 to 2026
$15.8M
Clinical Diagnostic Sequencing of Structural VariationR01HD081256 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2015 to 2025
$7.2M
Culling the human genome of disease variants using ultraconserved elementsR01HD091797 · NICHD · HARVARD MEDICAL SCHOOL · PI WU, CHAO-TING · 2016 to 2020
$5.5M
Scalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR01MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2019 to 2025
$5.4M
Sequence-resolved structural variation of human genomesR01HG010169 · NHGRI · UNIVERSITY OF WASHINGTON · PI Evan Eichler · 2018 to 2026
$4.5M
Natural Genetic Variation in the Human GenomeR01HG002898 · NHGRI · UNIVERSITY OF MARYLAND BALTIMORE · PI DEVINE, SCOTT E · 2004 to 2019
$3.7M
Molecular mechanisms and genetic drivers of reciprocal genomic disordersR01HD096326 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2018 to 2022
$3.5M
Structural variation analysis with and without a reference genomeR35GM138212 · NIGMS · UNIVERSITY OF VIRGINIA · PI Zechen Chong · 2020 to 2026
$2.6M
NCI NIH HHS P30 CA034196NHGRI NIH HHS F31 HG010569NHGRI NIH HHS R01 HG002898NHGRI NIH HHS R01 HG010169NHGRI NIH HHS T32 HG000040NHGRI NIH HHS T32 HG002295NHGRI NIH HHS U24 HG007497NHGRI NIH HHS UM1 HG008895NICHD NIH HHS R01 HD081256NICHD NIH HHS R01 HD091797NICHD NIH HHS R01 HD096326NICHD NIH HHS R03 HD099547NIDCR NIH HHS R00 DE026824NIGMS NIH HHS R35 GM138212NIMH NIH HHS R01 MH115957
6 · The paper itself

Abstract

Virtually all genome sequencing efforts in national biobanks, complex and Mendelian disease programs, and medical genetic initiatives are reliant upon short-read whole-genome sequencing (srWGS), which presents challenges for the detection of structural variants (SVs) relative to emerging long-read WGS (lrWGS) technologies. Given this ubiquity of srWGS in large-scale genomics initiatives, we sought to establish expectations for routine SV detection from this data type by comparison with lrWGS assembly, as well as to quantify the genomic properties and added value of SVs uniquely accessible to each technology. Analyses from the Human Genome Structural Variation Consortium (HGSVC) of three families captured ~11,000 SVs per genome from srWGS and ~25,000 SVs per genome from lrWGS assembly. Detection power and precision for SV discovery varied dramatically by genomic context and variant class: 9.7% of the current GRCh38 reference is defined by segmental duplication (SD) and simple repeat (SR), yet 91.4% of deletions that were specifically discovered by lrWGS localized to these regions. Across the remaining 90.3% of reference sequence, we observed extremely high (93.8%) concordance between technologies for deletions in these datasets. In contrast, lrWGS was superior for detection of insertions across all genomic contexts. Given that non-SD/SR sequences encompass 95.9% of currently annotated disease-associated exons, improved sensitivity from lrWGS to discover novel pathogenic deletions in these currently interpretable genomic regions is likely to be incremental. However, these analyses highlight the considerable added value of assembly-based lrWGS to create new catalogs of insertions and transposable elements, as well as disease-associated repeat expansions in genomic sequences that were previously recalcitrant to routine assessment.

Indexed as

Genomic Structural VariationGoalsDNA Copy Number VariationsExonsGenome, HumanGenomicsHumansResearch DesignSegmental Duplications, GenomicSequence AlignmentWhole Genome Sequencingcopy number variationgenome assemblylong-read technologysegmental duplicationsimple repeatsstructural variationwhole-genome sequencing

Identifiers

PMID33789087
PMCPMC8206509
OpenAlexW3145355063

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.