Multi-platform discovery of haplotype-resolved structural variation in human genomes

By Mark J. P. Chaisson, A. Sanders, Xuefang Zhao, Ankit Malhotra, David Porubsky, Tobias Rausch, E. Gardner, O. Rodriguez, Li Guo, Ryan L. Collins and 80 more. Nature Communications, 2017

796 citations recorded by the source corpus.

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies. Structural variants (SVs) in human genomes contribute diversity and diseases. Here, the authors use a multi-platform strategy to generate haplotype-resolved SVs for three human parent–child trios.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2ab359ebb20d70e9275cf2239b569107361c3fcc

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Citations in the corpus

The International Genome Sample Resource (IGSR) collection of open human genomic variation resources (2019, methodology): “These include data generated by the ongoing work of the HGSVC, ATACseq data generated for the 1000 Genomes Project British samples (ENA accession PRJEB28318) and HGDP transcriptome data (GEO accession GSE54308).”
Merqury: reference-free quality, completeness, and phasing assessment for genome assemblies (2020, background): “However, these reference sequences are incomplete, and recent studies have demonstrated the shortcomings of the current human reference genome and variant call sets [8, 21, 28].”
Haplotype-resolved diverse human genomes and integrated analysis of structural variation (2021, methodology): “S10) ( 1 , 4 , 19 – 21 ).”
Structural variant calling: the long and the short of it (2019, positive): “Nevertheless, multiple papers have re-ported a significant improvement in precision and recall for SV calling using long reads compared to short-read mapping approaches [2, 5, 19, 82, 97 – 99].”
Comprehensive evaluation of structural variation detection algorithms for whole genome sequencing (2019, methodology): “The real datasets of HG00514, including Illumina HiSeq and PacBio RS data [36], and HG002 PacBio RS dataset from the Genome in a Bottle (GIAB) Consortium [79] were downloaded from DDBJ.”
Accurate circular consensus long-read sequencing improves variant detection and assembly of a human genome (2019, methodology): “Large segmental duplications often result in contig breaks in de novo assemblies, and assemblies of noisy long reads typically span less than 50 of 175 Mb of segmental duplications in the human genome 15,18,45 .”
Detection of mosaic and population-level structural variants with Sniffles2 (2024, neutral): “Sniffles2 remains open source (MIT license) and is available at https://github.com/fritzsedlazeck/Sniffles.”
High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios (2021, positive): “The technical details of the method were previously described in Collins et al 19 for application to the genome aggregation database (gnomAD) for SV discovery, and further described in analyses from the HGSVC 18 .”
Long-read human genome sequencing and its applications (2020, neutral): “…and PacBio long-read platforms, for example, showed that 47% of the deletions and nearly 78% of insertions were missed by Illumina whole-genome sequencing even after application of 11 different variant callers designed to detect insertions, deletions, inversions and duplications in genomes 9 .”
A draft human pangenome reference (2022, background): “…paralogs from the reference genome, over two-thirds of SVs have been missed in studies using short-read data and the human reference assembly (Chaisson et al., 2019; Wenger et al., 2019; Zhao et al., 2021), despite individual SVs being more likely to impact gene function than either…”
HiCanu: accurate assembly of segmental duplications, satellites, and allelic variants from high-fidelity long reads (2020, background): “State-of-the-art methods integrate different sequencing technologies (Chaisson et al. 2019; Kronenberg et al. 2019) or parental information (Koren et al. 2018) to obtain chromosome-scale, haplotype-resolved assemblies.”