Expectations and blind spots for structural variation detection from long-read assemblies and short-read genome sequencing technologies.
Document Type
Article
Publication Date
5-6-2021
Publication Title
American journal of human genetics
Keywords
JGM
JAX Source
Am J Hum Genet 2021 May 6; 108(5):919-928
Volume
108
Issue
5
First Page
919
Last Page
928
ISSN
1537-6605
PMID
33789087
DOI
https://doi.org/10.1016/j.ajhg.2021.03.014
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.
Recommended Citation
Zhao X,
Collins R,
Lee W,
Weber A,
Jun Y,
Zhu Q,
Weisburd B,
Huang Y,
Audano P,
Wang H,
Walker M,
Lowther C,
Fu J,
Gerstein M,
Devine S,
Marschall T,
Korbel J,
Eichler E,
Chaisson M,
Lee C,
Mills R,
Brand H,
Talkowski M.
Expectations and blind spots for structural variation detection from long-read assemblies and short-read genome sequencing technologies. Am J Hum Genet 2021 May 6; 108(5):919-928